A polymer based delivery system for administration of Anti-cancer agents

Abstract

The present invention is directed to polymer-drug conjugates and / or compositions and / or nanoparticles comprising anti-cancer agents. The present invention is also directed to polymer- drug conjugates and / or compositions comprising docetaxel and the administration of docetaxel derivatives for the treatment of a number of diseases. The present invention is also directed to polymer-drug conjugates and / or compositions comprising gemcitabine or combretastatin A4 for the treatment of a number of diseases.

Description

[0001] A POLYMER BASED DELIVERY SYSTEM

[0002] FOR ADMINISTRATION OF ANTI-CANCER AGENTS

[0003] FIELD OF THE INVENTION

[0004] This invention relates to polymer-drug conjugates and their use for the treatment of diseases detailed in the specification.

[0005] The present invention is directed to polymer-drug conjugates and / or compositions and / or nanoparticles comprising anti-cancer agents. The present invention is also directed to polymer- drug conjugates and / or compositions comprising docetaxel and the administration of docetaxel derivatives for the treatment of a number of diseases. The present invention is also directed to polymer-drug conjugates and / or compositions comprising gemcitabine or combretastatin A4 for the treatment of a number of diseases.

[0006] BACKROUND OF THE INVENTION

[0007] Traditional chemotherapy drugs and polymeric drug conjugates represent two distinct approaches to cancer treatment, each with its own advantages and limitations. Traditional chemotherapy drugs are typically small molecules that can diffuse rapidly throughout the body, reaching both cancerous and healthy cells. This non-specific action often leads to significant side effects, such as nausea, hair loss, and immunosuppression, because the drugs do not distinguish between malignant and normal cells.

[0008] In recent years, there has been a growing emphasis on research exploring the use of polymer materials as drug carriers, reflecting the increasing importance of polymeric nanomedicines. Ensuring that carriers can effectively reach disease sites is crucial for their utilization as drug delivery systems. By attaching chemotherapy drugs to polymer backbones, these conjugates can enhance the solubility, stability, and circulation time of the drugs. Additionally, polymeric drug conjugates offer a passive targeting approach, they can exploit the Enhanced Permeability and Retention (EPR) effect, which allows them to accumulate preferentially in tumor tissues due to their larger size and the leaky vasculature of tumors. Polymeric drug conjugates have emerged as a promising approach in cancer therapy as targeted compositions due to their unique properties that enhance the delivery and efficacy of anti-cancer drugs. These conjugates involve attaching therapeutic agents to a polymer backbone, creating a macromolecular structure that can improve the pharmacokinetics and biodistribution of the drug.

[0009] Targeted drug delivery systems are usually classified into two categories: passive targeting and active targeting. Passive targeting is based on physicochemical properties. The accumulation of nano sized delivery systems in solid tumors is known as enhanced permeability and retention (EPR) effect. The EPR effect is a result of the tendency of macromolecular medicines to accumulate in tumor tissue at a rate that is higher than the amount that they accumulate in healthy tissues. Thus, the drug molecules are passively targeted to the tissue of the tumor, thereby reducing the amount of damage that chemotherapy drugs inflict on healthy tissues.

[0010] Active targeting in cancer drugs refers to the use of specific ligands that can selectively bind to cancer cell receptors or their microenvironment to deliver therapeutic agents directly to the target site. This strategy enhances the efficacy and reduces the side effects of cancer treatments by ensuring that the drugs are primarily concentrated in cancerous tissues rather than affecting healthy cells. The carriers having different types of ligands that involve surface modifications have the ability to interact the with particular receptors found on the surface of target cells. Active targeting can be further enhanced by adding specific ligands to the polymer, directing the drug to cancer cells with high precision.

[0011] The effectiveness of the active targeting method is based on the binding between a specific molecule and its corresponding receptor. This mechanism enhances the ability to accumulate at specific sites, allowing for a distinction between unhealthy and normal tissues. When achieving a high level of specificity, it is important for these receptors to be expressed at a significant level on tumor cells while being absent or minimally expressed on normal cells.

[0012] Unlike active targeting, passive targeting does not involve specific interactions with cellular receptors. The accumulation of therapeutic agents is more generalized and depends on the physical and physiological properties of the tumor microenvironment. While both active and passive targeting aim to enhance the delivery of cancer drugs, they differ significantly in their mechanisms, specificity, and clinical applications. Active targeting offers high specificity and potential for personalized treatments but comes with greater complexity.

[0013] As a traditional chemotherapy drug, docetaxel is a chemotherapy agent used to treat various types of cancer, including breast cancer, non-small cell lung cancer, prostate cancer, stomach cancer, and head and neck cancer. In traditional chemotherapy, docetaxel can cause neutropenia, a condition where the white blood cell count drops significantly, leading to an increased risk of infections. Patients may experience alopecia, losing hair not just on the scalp but also on other parts of the body. Gastrointestinal issues, such as nausea, vomiting, and diarrhea, are common and may severely affect a patient's quality of life. Fatigue is another prevalent side effect, making it challenging for patients to maintain their daily routines. Mucositis, or inflammation of the mouth and throat, can cause painful sores, complicating eating and drinking. Peripheral neuropathy, characterized by tingling, numbness, or pain in the hands and feet, occurs due to nerve damage. Additionally, patients might notice changes in their nails, including discoloration and brittleness, and experience fluid retention, leading to swelling of the extremities.

[0014] As another traditional chemotherapy drug, Combretastatin A4 (CA4) is an anticancer agent and works as a vascular-disrupting agent, collapsing the blood vessels that supply nutrients to tumors, leading to rapid tumor cell death. However, in its free form, CA4 has significant side effects. CA4 can cause damage to normal blood vessels, leading to hypertension, arrhythmias, and cardiac ischemia. Its strong action on vasculature disrupts not only tumor blood vessels but also those in critical organs. Moreover, the free form of CA4 has a narrow therapeutic window, meaning the dose that is effective in killing cancer cells is very close to the dose that causes significant harm to the patient. This makes it challenging to use Combretastatin effectively without causing toxicity.

[0015] Another chemotherapy drug is Gemcitabine, which has broad spectrum of effect against various cancers. It works by interfering with the DNA synthesis process in rapidly dividing cells, such as cancer cells. On the other hand, gemcitabine is quickly degraded in the bloodstream by deaminase enzymes, resulting in a short half-life. Moreover, myelosuppression is one of the most common side effects of gemcitabine, leading to leukopenia, anemia, and thrombocytopenia. This weakens the patient’s immune system, increasing the risk of infections, bleeding, and fatigue. Free gemcitabine often causes nausea, vomiting, diarrhea, and loss of appetite, which can significantly reduce the patient’s quality of life. These side effects occur because gemcitabine also affects rapidly dividing cells in the gastrointestinal tract. Gemcitabine is a highly effective chemotherapy drug, but its short half-life, rapid degradation, and significant side effects limit its usefulness when administered in free form.

[0016] Targeted chemotherapy aims to mitigate many of these side effects by focusing the drug's action on cancer cells and minimizing its impact on healthy tissues. Hence there is a demand for an improved targeting method that can greatly enhance the amount of drug delivered to the desired tissue, exceeding the effectiveness of both traditional chemotherapy and passively targeted drugs. Moreover, there is still a need to protect the anticancer agent such as gemcitabine or docetaxel from degradation, prolonging its half-life and ensuring the anti-cancer agent remains in circulation for longer periods.

[0017] Even though there are many drug delivery systems in literature, there is a still a significant need for an optimized solution for enhanced aqueous solubility and specific targeting. Given the aforementioned state of the art, it is evident that there exists a necessity for the development of a novel polymer-drug combination that possesses diminished side effects and the required pharmacokinetic characteristics.

[0018] BRIEF DESCRIPTION OF THE INVENTION

[0019] Based on the above-mentioned state of the art, an object of the present invention is to provide compounds for use in the treatment of solid tumor cancers. This objective is attained by the subjectmatter of the independent claims of the present specification.

[0020] It is another objective of the present invention to provide a pharmaceutical composition for treatment of solid tumors. It is another object of the present invention to provide compositions and methods for preferentially targeting specific integrin receptors on cancer cells. The present invention relates generally to compositions that preferentially bind or otherwise associate with specific integrin receptors on cancer cells. The present invention provides methods for delivering chemical agents to cancer cells in vitro or in vivo, using the conjugates of this invention.

[0021] In one aspect of aspect of the present invention, the present invention provides a polymer-based delivery system for administration of anti-cancer agents.

[0022] In another aspect of the invention, the present invention offers conjugates that can trigger a specific effect when delivered to a particular cancer cell which has specific integrin receptors. In one aspect, the binding of the receptor to the ligand encourages internalization into the cell.

[0023] An object of the present invention is to provide a polymer-drug conjugate which addresses the problem of drug cleavage before the polymer-drug conjugate reaches the targeted tissue. Another object of the invention is to develop a polymer-drug conjugate system that has high therapeutic efficacy while simultaneously reducing the systemic toxicity of the drug. An object of the present invention is to provide a polymer-drug conjugate for use in the treatment of solid tumors with overexpression of integrins.

[0024] The invention discloses a polymer-drug conjugate of Formula I for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, R is selected from -H or -CH3; x is a number between 15-200; y is a number between 1-100; Li is a cleavable linker comprising peptide sequence GFLG; n is a number between 2-20; Di is a therapeutic agent that is Docetaxel; T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD; B is an end group that is a polymerization initiator, a chain transfer agent, or a fragment thereof; and Formula I is a random copolymer. According to Formula I, B can be fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent).

[0025] Formula I is as follows:

[0026]

[0027] Formula I

[0028] In a possible embodiment, T is an integrin binding ligand comprising cyclic RGD. In another possible embodiment, T is an integrin binding ligand comprising linear RGD. In a possible embodiment, T is an integrin binding ligand comprising iRGD. In a possible embodiment, R is - H. In another possible embodiment, R is -CH3. In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula I for use in the treatment of solid tumors. In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula I for use in the treatment of endometrial cancers. In another possible embodiment, the present invention discloses a polymer-drug conjugate having Formula I for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having Formula I for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having Formula I for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having Formula I for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having Formula I for use in the treatment of head and neck cancer. According to another embodiment, the polymer- drug conjugate having Formula I is for use in the treatment of prostate cancer. In a possible embodiment, the present invention discloses a polymer-drug having Formula I for use in the treatment of colon adenocarcinoma. According to another embodiment, the polymer-drug conjugate having Formula I is for use in the treatment of brain cancer. In another possible embodiment, the present invention presents a polymer-drug having Formula I for use in the treatment of pancreatic cancer.

[0029] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula II for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, R is selected from -H or -CH3; x is a number between 15-200; y is a number between 1-100; n is a number between 2-20; t is a number between 0.5-10; Li is a cleavable linker comprising peptide sequence GFLG; Di is a first therapeutic agent that is Docetaxel; T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD; A is an end group that is a polymerization initiator, a chain transfer agent or a fragment thereof; B is an end group that is a polymerization initiator, a chain transfer agent or a fragment thereof; and Formula II is a random copolymer. According to Formula II, A is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent). B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent).

[0030] Formula II is as follows:

[0031] Formula II

[0032] In a possible embodiment, T is an integrin binding ligand comprising cyclic RGD. In another possible embodiment, T is an integrin binding ligand comprising linear RGD. In a possible embodiment, T is an integrin binding ligand comprising iRGD. In a possible embodiment, R is - H. In another possible embodiment, R is -CH3. In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula II for use in the treatment of solid tumors. In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula II for use in the treatment of endometrial cancers. In another possible embodiment, the present invention discloses a polymer-drug conjugate having Formula II for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having Formula II for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having Formula II for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having Formula II for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having Formula II for use in the treatment of head and neck cancer. According to another embodiment, the polymer- drug conjugate having Formula II is for use in the treatment of prostate cancer. In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula II for use in the treatment of colon adenocarcinoma. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula II for use in the treatment of pancreatic cancer. According to another embodiment, the polymer-drug conjugate having Formula II is for use in the treatment of brain cancer.

[0033] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula III for use in the treatment of solid tumors characterized with overexpression of integrins.

[0034] According to this embodiment, R is selected from -H or -CH3; x is a number between 15-200; y is a number between 1 - 100; z is a number between 0- 100; t is a number between 0.5-10; n is a number between 2-20; Li is a cleavable linker comprising peptide sequence GFLG; Di is a therapeutic agent that is Docetaxel; T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD; A is an end group that is a polymerization initiator, a chain transfer agent or a fragment thereof; B is an end group that is a polymerization initiator, a chain transfer agent or a fragment thereof; and, Formula III is a random copolymer.

[0035] Formula III is as follows:

[0036]

[0037] Formula III

[0038] According to Formula in, A is a fragment of a polymerization initiator that is a fragment of Azobisisobutyronitrile (AIBN) or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent). B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent). In a possible embodiment, T is an integrin binding ligand comprising cyclic RGD. In another possible embodiment, T is an integrin binding ligand comprising linear RGD. In a possible embodiment, T is an integrin binding ligand comprising iRGD. In a possible embodiment, R is -H. In another possible embodiment, R is -CH3. In a possible embodiment, z is a number between 1-100. In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula III for use in the treatment of endometrial cancers. In another possible embodiment, the present invention discloses a polymer- drug conjugate having Formula III for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having Formula III for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having Formula III for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having Formula III for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having Formula III for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate having Formula III is for use in the treatment of prostatic cancer. In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula III for use in the treatment of colon adenocarcinoma. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula III for use in the treatment of pancreatic tumor. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula III for use in the treatment of brain cancer.

[0039] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula IV for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, R is selected from -H or -CH3; x is a number between 15-200; y is a number between 1-200; z is a number between 0-100; n is a number between 2-20; Li is a cleavable linker comprising GFLG; L2 is a second cleavable linker; Di is a first therapeutic agent that is Docetaxel; D2 is a second therapeutic agent that is Gemcitabine or Combretastatin A4; T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD; B is an end group that is a polymerization initiator or a chain transfer agent or a fragment thereof; and, Formula IV is a random copolymer. In a possible embodiment, R is -CH3, Di is Docetaxel, D2 is Gemcitabine, T comprises cyclic RGD. In a possible embodiment, R is -CH3, Di is Docetaxel, D2 Combretastatin A4, T comprises cyclic RGD. In a possible embodiment, R is -CH3, Di is Docetaxel, D2 is Gemcitabine, T comprises iRGD. In a possible embodiment, R is -CH3, Di is Docetaxel, D2 Combretastatin A4, T comprises iRGD. In a possible embodiment, R is -CH3, Di is Docetaxel, D2 is Gemcitabine, T comprises linear RGD. In a possible embodiment, R is -CH3, Di is Docetaxel, D2 Combretastatin A4, T comprises linear RGD.

[0040] Formula IV is as follows: According to Formula IV, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent). In a possible embodiment, T is an integrin binding ligand comprising cyclic RGD. In another possible embodiment, T is an integrin binding ligand comprising linear RGD. In a possible embodiment, T is an integrin binding ligand comprising iRGD. In a possible embodiment, R is -H. In another possible embodiment, R is -CH3. In a possible embodiment, z is a number between 0-100. According to this embodiment, the second cleavable linker (L2) comprises one or more functional group that is selected from acetal, ester, imine, amide, disulfide, carbonate, carbamate or combinations thereof. In a possible embodiment, D2 is Gemcitabine. In another possible embodiment, D2 is Combretastatin A4. In a possible embodiment, R is -CH3, Di is Docetaxel, D2 is Gemcitabine, T comprises cyclic RGD. In a possible embodiment, R is -CH3, Di is Docetaxel, D2 Combretastatin A4, T comprises cyclic RGD. In a possible embodiment, R is -CH3, Di is Docetaxel, D2 is Gemcitabine, T comprises iRGD. In a possible embodiment, R is -CH3, Di is Docetaxel, D2 Combretastatin A4, T comprises iRGD. In a possible embodiment, R is -CH3, Di is Docetaxel, D2 is Gemcitabine, T comprises linear RGD. In a possible embodiment, R is -CH3, Di is Docetaxel, D2 Combretastatin A4, T comprises linear RGD.

[0041] In a possible embodiment, the present invention discloses a polymer-drug conjugate having the Formula IV for use in the treatment of endometrial cancers. In another possible embodiment, the present invention discloses a polymer-drug conjugate having the Formula IV for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having the Formula IV for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having the Formula IV for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having the Formula IV for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having the Formula IV for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate having the Formula IV is for use in the treatment of prostatic cancer. In a possible embodiment, the present invention discloses a polymer-drug conjugate having the Formula IV for use in the treatment of colon adenocarcinoma. In another possible embodiment, the present invention presents a polymer-drug conjugate having the Formula IV for use in the treatment of pancreatic tumor. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula III for use in the treatment of brain cancer.

[0042] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula V for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, R is selected from -H or -CH3; x is a number between 15-200; y is a number between 1-100; z is a number between 0-100; t is a number between 0.5-10; n is a number between 2-20; Li is a cleavable linker comprising GFLG; L2 is a second cleavable linker; Di is a first therapeutic agent that is Docetaxel; D2 is a second therapeutic agent that is Gemcitabine or Combretastatin; T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD; A is an end group that is a polymerization initiator or a chain transfer agent or a fragment thereof; B is an end group that is a polymerization initiator or a chain transfer agent or a fragment thereof; and, Formula V is a random copolymer.

[0043] Formula V is as follows:

[0044] Formula V

[0045] According to Formula V, A and B are fragments of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent). In a possible embodiment, T is an integrin binding ligand comprising cyclic RGD. In another possible embodiment, T is an integrin binding ligand comprising linear RGD. In a possible embodiment, T is an integrin binding ligand comprising iRGD. In a possible embodiment, R is -H. In another possible embodiment, R is -CH3. In a possible embodiment, z is a number between 0-100. According to this embodiment, the second cleavable linker (L2) comprises one or more functional group that is selected from acetal, ester, imine, amide, disulfide, carbonate, carbamate or combinations thereof. In a possible embodiment, D2 is Gemcitabine. In another possible embodiment, D2 is Combretastatin A4.

[0046] In a possible embodiment, the present invention discloses a polymer-drug conjugate having the Formula V for use in the treatment of endometrial cancers. In another possible embodiment, the present invention discloses a polymer-drug conjugate having the Formula V for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having the Formula V for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having the Formula V for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having the Formula V for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having the Formula V for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate having the Formula V is for use in the treatment of prostatic cancer. In a possible embodiment, the present invention discloses a polymer-drug having the Formula V for use in the treatment of colon adenocarcinoma. In another possible embodiment, the present invention presents a polymer-drug having the Formula V for use in the treatment of pancreatic tumor. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula III for use in the treatment of brain cancer.

[0047] In a possible embodiment R is -H; the first therapeutic agent (Di) is an anti-cancer agent that is docetaxel; the first cleavable linker (Li) comprises GFLG; the second therapeutic agent (D2) comprises gemcitabine, the integrin binding ligand (T) comprises RGD.

[0048] In a possible embodiment R is -H; the first therapeutic agent (Di) is an anti-cancer agent that is docetaxel; the first cleavable linker (Li) comprises GFLG; the second therapeutic agent (D2) comprises gemcitabine, the second cleavable linker (L2) comprises disulfide functional group, and the integrin binding ligand (T) comprises RGD. In a possible embodiment R is -H; the first therapeutic agent (Di) is an anti-cancer agent that is docetaxel; the first cleavable linker (Li) comprises GFLG; the second therapeutic agent (D2) comprises gemcitabine, the second cleavable linker (L2) comprises ester functional group, and the integrin binding ligand (T) comprises RGD.

[0049] In a possible embodiment R is -H; the first therapeutic (Di) agent is an anti-cancer agent that is docetaxel; the first cleavable linker (Li) comprises GFLG; the second therapeutic agent (D2) comprises combretastatin, the integrin binding ligand (T) comprises RGD.

[0050] In a possible embodiment R is -H; the first therapeutic agent (Di) is an anti-cancer agent that is docetaxel; the first cleavable linker (Li) comprises GFLG; the second therapeutic agent (D2) comprises combretastatin, second cleavable linker (L2) comprises ester functional group, and the integrin binding ligand (T) comprises RGD.

[0051] In a possible embodiment R is -H; the first therapeutic agent (Di) is an anti-cancer agent that is docetaxel; the first cleavable linker (Li) comprises GFLG; the second therapeutic agent (D2) comprises combretastatin, second cleavable linker (L2) comprise disulfide functional group, and the integrin binding ligand (T) comprises RGD.

[0052] In a possible embodiment R is -CH3; the first therapeutic agent (Di) is an anti-cancer agent that is docetaxel; the first cleavable linker (Li) comprises GFLG; the second therapeutic agent (D2) comprises gemcitabine, the integrin binding ligand (T) comprises RGD.

[0053] In a possible embodiment R is -CH3; the first therapeutic agent (Di) is an anti-cancer agent that is docetaxel; the first cleavable linker (Li) comprises GFLG; the second therapeutic agent (D2) comprises gemcitabine, the second cleavable linker (L2) comprising disulfide functional group, and the integrin binding ligand (T) comprises RGD. In a possible embodiment R is -CH3; the first therapeutic agent (Di) is an anti-cancer agent that is docetaxel; the first cleavable linker (Li) comprises GFLG; the second therapeutic agent (D2) comprises gemcitabine, the second cleavable linker (L2) comprises ester functional group, and the integrin binding ligand (T) comprises RGD. In a possible embodiment R is -CH3; the first therapeutic agent (Di) is an anti-cancer agent that is docetaxel; the first cleavable linker (Li) comprises GFLG; the second therapeutic agent (D2) comprises combretastatin, the integrin binding ligand (T) comprises RGD.

[0054] In a possible embodiment R is -CH3; the first therapeutic agent (Di) is an anti-cancer agent that is docetaxel; the first cleavable linker (Li) comprises GFLG; the second therapeutic agent (D2) comprises combretastatin, second cleavable linker (L2) comprises ester functional group, and the integrin binding ligand (T) comprises RGD.

[0055] In a possible embodiment R is -CH3; the first therapeutic agent (Di) is an anti-cancer agent that is docetaxel; the first cleavable linker(Li) comprises GFLG; the second therapeutic agent comprises combretastatin, second cleavable linker (L2) comprises disulfide functional group, and the integrin binding ligand (T) comprises RGD.

[0056] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula VI for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, n is a number that is 3 or 4, x is a number between 15- 200; y is a number between 1-100; and Formula VI is a random copolymer.

[0057] Formula VI is as follows:

[0058]

[0059] Formula VI

[0060] In a possible embodiment, a polymer-drug conjugate according to Formula VI is for use in the treatment of solid tumors. In another possible embodiment, the present invention discloses a polymer-drug conjugate according to Formula VI for use in the treatment of endometrial cancers. In another possible embodiment, the present invention discloses a polymer-drug conjugate having Formula VI for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having Formula VI for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having Formula VI for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having Formula VI for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having Formula VI for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate having Formula VI is for use in the treatment of prostate cancer. In a possible embodiment, the present invention discloses a polymer-drug having Formula VI for use in the treatment of colon adenocarcinoma. According to another embodiment, the polymer-drug conjugate having Formula VI is for use in the treatment of brain cancer. In another possible embodiment, the present invention presents a polymer-drug having Formula VI for use in the treatment of pancreatic tumor.

[0061] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula VII for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, n is a number that is 3 or 4, x is a number between 15- 200; y is a number between 1-100; z is a number between 0-100; t is a number between 0.5-10; and Formula VII is a random copolymer.

[0062] Formula VII is as follows: In a possible embodiment, n is 3. In another possible embodiment, n is 4. In a possible embodiment, a polymer-drug conjugate according to Formula VII is for use in the treatment of solid tumors. In another possible embodiment, the present invention discloses a polymer-drug conjugate according to Formula VII for use in the treatment of endometrial cancers. In another possible embodiment, the present invention discloses a polymer-drug conjugate having Formula VII for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having Formula VII for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having Formula VII for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having Formula VII for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having Formula VII for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate having Formula VII is for use in the treatment of prostate cancer. In a possible embodiment, the present invention discloses a polymer-drug having Formula VII for use in the treatment of colon adenocarcinoma. According to another embodiment, the polymer-drug conjugate having Formula VII is for use in the treatment of brain cancer. In another possible embodiment, the present invention presents a polymer-drug having Formula VII for use in the treatment of pancreatic tumor.

[0063] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula VIII for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, n is a number that is 3 or 4; x is a number between 15- 200; y is a number between 1-100; z is a number between 1-100; and Formula VIII is a random copolymer.

[0064] Formula VIII is as follows:

[0065]

[0066] Formula VIII

[0067] In a possible embodiment, a polymer-drug conjugate according to Formula VIII is for use in the treatment of solid tumors. In another possible embodiment, the present invention discloses a polymer-drug conjugate according to Formula VIII for use in the treatment of endometrial cancers. In another possible embodiment, the present invention discloses a polymer-drug conjugate having Formula VIII for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having Formula VIII for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having Formula VIII for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having Formula VIII for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having Formula VIII for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate having Formula VIII is for use in the treatment of prostate cancer. In a possible embodiment, the present invention discloses a polymer-drug having Formula VIII for use in the treatment of colon adenocarcinoma. According to another embodiment, the polymer-drug conjugate having Formula Vin is for use in the treatment of brain cancer. In another possible embodiment, the present invention presents a polymer-drug having Formula VIII for use in the treatment of pancreatic tumor.

[0068] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula IX for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, n is a number that is 3 or 4; x is a number between 15- 200; y is a number between 2-100; z is a number between 2-100; and Formula IX is a random copolymer.

[0069] Formula IX is as follows: In a possible embodiment, a polymer-drug conjugate according to Formula IX is for use in the treatment of solid tumors. In another possible embodiment, the present invention discloses a polymer-drug conjugate according to Formula IX for use in the treatment of endometrial cancers. In another possible embodiment, the present invention discloses a polymer-drug conjugate having Formula IX for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having Formula IX for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having Formula IX for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having Formula IX for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having Formula IX for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate having Formula IX is for use in the treatment of prostate cancer. In a possible embodiment, the present invention discloses a polymer-drug having Formula IX for use in the treatment of colon adenocarcinoma. According to another embodiment, the polymer-drug conjugate having Formula IX is for use in the treatment of brain cancer. In another possible embodiment, the present invention presents a polymer-drug having Formula IX for use in the treatment of pancreatic tumor.

[0070] BRIEF DESCRIPTION OF THE FIGURES

[0071] Figure 1 is a graph showing cell viability of MDA-MB-231 cell lines when the cells were treated with the free DTX and more than one embodiment of the present invention.

[0072] Figure 2 is a graph showing cell viability of A549 cell lines when the cells were treated with the free DTX and more than one embodiment of the present invention.

[0073] Figure 3 is a graph showing cell viability of NCI-H460 cell lines when the cells were treated with the free DTX and more than one embodiment of the present invention.

[0074] Figure 4 is a graph showing cell viability of SK-OV-3 cell lines when the cells were treated with the free DTX and more than one embodiment of the present invention.

[0075] Figure 5 is a graph illustrating the regression of SK0V3 tumor xenografts treated with the polymer-drug conjugates according to the present invention. Figure 6 is a graph showing cell viability of U87MG cell lines when the cells were treated with the free DTX and more than one embodiment of the present invention.

[0076] Figure 7 is a graph showing cell viability of HUVEC cell lines when the cells were treated with the free DTX and the polymer-drug conjugates according to the present invention.

[0077] Figure 8 is a graph showing cell viability of CAL27 cell lines when the cells were treated with the free DTX and the polymer-drug conjugates according to the present invention.

[0078] Figure 9 is a graph showing cell viability of Caov-3 cell lines when the cells were treated with the free DTX and more than one embodiment of the present invention.

[0079] Figure 10 is a graph showing cell viability of BxPc-3 cell lines when the cells were treated with the free DTX and more than one embodiment of the present invention.

[0080] Figure 11 is a graph showing cell viability of PC-3 cell lines when the cells were treated with the free DTX and more than one embodiment of the present invention.

[0081] Figure 12 is a graph showing cell viability of MDA-MB-231 cell lines when the cells were treated with the free DTX + CA4 and more than one embodiment of the present invention.

[0082] Figure 13 is a graph showing cell viability of A549 cell lines when the cells were treated with the free DTX+ CA4 and more than one embodiment of the present invention.

[0083] Figure 14 is a graph showing cell viability of NCI-H460 cell lines when the cells were treated with the free DTX+ CA4 and more than one embodiment of the present invention.

[0084] Figure 15 is a graph showing cell viability of SK-OV-3 cell lines when the cells were treated with the free DTX + CA4 and more than one embodiment of the present invention.

[0085] Figure 16 is a graph illustrating the regression of SKOV3 tumor xenografts treated with the polymer-drug conjugates according to the present invention.

[0086] Figure 17 is a graph showing cell viability of CaOV-3 cell lines when the cells were treated with the free DTX and more than one embodiment of the present invention. Figure 18 is a graph showing cell viability of Pane- 1 cell lines when the cells were treated with the free DTX and more than one embodiment of the present invention.

[0087] Figure 19 illustrates the regression of NSCLC tumor xenografts.

[0088] Figure 20 illustrates the regression of 22RV1 tumor xenografts.

[0089] Figure 21 illustrates the regression of HUH7 tumor xenografts.

[0090] Figure 22 illustrates the changing of the liver tumor volume.

[0091] Figure 23 illustrates the changing of the liver tumor weight.

[0092] Figure 24 illustrates a graph of particle size analysis of nontargeted PEGMEMA-GEM nanoparticle.

[0093] Figure 25 illustrates a graph of dilution stability of polymer-based nanoparticles.

[0094] Figure 26 illustrates a graph of particle size analysis of targeted PEGMEMA-GEM nanoparticle.

[0095] Figure 27 illustrates a graph of dilution stability of targeted polymer-based nanoparticles.

[0096] Figure 28 illustrates a graph representing a cell viability study.

[0097] Figure 29 illustrates a graph of particle size analysis.

[0098] Figure 30 is a graph showing cell viability of MCF-7 cell lines.

[0099] DETAILED DESCRIPTION OF THE INVENTION

[0100] Before the present invention is described in detail, it is to be understood that this invention is not limited to the processes, formulations, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing particular versions or embodiments only and is not intended to limit the scope of embodiments herein which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments herein, the preferred methods, devices, and materials are now described.

[0101] It is also noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

[0102] The technical problem underlying the present invention is to provide alternative and / or improved means for reducing the side effects of the therapeutic agents and improve their pharmacokinetic properties. This problem is solved by the features of the independent claims. Optional, possible, or preferred or exemplary embodiments of the present invention are provided by the dependent claims.

[0103] The invention is based on the surprising finding that the present invention pertains to a novel pharmaceutical composition comprising a polymer-drug conjugate according to the invention for use as a medicament and / or for use in the treatment of a disease selected from the group comprising endometrial cancer, breast cancer, ovarian cancer, lung cancer, liver cancer, head and neck cancer, prostatic cancer, brain cancer, and pancreatic cancer.

[0104] The disclosure further provides methods of using docetaxel combinations and the pharmaceutical compositions comprising combinations with other therapies. Furthermore, the disclosure provides a detailed description of exemplary agents, therapies, and methods of combination therapy.

[0105] The term "polymer-drug conjugate” hereinafter refers to a polymeric structure having a therapeutic agent covalently attached to the polymer.

[0106] The terms "polymeric backbone" and "polymer backbone” hereinafter can be used interchangeably and refer to a polymer chain having side chains or pendant groups. For example, a side chain may have an oligo ethylene glycol unit and a pendant group may be bearing one therapeutic agent or any other group that can be utilized to attach a therapeutic and / or diagnostic agent or a targeting group. The term "random copolymer" refers to a copolymer wherein the monomers forming the copolymer follow in any order. The polymer-drug conjugates of the invention are in the form of random copolymer.

[0107] Throughout the text, the term "the polymer-drug conjugate of the invention" hereinafter should be construed to mean "a polymer-drug conjugate according to Formula I" or "a polymer-drug conjugate of Formula I" or "Formula I" and these terms can be used interchangeably.

[0108] Throughout the text, the term "the polymer-drug conjugate of the invention" hereinafter should be construed to mean "a polymer-drug conjugate according to Formula II" or "a polymer-drug conjugate of Formula II" or "Formula II" and these terms can be used interchangeably.

[0109] Throughout the text, the term "the polymer-drug conjugate of the invention" hereinafter should be construed to mean "a polymer-drug conjugate according to Formula III" or "a polymer-drug conjugate of Formula III" or "Formula III" and these terms can be used interchangeably.

[0110] Throughout the text, the term "the polymer-drug conjugate of the invention" hereinafter should be construed to mean "a polymer-drug conjugate according to Formula IV" or "a polymer-drug conjugate of Formula IV" or "Formula IV" and these terms can be used interchangeably.

[0111] Throughout the text, the term "the polymer-drug conjugate of the invention" hereinafter should be construed to mean "a polymer-drug conjugate according to Formula V" or "a polymer-drug conjugate of Formula V" or "Formula V" and these terms can be used interchangeably.

[0112] Throughout the text, the term "the polymer-drug conjugate of the invention" hereinafter should be construed to mean "a polymer-drug conjugate according to Formula VI" or "a polymer-drug conjugate of Formula VI" or "Formula VI" and these terms can be used interchangeably.

[0113] Throughout the text, the term "the polymer-drug conjugate of the invention" hereinafter should be construed to mean "a polymer-drug conjugate according to Formula VII" or "a polymer-drug conjugate of Formula VII" or "Formula VII" and these terms can be used interchangeably. Throughout the text, the term "the polymer-drug conjugate of the invention" hereinafter should be construed to mean "a polymer-drug conjugate according to Formula VUI" or "a polymer-drug conjugate of Formula VIII" or "Formula VUI" and these terms can be used interchangeably.

[0114] Throughout the text, the term "the polymer-drug conjugate of the invention" hereinafter should be construed to mean "a polymer-drug conjugate according to Formula IX" or "a polymer-drug conjugate of Formula IX " or "Formula IX " and these terms can be used interchangeably. This acceptance also applies to other formulations and polymer-drug conjugates listed below.

[0115] The term "agent(s)" hereinafter refers to at least one or more therapeutic agents. “Therapeutic agent" refers to any compound that is suitable for use in the treatment of a disease. The term "therapeutic agent” refers to the compounds suitable for use in the treatment of a disease, and these terms can be used interchangeably.

[0116] Additionally, a "therapeutic agent" also refers to any agent that is suitable for use in treating a disease. Any therapeutic agent that can be directly or indirectly attached to the polymer-drug conjugate of the invention can be used.

[0117] The term "therapeutic agent" refers to any compound that is suitable for use in treatment of a disease. The term “therapeutic agent", "anticancer agent", "chemotherapy agent", " cytotoxin", “cytotoxic agent” and "antineoplastic agent" all refer to the compounds suitable for use in treatment of a disease and these terms can be used interchangeably. In one embodiment, the disease is cancer.

[0118] The patent application WO2018002761 Al also describes agents, and this document is incorporated herein by reference. As used herein, "treat" or "treating" means to inhibit, reduce, modulate, ameliorate, or block at least one symptom that characterizes a pathologic condition in a subject threatened by or afflicted with the condition. The term “treatment” includes either therapeutic or prophylactic therapy.

[0119] Docetaxel is an anti-cancer or antineoplastic agent. The term " docetaxel” hereinafter may refer to C43H53NO14 or [(lS,2S,3R,4S,7R,9S,10S,12R,15S)-4-acetyloxy-l,9,12-trihydroxy-15-[(2R,3S)- 2-hy dr oxy-3 - [(2-methylpropan-2-yl)oxy carbonylamino] -3 -phenylpropanoy 1] oxy- 10, 14,17,17- tetramethyl- 11 -oxo-6-oxatetracyclo[ 11.3.1.03, 10.04,7]heptadec- 13 -en-2-yl] benzoate or Docetaxel trihydrate pharmaceutically acceptable salts thereof.

[0120] Gemcitabine is an anti-cancer or antineoplastic agent. The term "gemcitabine" hereinafter may refer to C9H11F2N3O4 or (2R)-2'-Deoxy-2', 2' -difluorocytidine or 4-Amino-l-[(2R,4S,5R)-3,3- difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one.

[0121] Combretastatin A-4 (CA4) is also an anti-cancer agent, and the term "CA4" hereinafter may refer to C18H20O5 or (Z)-2-Methoxy-5-[(lE)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol.

[0122] The term "PEG" hereinafter refers to a polyether compound having the structure of H-(0-CH2 - CH2 )n-0R , n being a number between 1-100 and R selected from -H or -CH3. PEG is defined as an oligomer or polymer of ethylene oxide. The terms "PEG", "polyethylene glycol", "polyethylene oxide", "PEO", "polyoxyethylene" and "POE" refer to the same structure and may be used interchangeably within this text.

[0123] The term “solid tumor” refers to mass of tissue that arises abnormally and does not typically include cysts or liquid areas. Common types of solid tumors include carcinomas, sarcomas, and lymphomas. They originate from the uncontrolled growth of cells and can disrupt normal tissue function by either invading nearby tissues or spreading to distant parts of the body (metastasis) if they are malignant. For the purposes of this specification, the term 'solid tumor' is understood to encompass endometrial cancer, ovarian cancer, prostate cancer, breast cancer, liver cancer, pancreatic cancer, head and neck cancer, colon adenocarcinoma, brain cancer and lung cancer.

[0124] The term “integrin-positive tumor” refers to a type of growth characterized by the overexpression of integrin proteins on the surface of the tumor cells. In the context of tumors, integrins contribute significantly to the behavior and progression of cancer cells. Identifying integrin-positive tumors aids in the development of targeted therapies aimed at inhibiting integrin-mediated pathways. An “integrin-positive tumor” refers to a tumor that expresses high levels of integrins, which are proteins located on the surface of cells. The terms “integrin-positive tumor”, “integrin-positive cancer”, and “overexpression of integrin” can be used interchangeably to describe tumors or cancers that have high levels of integrin proteins on the surface of their cells.

[0125] The polymer-drug conjugate disclosed in the present invention facilitates active targeting by including cellular targeting moieties that specifically bind to integrin receptors found on the surface of solid tumors, such as av03 integrin, 0^05 integrin, and / or av06 integrin. Cell-specific binding of RGD peptides to integrin receptors that are overexpressed on the outer surface of solid tumor cells is achieved by the present invention. The process of endocytosis, which is triggered by the interaction between targeting ligands and corresponding receptors, contributes to a higher concentration of the polymer-drug conjugate inside the cells, which provides an enhanced therapeutic effect. Integrin overexpression refers to the condition in which integrins are produced in abnormally higher quantities on the surface of cells. Overexpressed integrins in cancer according to present invention include integrin av03, av05, and av06.

[0126] Overexpressed integrins in cancer according to present invention include integrin av03, av05, av06 and / or 0.501. The percentages of integrin expression (av03, av05, av06, as01) can vary significantly between tumor samples. For example, if the expression levels of av03, av05, or av06 are in the range of 15-56%, the term "integrin-positive" or "overexpression of integrin" is used to define the term. For av03, av05, and / or av06, when the expression levels of each, or a combination of two or all three integrins, fall within the ranges of 5-95%, 10-85%, 24-70%, or 30-60%, the term "overexpression of integrin" or "integrin-positive" can be used.

[0127] The definition of integrin-positive tumors includes a variety of cancers with elevated expression of integrins. For example, Biliary Tract Cancer may show av06 expression in the range of 43-45%, while Breast Cancer may express av03, av05, and av06 in the range of 15-17%. In Cervical Cancer, av06 expression may be in the range of 55-58%, and in Colorectal Carcinoma (CRC), av06 levels may range from 23-43%. Endometrial Cancer is marked by av06 expression at 42%, and Gastric Cancer expresses av03, av05, and av06 within the range of 35-37%. Additionally, Head and Neck Squamous Cell Carcinoma (SCC) shows av06 expression levels between 56-78%, while Lung Cancer has av06 expression of 54-56%. In accordance with the invention, RGD peptides (arginine-glycine-aspartic acid) is used as an integrin binding ligand that specifically binds to integrins that are often overexpressed in cancer cells and play a crucial role in tumor growth, angiogenesis, and metastasis. The RGD sequences (i.e cRGD, iRGD or linear RGD) are tripeptide including arginine (R), glycine (G), and aspartic acid (D). The RGD-based targeting moieties described herein include iRGD (SEQ ID NO: 3), cRGD (SEQ ID NO: 4), and various linear RGD peptides such as RGD (SEQ ID NO: 5), GRGDSP (SEQ ID NO: 6), GRGDSC (SEQ ID NO: 7), and RGDSK (SEQ ID NO: 8). This sequence is recognized by several integrin receptors, particularly those involved in tumor progression, such as avp3, av05, and a?Q i integrins. According to invention, the RGD peptide binds specifically to the integrin receptors on the surface of cancer cells, wherein this interaction is highly selective due to the affinity of the RGD sequence for the integrin binding sites. By conjugating RGD peptides to polymer-drug conjugates, the anti-cancer agent is preferentially delivered to the tumor cells. This enhances the concentration of the drug at the tumor site while minimizing systemic toxicity.

[0128] Overexpression of integrins refers to the increased production and presentation of integrin proteins on the surface of cells beyond normal levels. Overexpression of integrins is commonly observed in various cancer cells and plays a critical role in tumor progression, metastasis, and resistance to apoptosis.

[0129] Moreover, the overexpression of integrins also refers to the condition where these receptors are produced at levels significantly higher than what is typically observed in normal, healthy cells. In healthy cells, integrin expression levels are tightly regulated to maintain normal cellular functions such as adhesion, migration, and signal transduction. Normal expression levels are usually quantified using techniques like flow cytometry, immunohistochemistry, or Western blotting, and are presented as a baseline or control value. The overexpression of integrins can be defined by a significant increase in integrin levels compared to the baseline expression in normal cells. This can be quantified as fold changes (a common threshold being a 2-fold or greater increase) relative to normal levels.

[0130] Various quantitative methods can be used for determining overexpression of the integrin such as flow cytometry, immunohistochemistry and western blotting. Western blotting measures the protein levels of integrins in cell lysates. Overexpression is determined by comparing the band intensity corresponding to integrins in cancer cells to that in normal cells. Some studies on breast cancer cells have shown that primary breast cancer cells exhibit overexpression of integrin a p? compared to normal breast epithelial cells. This significant increase in integrin a p? expression in cancer cells as opposed to normal cells illustrates how overexpression is defined: normal cells might have 10,000 integrin molecules per cell, while cancer cells can have levels up to ten times higher, around 100,000 molecules per cell, demonstrating the contrast between normal and pathological states (https: / / doi.org / 10.1186 / 1471-2407-ll-293) (https: / / doi.org / 10.1186 / 1475- 2867-7-16).

[0131] The term "end group" refers to functionalities or constitutional units that are at the extremity of a polymer. A and B can optionally be a polymerization initiator or a fragment thereof. Particularly when an initiator is used in the polymerization reaction, the initiator fragment may stay as an end group to the polymer. The initiator used herein, may be any material suitable for initiating the polymerization reaction known in the art. The patent application WO2018002761 Al also describes the end groups, and this document is incorporated herein by reference.

[0132] The polymer-drug conjugate of the invention comprises PEG side chains. The side chains provide important physicochemical properties to the polymer-drug conjugate of the invention and lead to a polymer-drug conjugate that has better physicochemical properties such as aqueous solubility in comparison to the conjugates that do not have said side chains.

[0133] As mentioned above, "L" or “Li” or “L2” in formulas denotes a cleavable linker. The term "Cleavable linker" refers to a group that spatially separates drug or a targeting group from the carrier molecule. The terms "linker", "L", “Li”. “L2” and "cleavable linker" refer to the same entity and can be used interchangeably.

[0134] The linkers are cleavable so that the therapeutic agent can be released, for example, under reducing conditions, oxidizing conditions or by hydrolysis of an ester, amide, hydrazone, or similar linkage that forms the covalent bond between the linker and the therapeutic agent. Additionally, the type of linker may augment the selective cytotoxicity (and thus improve the therapeutic index) by permitting selective release of the therapeutic agent adjacent to or inside the cell. Said cleavable linker can be any hydrocarbon or substituted hydrocarbon based compound which is capable of dissociating under physiological conditions. In a possible embodiment, the linker can be selected from compounds that are cleaved under the acidic conditions of the tumor (such as any C1-C10 substituted hydrocarbon comprising an acetal or an ester functional group) or with the help of the overexpressed enzymes present in the intercellular or intracellular matrix of the tumor cells.

[0135] The linker can be any sort of entity capable of binding to both the polymer backbone and to the drug, such as, a poly(ethylene glycol), an amino acid, poly(amino acid) (e.g. a peptide or oligopeptide), or polypeptide (e.g. a protein), such that one end of it is capable of forming a covalent bond with the polymer backbone and the other end of it is capable of forming a covalent bond with the therapeutic agent. The linkers may also include short peptides with specific peptide sequences that are cathepsin B labile, such as Gly-Phe-Leu-Gly (SEQ ID NO: 1) also denoted as GFLG or Val-Cit or Phe-Lys or Vai-Ala or Ala-Leu-Ala-Leu (SEQ ID NO: 2).

[0136] The linker can also be a C1-C10 hydrocarbon or a C1-C10 substituted or hetero substituted hydrocarbon such that it comprises a functional group that dissociates under physiological conditions, such as an acetal, ester, imine, amide, disulfide, carbonate, carbamate, or hydrazone.

[0137] The term "C1-C10 hydrocarbon" refers to a hydrocarbon chain having 1 to 10 C atoms in the backbone.The term "Ci-Cio substituted hydrocarbon" refers to a hydrocarbon chain having 1 to 10 C atoms in the backbone wherein one or more of its hydrogen atoms replaced by atoms of groups of other elements such as alcohol, amine, carboxyl or thiol.

[0138] The term "Ci-Cio heterosubstituted hydrocarbon" refers to a hydrocarbon chain having 1 to 10 C atoms in the backbone wherein at least one of the C atoms is substituted with an atom other than C such as nitrogen, oxygen, phosphorus, sulfur or a halogen atom. These substituents include but not limited to lower alkoxy such as methoxy, ethoxy, butoxy; ethers; acetals; ketals; esters; hetroaryl; heterocyclic; hydroxyl; protected hydroxyl; acyl; acyloxy; amino; amido; imine, disulfide, carbonate, carbamate, or hydrozone.

[0139] In an embodiment of the invention, the linker (L) is GFLG (SEQ ID NO: 1). In an embodiment of the invention, the linker is Val-Cit. In an embodiment of the invention, the linker is Phe-Lys. In an embodiment of the invention, the linker is Vai-Ala. In an embodiment of the invention, the linker is Ala-Leu-Ala-Leu (SEQ ID NO: 2).

[0140] In an embodiment of the invention, the linker is a C1-C10 hetero substituted hydrocarbon comprising at least one disulfide functional group. In an embodiment of the invention, the linker is a C1-C10 hetero substituted hydrocarbon comprising at least one acetal functional group. In an embodiment of the invention, the linker is a C1-C10 hetero substituted hydrocarbon comprising at least one ester functional group. In an embodiment of the invention, the linker is a C1-C10 hetero substituted hydrocarbon comprising at least one imine functional group. In an embodiment of the invention, the linker is a C1-C10 hetero substituted hydrocarbon comprising at least one amide functional group. In an embodiment of the invention, the linker is a C1-C10 hetero substituted hydrocarbon comprising at least one carbonate functional group. In an embodiment of the invention, the linker is a C1-C10 hetero substituted hydrocarbon comprising at least one carbamate functional group. In an embodiment of the invention, the linker is a C1-C10 hetero substituted hydrocarbon comprising at least one hydrazone functional group.

[0141] In another embodiment of the invention, the linker may comprise a C1-C10 substituted or hetero substituted hydrocarbon comprising two or more functional groups selected from the group comprising acetal, ester, imine, amide, disulfide, carbonate, carbamate, and hydrazone. In another embodiment of the invention, the linker may be a combination of a C1-C10 substituted hydrocarbon comprising at least one functional group selected from the group comprising acetal, ester, imine, amide, disulfide, carbonate, carbamate, and hydrazone, and a peptide chain selected from the group comprising GFLG (SEQ ID NO: 1), Val-Cit or Phe-Lys or Vai- Ala or Ala-Leu- Ala-Leu (SEQ ID NO: 2).

[0142] The term "anti-cancer agent" refers to any compound that is suitable for use in treatment of a disease. The terms "therapeutic agent", "chemotherapy agent", "anticancer agent" and "antineoplastic agent" all refer to the compounds suitable for use in treatment of a disease and these terms can be used interchangeably. The anti-cancer agent can be present in an amount in between 1% to 30% by weight of the polymer-drug conjugate, preferably in an amount between 2% to 20% by weight of the drug-polymer conjugate and most preferably in an amount between 3% to 15% by weight of the drug-polymer conjugate. In one embodiment, the anti-cancer agent selected from combretastatin, 5-Fluorouracil, gemcitabine, and docetaxel. Moreover, the therapeutic agent(s) can be a combination of two or more therapeutic agents selected from combretastatin 5-Fluorouracil, gemcitabine and docetaxel. In one embodiment providing nanoparticles, the anti-cancer agent can be present in an amount in between 16% to 20% by weight of the polymer-drug conjugate or the anti-cancer agent can be present in an amount in between 18% to 24% by weight of the polymer-drug conjugate or the anti-cancer agent can be present in an amount in between 19% to 27% by weight of the polymer-drug conjugate.

[0143] According to the present application, the term “RGD” refers to Arg-Gly-Asp peptides comprising cyclic RGD (RGDDYK) (SEQ ID NO: 4), linear RGD, or 1RGD (CRGDKGPDC) (SEQ ID NO: 3).

[0144] The polymer-drug conjugates disclosed in the present invention comprises a (meth)acrylate based polymer backbone, at least two types of side chains wherein one of the side chains is a PEG chain such as -COOCFECH OCFECFEjnOR and the other side chain includes at least one therapeutic agent covalently bonded to a cleavable linker.

[0145] The invention discloses a polymer-drug conjugate of Formula I for use in the treatment of solid tumors characterized with overexpression of integrins.

[0146] Formula I is as follows: In one aspect, x is a number between 15-200; y is a number between 1 -200; n is a number between 2-20; Li is a cleavable linker comprising GFLG; Di is Docetaxel. B is an end group that is a polymerization initiator or a fragment thereof; Formula I is a random copolymer and R is -H. In another aspect, R is -CH3. T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD.B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent). In a possible embodiment, T is an integrin binding ligand comprising cyclic RGD. In another possible embodiment, T is an integrin binding ligand comprising linear RGD. In a possible embodiment, T is an integrin binding ligand comprising iRGD. In a possible embodiment, R is -H. In another possible embodiment, R is -CH3. In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula I for use in the treatment of endometrial cancer. In another possible embodiment, the present invention discloses a polymer-drug conjugate having Formula I for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having Formula I for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer- drug conjugate having Formula I for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having Formula I for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having Formula I for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate having Formula I is for use in the treatment of prostatic cancer. In a possible embodiment, the present invention discloses a polymer-drug having Formula I for use in the treatment of adenocarcinoma. In another possible embodiment, the present invention presents a polymer-drug having Formula I for use in the treatment of pancreatic tumor. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula I for use in the treatment of brain cancer.

[0147] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula II for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, R is selected from -H or -CH3; x is a number between 15-200; y is a number between 1-100; n is a number between 2-20; t is a number between 0.5-10; Li is a cleavable linker comprising GFLG; Di is a first therapeutic agent that is Docetaxel; T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD; A is an end group that is a polymerization initiator or a fragment thereof; B is an end group that is a polymerization initiator or a fragment thereof; and Formula II is a random copolymer.

[0148] Formula II is as follows:

[0149] Formula II

[0150] According to Formula II, A is a fragment of a polymerization initiator that is a fragment of Azobisisobutyronitrile (AIBN) and B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent). In a possible embodiment, T is an integrin binding ligand comprising cyclic RGD. In another possible embodiment, T is an integrin binding ligand comprising linear RGD. In a possible embodiment, T is an integrin binding ligand comprising iRGD. In a possible embodiment, R is -H. In another possible embodiment, R is -CH3.

[0151] In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula II for use in the treatment of endometrial cancer. In another possible embodiment, the present invention discloses a polymer-drug conjugate having Formula II for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having Formula II for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having Formula II for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having Formula II for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having Formula II for use in the treatment of head and neck cancer. According to another embodiment, the polymer- drug conjugate having Formula II is for use in the treatment of prostatic cancer. In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula II for use in the treatment of adenocarcinoma. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula II for use in the treatment of pancreatic tumor. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula II for use in the treatment of brain cancer.

[0152] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula III for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, R is selected from -H or -CH3; x is a number between 15-200; y is a number between 1-200; z is a number between 0-100; t is a number between 0.5-10; n is a number between 2-20; Li is a cleavable linker comprising GFLG; Di is a therapeutic agent that is Docetaxel; T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD; A is an end group that is a polymerization initiator or a fragment thereof; B is an end group that is a polymerization initiator or a fragment thereof; and, Formula III is a random copolymer.

[0153] Formula III is as follows: According to Formula III, A is a fragment of a polymerization initiator that is a fragment of Azobisisobutyronitrile (AIBN) and B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent). In a possible embodiment, T is an integrin binding ligand comprising cyclic RGD. In another possible embodiment, T is an integrin binding ligand comprising linear RGD. In a possible embodiment, T is an integrin binding ligand comprising iRGD. In a possible embodiment, R is -H. In another possible embodiment, R is -CH3. In a possible embodiment, z is a number between 1-100.

[0154] In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula III for use in the treatment of endometrial cancer. In another possible embodiment, the present invention discloses a polymer-drug conjugate having Formula III for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having Formula III for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having Formula III for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having Formula III for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having Formula III for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate having Formula III is for use in the treatment of prostatic cancer. In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula III for use in the treatment of adenocarcinoma. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula III for use in the treatment of pancreatic tumor. In another possible embodiment, the present invention presents a polymer- drug conjugate having Formula III for use in the treatment of brain cancer.

[0155] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula IV for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, R is selected from -H or -CH3; x is a number between 15-200; y is a number between 1-20; z is a number between 1-100; n is a number between 2-20; Li is a cleavable linker comprising GFLG; L2 is a second cleavable linker; Di is a first therapeutic agent that is Docetaxel; D2 is a second therapeutic agent that is Gemcitabine or Combretastatin A4; T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD; B is an end group that is a polymerization initiator or a fragment thereof; and, Formula IV is a random copolymer. Formula IV is as follows:

[0156] Formula IV

[0157] According to Formula IV, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent). In a possible embodiment, T is an integrin binding ligand comprising cyclic RGD. In another possible embodiment, T is an integrin binding ligand comprising linear RGD. In a possible embodiment, T is an integrin binding ligand comprising iRGD. In a possible embodiment, R is -H. In another possible embodiment, R is -CH3. In a possible embodiment, z is a number between 1-100. According to this embodiment, the second cleavable linker (L2) comprises one or more functional group that is selected from acetal, ester, imine, amide, disulfide, carbonate, carbamate or combinations thereof. In a possible embodiment, D2 is Gemcitabine. In another possible embodiment, D2 is Combretastatin A4.

[0158] In a possible embodiment, the present invention discloses a polymer-drug conjugate having the Formula IV for use in the treatment of endometrial cancer. In another possible embodiment, the present invention discloses a polymer-drug conjugate having the Formula IV for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having the Formula IV for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having the Formula IV for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having the Formula IV for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having the Formula IV for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate having the Formula IV is for use in the treatment of prostatic cancer. In a possible embodiment, the present invention discloses a polymer-drug conjugate having the Formula IV for use in the treatment of adenocarcinoma. In another possible embodiment, the present invention presents a polymer-drug conjugate having the Formula IV for use in the treatment of pancreatic tumor. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula IV for use in the treatment of brain cancer.

[0159] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula V for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, R is selected from -H or -CH3; x is a number between 15-200; y is a number between 1-100; z is a number between 0-100; t is a number between 0.5-10; n is a number between 2-20; Li is a cleavable linker comprising GFLG; L2 is a second cleavable linker; Di is a first therapeutic agent that is Docetaxel; D2 is a second therapeutic agent that is Gemcitabine or Combretastatin; T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD; A is an end group that is a polymerization initiator or a fragment thereof; B is an end group that is a polymerization initiator or a fragment thereof; and, Formula V is a random copolymer.

[0160] Formula V is as follows: According to Formula V, A is a fragment of a polymerization initiator that is a fragment of Azobisisobutyronitrile (AIBN) and B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent). In a possible embodiment, T is an integrin binding ligand comprising cyclic RGD. In another possible embodiment, T is an integrin binding ligand comprising linear RGD. In a possible embodiment, T is an integrin binding ligand comprising iRGD. In a possible embodiment, R is -H. In another possible embodiment, R is -CH3. In a possible embodiment, z is a number between 1-100. According to this embodiment, the second cleavable linker (L2) comprises one or more functional group that is selected from acetal, ester, imine, amide, disulfide, carbonate, carbamate or combinations thereof. In a possible embodiment, D2 is Gemcitabine. In another possible embodiment, D2 is Combretastatin A4.

[0161] In a possible embodiment, the present invention discloses a polymer-drug conjugate having the Formula V for use in the treatment of endometrial cancer. In another possible embodiment, the present invention discloses a polymer-drug conjugate having the Formula V for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having the Formula V for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having the Formula V for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having the Formula V for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having the Formula V for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate having the Formula V is for use in the treatment of prostatic cancer. In a possible embodiment, the present invention discloses a polymer-drug having the Formula V for use in the treatment of adenocarcinoma. In another possible embodiment, the present invention presents a polymer-drug having the Formula V for use in the treatment of pancreatic tumor. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula V for use in the treatment of brain cancer.

[0162] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula VI for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, n is a number that is 3 or 4, x is a number between 15- 200; y is a number between 1-100; and, Formula VI is a random copolymer. Formula VI is as follows:

[0163] Formula VI

[0164] In a possible embodiment, a polymer-drug conjugate according to Formula VI is for use in the treatment of endometrial cancer. In another possible embodiment, the present invention discloses a polymer-drug conjugate according to Formula VI for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having Formula VI for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer- drug conjugate having Formula VI for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having Formula VI for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having Formula VI for use in the treatment of head and neck cancer. According to another embodiment, the polymer- drug conjugate having Formula VI is for use in the treatment of prostatic cancer. In a possible embodiment, the present invention discloses a polymer-drug having Formula VI for use in the treatment of adenocarcinoma. In another possible embodiment, the present invention presents a polymer-drug having Formula VI for use in the treatment of pancreatic tumor. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula VI for use in the treatment of brain cancer.

[0165] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula VII for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, n is a number that is 3 or 4, x is a number between 15- 200; y is a number between 1-100; z is a number between 1-100; t is a number between 0.5-10; and, Formula VII is a random copolymer.

[0166] Formula VII is as follows: In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula VII for use in the treatment of endometrial cancer. In another possible embodiment, the present invention discloses a polymer-drug conjugate having Formula VII for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having Formula VII for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having Formula VII for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having Formula VII for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having Formula VII for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate having Formula VII is for use in the treatment of prostatic cancer. In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula VII for use in the treatment of adenocarcinoma. In another possible embodiment, the present invention presents a polymer-drug having Formula VII for use in the treatment of pancreatic tumor. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula VII for use in the treatment of brain cancer.

[0167] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula VIII for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, n is a number that is 3 or 4; x is a number between 15- 200; y is a number between 1-100; z is a number between 1-100 and, Formula VTH is a random copolymer.

[0168] Formula VIII is as follows:

[0169]

[0170] Formula VIII

[0171] In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula VIII for use in the treatment of endometrial cancer. In another possible embodiment, the present invention discloses a polymer-drug conjugate having Formula VIII for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having Formula VIII for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having Formula VIII for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having Formula VIII for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having Formula VIII for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate having Formula VIII is for use in the treatment of prostatic cancer. In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula VIII for use in the treatment of adenocarcinoma. In another possible embodiment, the present invention presents a polymer-drug having Formula VIII for use in the treatment of pancreatic tumor. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula VIII for use in the treatment of brain cancer.

[0172] In a possible embodiment, the present invention further discloses a polymer-drug conjugate having the Formula IX for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, n is a number that is 3 or 4; x is a number between 15- 200; y is a number between 1-100; z is a number between 1-100; and, Formula IX is a random copolymer.

[0173] Formula IX is as follows: The specific embodiments described herein are offered by way of example, not by way of limitation. Any subtitles herein are included for convenience only, and are not to be construed as limiting the disclosure in any way. Any embodiments specifically and explicitly recited herein may form the basis of a disclaimer either alone or in combination with one or more further embodiments.

[0174] In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula IX for use in the treatment of endometrial cancer. In another possible embodiment, the present invention discloses a polymer-drug conjugate having Formula IX for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate having Formula IX for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate having Formula IX for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate having Formula IX for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate having Formula IX for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate having Formula IX is for use in the treatment of prostatic cancer. In a possible embodiment, the present invention discloses a polymer-drug conjugate having Formula IX for use in the treatment of adenocarcinoma. In another possible embodiment, the present invention presents a polymer-drug having Formula IX for use in the treatment of pancreatic tumor. In another possible embodiment, the present invention presents a polymer-drug conjugate having Formula IX for use in the treatment of brain cancer.

[0175] In a possible embodiment, the present invention discloses a polymer-drug conjugate for use in the treatment of endometrial cancer. In another possible embodiment, the present invention discloses a polymer-drug conjugate for use in the treatment of breast cancer. The present invention further discloses a polymer-drug conjugate for use in the treatment of ovarian cancer. In another embodiment, the present invention discloses a polymer-drug conjugate for use in the treatment of lung cancer. The present invention further presents a polymer-drug conjugate for use in the treatment of liver cancer. Moreover, the present invention discloses a polymer-drug conjugate for use in the treatment of head and neck cancer. According to another embodiment, the polymer-drug conjugate is for use in the treatment of prostatic cancer. In a possible embodiment, the present invention discloses a polymer-drug for use in the treatment of adenocarcinoma. In another possible embodiment, the present invention presents a polymer-drug for use in the treatment of pancreatic tumor. In another possible embodiment, the present invention presents a polymer-drug conjugate for use in the treatment of brain cancer.

[0176] As another exemplary embodiment, the polymer-drug conjugate is for use in the treatment of solid tumors with overexpression of integrins, wherein R is -CH3; Li comprises amide, GFLG and ester group; n is 3 and / or 4, Di is Docetaxel; D2 is null, T is cRGD, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent). In accordance with this embodiment, the polymer-drug conjugates comprise an integrin binding ligand comprising Arg-Gly-Asp (RGD) peptide at the chain end. Moreover, the Formula VII is arranged as the end-chain functionality of the polymer. Formula VII can be defined as cRGD-end- functionalized polymers as the main part of the targeted drug delivery systems.

[0177] The addition of the RGD motif to the side chain in the polymer-drug conjugate increases the specificity of the drug to tumor cell lines. Furthermore, cRGD-end-functionalized polymer-drug conjugates that comprise RGD as integrin receptor ligand enables active direct targeting efficacy.

[0178] To confirm the anticancer effect of the polymer-drug conjugates according to present invention, various kinds of cell lines were treated and cell viability was measured through CCK-8 assay. The tumor cell lines MDA-MB-231, MCF-7, A549, NCI-H460, SK-OV-3, U87MG, HUVECs, CAL 27, Caov-3, BxPc-3, PC-3, NSCLC, 22RV1, Pac-1 and Huh7 cell line were treated with the formulas disclosed herein such as Formula VI, Formula VII and Formula VIII.

[0179] In some of the preferred embodiments, the polymer-drug conjugate of invention comprises one or more of the following;

[0180] - GFLG is the first cleavable linker (Li), the second cleavable linker (L2) comprises at least one disulfide group, the first anti-cancer agent is docetaxel, the second anti-cancer is combretastatin A4, T is cRGD, n is 3, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent).

[0181] - GFLG is the first cleavable linker (Li), the second cleavable linker (L2) comprises at least one disulfide group, the first anti-cancer agent (Di) is docetaxel, the second anti-cancer (D2) is gemcitabine, T is cRGD, n is 3, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent).

[0182] - GFLG is the first cleavable linker (Li), the second cleavable linker (L2) comprises at least one disulfide group, the first anti-cancer agent (Di) is docetaxel, the second anti-cancer (D2) is combretastatin A4, T is cRGD, n is 4, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent).

[0183] - GFLG is the first cleavable linker (Li), the second cleavable linker (L2) comprises at least one disulfide group, the first anti-cancer agent (Di) is docetaxel, the second anti-cancer (D2) is gemcitabine, T is cRGD, n is 4, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent).

[0184] - GFLG is the first cleavable linker (Li), the second cleavable linker (L2) comprises at least one disulfide group, the first anti-cancer agent is docetaxel, the second anti-cancer is combretastatin A4, T is iRGD, n is 3, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent).

[0185] - GFLG is the first cleavable linker (Li), the second cleavable linker (L2) comprises at least one disulfide group, the first anti-cancer agent (Di) is docetaxel, the second anti-cancer (D2) is gemcitabine, T is iRGD, n is 3, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent).

[0186] - GFLG is the first cleavable linker (Li), the second cleavable linker (L2) comprises at least one disulfide group, the first anti-cancer agent (Di) is docetaxel, the second anti-cancer (D2) is combretastatin A4, T is iRGD, n is 4, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent).

[0187] - GFLG is the first cleavable linker (Li), the second cleavable linker (L2) comprises at least one disulfide group, the first anti-cancer agent (Di) is docetaxel, the second anti-cancer (D2) is gemcitabine, T is iRGD, n is 4, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent).

[0188] - GFLG is the first cleavable linker (Li), the second cleavable linker (L2) comprises at least one disulfide group, the first anti-cancer agent (Di) is docetaxel, the second anti-cancer (D2) is combretastatin A4, T is linear RGD, n is 3, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent). - GFLG is the first cleavable linker (Li), the second cleavable linker (L2) comprises at least one disulfide group, the first anti-cancer agent (Di) is docetaxel, the second anti-cancer (D2) is gemcitabine, T is linear RGD, n is 3, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent).

[0189] - GFLG is the first cleavable linker (Li), the second cleavable linker (L2) comprises at least one disulfide group, the first anti-cancer agent (Di) is docetaxel, the second anti-cancer (D2) is combretastatin A4, T is linear RGD, n is 4, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent).

[0190] - GFLG is the first cleavable linker (Li), the second cleavable linker (L2) comprises at least one disulfide group, the first anti-cancer agent (Di) is docetaxel, the second anti-cancer (D2) is gemcitabine, T is linear RGD, n is 4, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent).

[0191] - GFLG is the first cleavable linker (Li), the second linker (L2) is selected from C1-C10 substituted or hetero substituted hydrocarbon comprising two or more functional groups selected from the group comprising acetal, ester, imine, amide, disulfide, carbonate, carbamate as the second cleavable linker (L2), the first anti-cancer agent (Di) is docetaxel, the second anti-cancer (D2) is gemcitabine, T is linear RGD, n is 3 or 4, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent).

[0192] The specific embodiments described herein are offered by way of example, not by way of limitation. Any subtitles herein are included for convenience only, and are not to be construed as limiting the disclosure in any way.

[0193] Example 1: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-cRGD conjugate according to Formula VII and free DTX for MDA-MB-231 Cells

[0194] Human breast adenocarcinoma (MDA-MB-231 Cells) were treated with conjugates as depicted in Formula VII and free DTX for 48 hours in DMEM medium. CCK-8 assay was performed to measure cell viability. The EC50 values of the polymer-drug conjugates and free DTX are shown in Table 1 and Figure 1. Example 2: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-cRGD conjugate according to Formula VI and free DTX for MDA-MB-231 Cells

[0195] Human breast adenocarcinoma (MDA-MB-231 Cells) were treated with conjugates as depicted in Formula VI or free DTX for 48 hours in DMEM medium. CCK-8 assay was performed to measure cell viability. The EC50 values of the polymer-drug conjugates and free DTX are shown in Table 1 and Figure 1.

[0196] Table 1: EC50 values of Free DTX and PEGMEMA-Docetaxel (DTX)-cRGD conjugates for MDA-MB-231 cells

[0197] A dose-response study shown in Table 1 was performed to provide the concentration of the compounds that gives half-maximal response.

[0198] Figure 1 illustrates the cell viability of MDA-MB-231 cells treated with polymer-drug-conjugates of the present disclosure compared with the free DTX, and confirmed that polymer-drug conjugates presents an enhanced effect of killing adenocarcinoma cells.

[0199] Example 3: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for A549 Cells

[0200] Adenocarcinomic human alveolar basal epithelial (A549) cells were treated with conjugates as depicted in Formula VII or free DTX for 48 hours in DMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)-cRGD conjugates showed less cytotoxicity compared to free DTX as shown in Table 2 and Figure 2.

[0201] Example 4: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for A549 Cells Adenocarcinomic human alveolar basal epithelial (A549) cells were treated with conjugates as depicted in Formula VI or free DTX for 48 hours in DMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)-cRGD conjugates showed less cytotoxicity compared to free DTX as shown in Table 2 and Figure 2.

[0202] Table 2: EC50 values of Free DTX and PEGMEMA-Docetaxel (DTX)-cRGD conjugates for A549 Cells

[0203] A dose-response study shown in Table 2 was performed to provide the concentration of the compounds that gives half-maximal response. Figure 2 reports the different cell viability between the Free DTX and the polymer-drug conjugates according to Formula VII and Formula VI.

[0204] Example 5: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for NCI-H460 Cells

[0205] Large cell lung cancer cell lines (NCI-H460) were treated with conjugates as depicted in Formula VII and free DTX for 48 hours in RPMI-1640 medium. CCK-8 assay was performed to measure cell viability. The EC50 values of the polymer-drug conjugates and free DTX are shown in Table 3 and Figure 3.

[0206] Example 6: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for NCI-H460 Cells Large cell lung cancer cell lines (NCI-H460) were treated with conjugates as depicted in Formula VI and free DTX for 48 hours in RPML1640 medium. CCK-8 assay was performed to measure cell viability. The EC50 values of the polymer-drug conjugates and free DTX are shown in Table 3 and Figure 3.

[0207] Table 3: EC50 values of Free DTX and PEGMEMA-Docetaxel (DTX)-cRGD conjugates for NCI-H460 Cells

[0208] A dose-response study shown in Table 3 was performed to provide the concentration of the compounds that gives half-maximal response.

[0209] Figure 3 illustrates the cell viability of NCI-H460 cells treated with polymer-drug conjugates of the present disclosure compared with the free DTX and confirmed that polymer-drug conjugates of the invention present an enhanced effect of killing lung cancer cells. Example 7: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for SK-OV-3 Cells

[0210] Human Ovarian Cancer (SK-OV-3) cells were treated with conjugates as depicted in Formula VII and free DTX for 48 hours in RPMI-1640 medium. CCK-8 assay was performed to measure cell viability. The EC50 values of the polymer-drug conjugates and free DTX are shown in Table 4 and Figure 4.

[0211] Example 8: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for SK-OV-3 Cells

[0212] Human Ovarian Cancer (SK-OV-3) cells were treated with conjugates as depicted in Formula VI and free DTX for 48 hours in RPMI-1640 medium. CCK-8 assay was performed to measure cell viability. The EC50 values of the polymer-drug conjugates and free DTX are shown in Table 4 and Figure 4.

[0213] Table 4: EC50 values of Free DTX and PEGMEMA-Docetaxel (DTX)-cRGD conjugates for SK-OV-3 Cells

[0214] Referring to Table 4 and Figure 4, compared with the free DTX, the polymer-drug conjugates of the present disclosure, when were used to treat SK-OV-3, showed a similar cell-killing effect to the free DTX, indicating that the present disclosure had a treatment effect on integrin positive cancers. Example 9: The experiment of tumor growth inhibition induced by the polymer-drug conjugate comprising docetaxel and RGD as an integrin binding ligand on Human Ovarian Cancer (SK-OV-3) xenograft tumors in nude mice

[0215] Figure 5 illustrates the regression of SK-OV-3 tumor xenografts treated with a polymer-drug conjugate having RGD as a targeting group, free DTX and saline as a control group. The doses are depicted by the arrows below the x-axis and given every 10 days (three doses of administration at days 0, 10, 20 days). The utilization of equal doses of free DTX and targeted polymer-drug conjugate adds importance to this investigation. Every 10 days, three doses were delivered intravenously at predetermined concentrations.

[0216] Figure 5 shows that only three doses of treatment were given, and the last dose was taken on day 20, ending the treatment. Regression of the human SK-OV-3 tumor was observed both DTX and the targeted polymer-drug conjugate. Tumor weights were shown to be lower in mice administered with DTX compared to the control group (i.e., saline), with a reduction of x2.7 in mean tumor size as compared to control. In mice treated with the claimed invention, the tumor weights showed a dramatic x21 decrease in mean tumor size.

[0217] As can be seen from the Figure 5, the tumor volume remained larger than initial volume following the completion of three doses of DTX treatment at 20th day. Surprisingly, the tumor volume treated with the present invention continues to decline even after 40th day.

[0218] Example 10: Cytotoxicity Results ofPEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for U87-MG Cells

[0219] Human Glioblastoma (U87-MG) cells were treated with conjugates as depicted in Formula VII and free DTX for 48 hours in EMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)-cRGD conjugates showed less cytotoxicity compared to free DTX as shown in Table 5 and Figure 6. Example 11: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for U87-MG

[0220] Human Glioblastoma (U87-MG) cells were treated with conjugates as depicted in Formula VI and free DTX for 48 hours in EMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)-cRGD conjugates showed less cytotoxicity compared to free DTX as shown in Table 5 and Figure 6.

[0221] Table 5: EC50 values of Free DTX and PEGMEMA-Docetaxel (DTX)-cRGD conjugates for U87-MG Cells

[0222] Figure 6 illustrates the cell viability of U87-MG cells treated with polymer-drug conjugates of the present disclosure compared with the free DTX and confirmed that polymer-drug conjugates present an enhanced treatment effect on integrin positive cancers.

[0223] Example 12: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for HUVECs

[0224] Human umbilical vein endothelial cells (HUVECs) were treated with conjugates as depicted in Formula VII and free DTX for 48 hours in EMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)-cRGD conjugates showed less cytotoxicity compared to free DTX as shown in Table 6 and Figure 7. Table 6: EC50 values of Free DTX and PEGMEMA-Docetaxel (DTX)-cRGD conjugates for HUVECs

[0225] Figure 7 illustrates the cell viability of HUVECs treated with polymer-drug conjugates of the present disclosure compared with the free DTX and confirmed that polymer-drug conjugates present an enhanced effect of killing integrin positive tumors.

[0226] Example 13: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for CAL 27

[0227] Oral adenosquamous carcinoma cell line (CAL 27) were treated with conjugates as depicted in Formula VIII and free DTX for 48 hours in EMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)-cRGD conjugates showed less cytotoxicity compared to free DTX as shown in Table 7 and Figure 8.

[0228] Table 7: EC50 values of Free DTX and PEGMEMA-Docetaxel (DTX)-cRGD conjugates for CAL 27 Figure 8 illustrates the cell viability of CAL 27 cell line treated with polymer-drug conjugates of the present disclosure compared with the free DTX and confirmed that polymer-drug conjugates present an enhanced effect of killing integrin positive tumors.

[0229] Example 14: Cytotoxicity Results ofPEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for Caov-3

[0230] Ovarian Adenocarcinoma (Caov-3) cell lines were treated with conjugates as depicted in Formula VII or free DTX for 48 hours in EMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)-cRGD conjugates showed less cytotoxicity compared to free DTX as shown in Table 8 and Figure 9. Example 15: Cytotoxicity Results ofPEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for Caov-3

[0231] Ovarian Adenocarcinoma (Caov-3) cell lines were treated with conjugates as depicted in Formula VI or free DTX for 48 hours in EMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)-cRGD conjugates showed less cytotoxicity compared to free DTX as shown in Table 8 and Figure 9.

[0232] Table 8: EC50 values of Free DTX and PEGMEMA-Docetaxel (DTX)-cRGD conjugates for Caov-3 Referring to Table 8 and Figure 9, compared with the free DTX, the polymer-drug conjugates of the present disclosure, when were used to treat Caov-3, showed a similar cell-killing effect to the free DTX, indicating that the present disclosure had a treatment effect on integrin positive cancers.

[0233] Example 16: Cytotoxicity Results ofPEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for BxPc-3

[0234] The pancreatic tumor line (BxPc-3) cell lines were treated with conjugates as depicted in Formula VII or free DTX for 48 hours in EMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)-cRGD conjugates showed less cytotoxicity compared to free DTX as shown in Table 9 and Figure 10. Example 17 : Cytotoxicity Results ofPEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for BxPc-3

[0235] The pancreatic tumor line (BxPc-3) cell lines were treated with conjugates as depicted in Formula VI or free DTX for 48 hours in EMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)-cRGD conjugates showed less cytotoxicity compared to free DTX as shown in Table 9 and Figure 10.

[0236] Table 9: EC50 values of Free DTX and PEGMEMA-Docetaxel (DTX)-cRGD conjugates for BxPc-3 Referring to Table 9 and Figure 10, compared with the free DTX, the polymer-drug conjugates of the present disclosure, when were used to treat BxPc-3, showed a similar cell-killing effect to the free DTX, indicating that the present disclosure had a treatment effect on integrin positive cancers.

[0237] Example 18: Cytotoxicity Results ofPEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for PC-3

[0238] Prostate Carcinoma (PC-3) cell lines were treated with conjugates as depicted in Formula VII or free DTX for 48 hours in EMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)-cRGD conjugates showed less cytotoxicity compared to free DTX as shown in Table 10 and Figure 11. Example 19: Cytotoxicity Results ofPEGMEMA-Docetaxel (DTX)-cRGD conjugate and free DTX for PC-3

[0239] Prostate Carcinoma (PC-3) cell lines were treated with conjugates as depicted in Formula VI or free DTX for 48 hours in EMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)-cRGD conjugates showed less cytotoxicity compared to free DTX as shown in Table 10 and Figure 11.

[0240] Table 10: EC50 values of Free DTX and PEGMEMA-Docetaxel (DTX)-cRGD conjugates for PC-3 Referring to Table 10 and Figure 11, compared with the free DTX, the polymer-drug conjugates of the present disclosure, when were used to treat PC-3, showed a similar cell-killing effect to the free DTX, indicating that the present disclosure had a treatment effect on integrin positive cancers.

[0241] As another exemplary embodiment, the polymer-drug conjugate of formula I for use in the treatment of solid tumors with overexpression of integrins, wherein R is -CH3; Li comprises GFLG and ester functional group; n is 3 and / or 4; Di is Docetaxel; D2 is a second therapeutic agent that is Combretastatin A4; L2 comprises ester functional group, T is cRGD, B is fragment of a polymerization initiator or chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent), and A is a fragment of a polymerization initiator that is a part of Azobisisobutyronitrile (AIBN). The exemplary embodiment of the polymer-drug conjugate can be defined as Formula X.

[0242] Formula X is as follows: As another exemplary embodiment, the polymer-drug conjugate of Formula X is for use in the treatment of solid tumors characterized with over expression of integrins, wherein R is -CH3; Li comprises amide, GFLG and ester group; L2 comprises disulfide and ester functional group, n is 3 and / or 4, Di is Docetaxel; D2 is a second therapeutic agent that is Combretastatin A4; T is cRGD, B is fragment of a polymerization initiator or a chain transfer agent that is a part of a trithiocarbonate or a dithioate (RAFT agent). In accordance with this embodiment, the polymer- drug conjugates comprise an integrin binding ligand comprising Arg-Gly-Asp (RGD) peptide at the chain end.

[0243] Example 20: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-Combretastatin A4 (CA4) with S-S linker)-cRGD conjugate according to Formula VIII, free DTX or free DTX+CA4 for MDA-MB-231 Cells

[0244] Human breast adenocarcinoma (MDA-MB-231 Cells) were treated with conjugates as depicted in Formula VIII (i.e. cRGD peptide at the chain end), free DTX+CA4 or free DTX for 48 hours in DMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-DTX- CA4- cRGD conjugates showed less cytotoxicity compared to free DTX and free DTX+CA4. The EC50 values of the polymer-drug conjugates, free DTX and free DTX+CA4 are shown in Table 11.

[0245] Table 11: EC50 values of free DTX, free DTX+CA4 and PEGMEMA-DTX-CA4- cRGD conjugates for MDA-MB-231 cells Referring to Table 11 and Figure 12, compared with the free DTX and free DTX+CA4, the polymer-drug conjugates of the present disclosure, when were used to treat MDA-MB-231, showed a similar cell-killing effect to the free DTX and free DTX+CA4, indicating that the present disclosure had a treatment effect on integrin positive cancers.

[0246] Example 21: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-CA4 cRGD conjugate according to Formula X, free DTX, free DTX+CA4 or PEGMEMA-DTX-A4 conjugate (without RGD) for A549 Cells

[0247] Adenocarcinomic human alveolar basal epithelial (A549) cells were treated with conjugates as depicted in Formula X (i.e. cRGD peptide at the side chain), free DTX and free DTX+CA4 for 48 hours in DMEM medium. CCK-8 assay was performed to measure cell viability. Moreover, A549 cells were treated with PEGMEMA-DTX-A4 conjugate (without RGD). PEGMEMA-Docetaxel (DTX)-Combretastatin A4 (CA4)-cRGD according to Formula X showed less cytotoxicity compared to free drugs, as shown in Table 12 and Figure 13.

[0248] Example 22: Cytotoxicity Results of of PEGMEMA-Docetaxel (DTX)-CA4-(with S-S linker)- cRGD conjugate according to Formula VIII, free DTX, free DTX+CA4 or PEGMEMA- DTX-CA4 conjugate (without RGD) for A549 Cells

[0249] Adenocarcinomic human alveolar basal epithelial (A549) cells were treated with conjugates as depicted in Formula VHI (i.e. cRGD peptide at the chain end), free DTX and free DTX+CA4 for 48 hours in DMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA- Docetaxel (DTX)-CA4-cRGD conjugates according to Formula VIII showed less cytotoxicity compared to free drugs, as shown in Table 12.

[0250] Table 12: EC50 values of free DTX, free DTX+CA4, and PEGMEMA-DTX-CA4-cRGD conjugates for A549 Cells

[0251] Referring to Table 12 and Figure 13, compared with the free DTX and free DTX+CA4, the polymer-drug conjugates of the present disclosure, when were used to treat A549, showed a similar cell-killing effect to the free DTX and free DTX+CA4, indicating that the present disclosure had a treatment effect on integrin positive cancers.

[0252] Example 23: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-Combretastatin A4 (CA4)-cRGD conjugate according to Formula X, free DTX or free DTX+CA4 for NCI-H460 Cells

[0253] Large cell lung cancer cell lines (NCI-H460) were treated with conjugates as depicted in Formula X, free DTX and free DTX+CA4 for 48 hours in RPMI-1640 medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)-CA4-cRGD (i.e. RGD at side chain) conjugates showed less cytotoxicity compared to free drugs, as shown in Table 13.

[0254] Example 24: Cytotoxicity Results of of PEGMEMA-Docetaxel (DTX)- CA4-(with S-S linker)-cRGD conjugate according to Formula VIII, free DTX or free DTX+CA4) for NCI- 11460 Cells

[0255] Large cell lung cancer cell lines (NCI-H460) were treated with conjugates as depicted in Formula VIII and free DTX for 48 hours in RPMI-1640 medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)CA4(S-S)-cRGD conjugates (i.e. RGD at chain end showed less cytotoxicity compared to free drugs, as shown in Table 13. Table 13: EC50 values of free DTX, free DTX+CA4 and PEGMEMA- DTX-CA4- cRGD conjugates for NCI-H460 Cells Referring to Table 13 and Figure 14, compared with the free DTX and free DTX+CA4, the polymer-drug conjugates of the present disclosure, when were used to treat NCI-H460, showed a similar cell-killing effect to the free DTX and free DTX+CA4, indicating that the present disclosure had a treatment effect on integrin positive cancers.

[0256] Example 25: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-CA4-cRGD conjugate according to Formula X, free DTX, free DTX+CA4 or PEGMEMA-DTX-CA4 conjugate (without RGD) for SK-OV-3 Cells

[0257] Human Ovarian Cancer (SK-OV-3) cells were treated with conjugates as depicted in Formula X (i.e. cRGD peptide at the side chain), free DTX and free DTX+CA4 for 48 hours in RPMI-1640 medium. Moreover, SK-OV-3 cells were treated with PEGMEMA-DTX-A4 conjugate (without RGD). CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)- Combretastatin A4 (CA4)-cRGD conjugates according to Formula X showed less cytotoxicity compared to free drugs as shown in Table 14. Example 26: Cytotoxicity Results of ofPEGMEMA-Docetaxel (DTX)-CA4 (with S-S linker)- cRGD conjugate according to Formula VIII, free DTX, free DTX+CA4 or PEGMEMA- DTX-CA4 conjugate (without RGD) for SK-OV-3 Cells

[0258] Human Ovarian Cancer (SK-OV-3) cells were treated with conjugates as depicted in Formula VIII (i.e. cRGD peptide at the chain end), free DTX and free DTX+CA4 for 48 hours in RPMI-1640 medium. Moreover, SK-OV-3 cells were treated with PEGMEMA-DTX-A4 conjugate (without RGD). CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)- Combretastatin A4 (CA4)-cRGD conjugates according to Formula VUI showed less cytotoxicity compared to free drugs as shown in Table 14.

[0259] Table 14: EC50 values of free DTX, free DTX+CA4 and PEGMEMA-DTX-CA4- cRGD conjugates for SK-OV-3 Cells

[0260] Referring to Table 14 and Figure 15, compared with the free DTX or free DTX+CA4, the polymer- drug conjugates of the present disclosure, when were used to treat SK-OV-3, showed a similar cell- killing effect to the free DTX and free DTX+CA4, indicating that the present disclosure had a treatment effect on integrin positive cancers. Example 26: The experiment of tumor growth inhibition induced by the polymer-drug conjugate comprising both Docetaxel and Combretastatin A4 as a therapeutic agent, and RGD as an integrin binding ligand on Human Ovarian Cancer (SK-OV-3) xenograft tumors in nude mice

[0261] Animal study was conducted to evaluate the efficacy of a targeted polymer-drug conjugate containing DTX and CA4 together. Figure 16 illustrates the regression of SK0V3 tumor xenografts treated with the polymer-drug conjugate as mentioned above. Significant reductions in tumor volume treated with the present application were observed when compared to control group (saline) and free DTX.

[0262] Example 27: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-CA4-cRGD conjugate according to Formula X, free DTX, free DTX+CA4 or PEGMEMA-DTX-CA4 conjugate (without RGD) for Caov-3 Cells

[0263] Human Ovarian Cancer (Caov-3) cells were treated with conjugates as depicted in Formula X (i.e. cRGD peptide at the side chain), free DTX and free DTX+CA4 for 48 hours in RPMI-1640 medium. Moreover, Caov-3 cells were treated with PEGMEMA-DTX-A4 conjugate (without RGD). CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)- Combretastatin A4 (CA4)-cRGD conjugates according to Formula X showed less cytotoxicity compared to free drugs as shown in Table 15.

[0264] Example 28: Cytotoxicity Results of of PEGMEMA-Docetaxel (DTX)- CA4 (with S-S linker)- cRGD conjugate according to Formula VHI, free DTX, free DTX+CA4 or PEGMEMA- DTX-CA4 conjugate (without RGD) for Caov-3 Cells

[0265] Human Ovarian Cancer (Caov-3) cells were treated with conjugates as depicted in Formula VIII (i.e. cRGD peptide at the chain end), free DTX and free DTX+CA4 for 48 hours in RPMI-1640 medium. Moreover, SK-OV-3 cells were treated with PEGMEMA-DTX-A4 conjugate (without RGD). CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)- Combretastatin A4 (CA4)-cRGD conjugates according to Formula VHI showed less cytotoxicity compared to free drugs as shown in Table 15 and Figure 17. Table 15: EC50 values of free DTX, free DTX+CA4, and PEGMEMA-DTX-CA4- cRGD conjugates for Caov-3 Referring to Table 15 and Figure 17, compared with the free DTX and free DTX+CA4, the polymer-drug conjugates of the present disclosure, when were used to treat Caov-3, showed a similar cell-killing effect to the free DTX and free DTX+CA4, indicating that the present disclosure had a treatment effect on integrin positive cancers.

[0266] Example 29: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)- CA4 (with S-S linker) - cRGD conjugate according to Formula VIII, free DTX and free DTX+CA4 for Panc-1 Cells

[0267] Human pancreatic cancer (Panc-1) cells were treated with conjugates as depicted in Formula VIII (i.e. cRGD peptide at the chain end), free DTX+CA4 and free DTX for 48 hours in DMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-DTX-CA4-cRGD conjugates showed less cytotoxicity compared to free DTX and free DTX+CA4. The EC50 values of the polymer-drug conjugates, free DTX and free DTX+CA4 are shown in Table 16. Table 16: EC50 values of Free DTX, free DTX+CA4 or PEGMEMA-DTX-CA4-cRGD conjugates for Panc-1 cells

[0268] Referring to Table 16 and Figure 18, compared with the free DTX and free DTX+CA4, the polymer-drug conjugates of the present disclosure, when were used to treat Panc-1, showed a similar cell-killing effect to the free DTX and free DTX+CA4, indicating that the present disclosure had a treatment effect on integrin positive cancers.

[0269] Example 30: Cytotoxicity Results of PEGMEMA-Docetaxel (DTX)-CA4-(with S-S linker)- cRGD with disulfide (S-S) functional group conjugate according to Formula VIII, free DTX or free DTX+CA4 for HUVECs

[0270] Human Umbilical Vein Endothelial Cells (HUVECs) were treated with conjugates as depicted in Formula VIII (i.e. cRGD peptide at the chain end), free DTX+CA4 and free DTX for 48 hours in DMEM medium. CCK-8 assay was performed to measure cell viability. PEGMEMA-DTX- CA4- cRGD conjugates showed less cytotoxicity compared to free DTX and free DTX+CA4. The EC50 values of the polymer-drug conjugates, free DTX and free DTX+CA4 are shown in Table 17.

[0271] Table 17: EC50 values of Free DTX, free DTX+CA4 and PEGMEMA-DTX-CA4- cRGD conjugates for HUVECs

[0272] According to another exemplary embodiment, the present invention provides a polymer-drug conjugate for use in the treatment of solid tumors characterized with overexpression of integrins, wherein R is -CH3; Li comprises amide, GFLG and ester group; L2 comprises of a linker bearing disulfide functional group; n is 3.5 (n: 3.5 refers to both the polymer chain including n:3 and n:4); Di is Docetaxel; D2 is a second therapeutic agent that is Gemcitabine; T is cRGD, B is fragment of a polymerization initiator that is a part of phenyl dithioester. Ligand is comprising of cyclic Arg- Gly-Asp (cRGD) peptide at the chain end.

[0273] Example 31: Cytotoxicity Results of free DTX, free DTX+GEM, PEGMEMA-Docetaxel (DTX)- Gemcitabine (with S-S linker)-cRGD conjugate according to Formula IX or PEGMEMA-DTX-Gemcitabin conjugate (without RGD) for MCF-7 Cells

[0274] Breast cancer (MCF-7) cells were treated with conjugates as depicted in Formula IX (i.e. cRGD peptide at the chain end), free DTX and free DTX+Gemcitabin for 48 hours in RPMI-1640 medium. Moreover, MCF-7 cells were treated with PEGMEMA-DTX-Gemcitabin conjugate (without RGD). CCK-8 assay was performed to measure cell viability. PEGMEMA-Docetaxel (DTX)-PEGMEMA-DTX-Gemcitabin conjugate according to Formula IX showed less cytotoxicity compared to free drugs. Example 32: The experiment of tumor growth inhibition induced by the polymer-drug conjugate comprising docetaxel or RGD as an integrin binding ligand on non-small cell lung cancer (NSCLC) xenograft tumors in nude mice

[0275] Any kind of epithelial lung cancer other than small cell lung cancer (SCLC) is referred to as NSCLC. Figure 19 illustrates the regression of NSCLC tumor xenografts treated with the free DTX, polymer-drug conjugate without a targeting group, the polymer-drug conjugate with a targeting group and saline as a control group. The doses are depicted by the arrows below the x- axis and given every 10 days (i.e. three doses of administration at days 0, 10, 20.). At day 24, both non-targeting and targeting polymer-drug conjugate (3.7-fold and 4.0-fold, respectively) showed significant tumor reduction compared to the saline group. At day 45, another significant reduction in mean tumor size (3.4-fold and 5.1 -fold respectively) was observed in mice injected with nontargeting and targeting polymer-drug conjugate on day 45.

[0276] Figure 19 shows that only three doses of treatment were given and the last dose was taken on day 20, ending the treatment. During the use of free DTX (i.e. the drug used in the relevant technical field), tumor volume continues to increase after free DTX is terminated on day 20.

[0277] As referring to Figure 19, the claimed invention shows a surprising trend of tumor volume reduction. At 20 days, the treatment was terminated, but even at 90 days there was a surprising reduction in NSCLC tumor volume.

[0278] The present invention surprisingly achieved massive tumor regression even with only three doses of treatment. Because unlike SCLC, NSCLC typically responds poorly to radiation and chemotherapy. In this instance, it was also possible to understand the difference between the polymer-drug conjugate with targeting group and the conjugation without targeting agent, and it was proven that the conjugate with targeting agent had a considerably greater anti-cancer impact.

[0279] Example 33: The experiment of tumor growth inhibition induced by the polymer-drug conjugate comprising docetaxel and RGD as an integrin binding ligand on athymic nude mice bearing 22RV1 castration resistant prostate cancer tumor xenografts Two doses of the present invention (14 mg / kg), free DTX (14 mg / kg) and control were administered intravenously every 10 days as per the predetermined concentrations.

[0280] Using athymic nude mice with 22RV1 castration-resistant prostate cancer tumor xenografts, the effectiveness of claimed invention was assessed. Referring to Figure 20, comparing the dosed mice with the present invention to both control and free DTX treatments, a substantial reduction of tumor growth was observed.

[0281] The targeted polymer-drug conjugate was found to be highly efficient, hence, a third dose was considered unnecessary. As can be seen from Figure 20, surprisingly, with just two doses of the treatment, there was a remarkable reduction in tumor volume, underscoring the superior therapeutic efficacy of the polymer-drug conjugate compared to the free DTX.

[0282] Example 34: The experiment of tumor growth inhibition induced by the polymer-drug conjugate comprising docetaxel and RGD as an integrin binding ligand on athymic nude mice hepatocellular CA (Huh7 cell line) tumor xenografts

[0283] The effectiveness of targeted polymer-drug conjugate was assessed in athymic nude mice hosting Huh7 hepatocarcinoma tumor xenografts. Subjects were administered two doses of the targeted polymer-drug conjugate (14 mg / kg), free DTX (14 mg / kg), or a control intravenously every 10 days, adhering to predetermined concentrations. The tumor growth dynamics of mice harboring Huh7 tumors are depicted in Figure 21. Results indicate that mice treated with free DTX did not exhibit significant tumor growth inhibition compared to the control group. Conversely, animals dosed with the targeted polymer-drug conjugate (14 mg / kg) demonstrated substantial tumor growth inhibition relative to the vehicle control. The remarkable efficacy of the targeted polymer- drug conjugate rendered a third dose unnecessary during the experiment. Surprisingly, animals treated with the targeted polymer-drug conjugate were monitored until day 23, revealing no tumor regrowth in any of the subjects. Upon comparison between the free DTX-dosed and control groups, it becomes evident that there was negligible inhibition of tumor growth observed. Conversely, subjects treated with the targeted polymer-drug conjugate exhibited significant suppression of tumor growth, which was striking when compared to the control group. The data depicted in the Figure 21 unequivocally establishes the surprisingly high therapeutic efficacy of targeted polymer- drug conjugates.

[0284] Example 35: The polymer-drug conjugate effects on Liver cancer cell lines

[0285] The effectiveness of the polymer-drug conjugate on Liver cancer cell, comprising Docetaxel and RGD as an integrin binding ligand, was evaluated in athymic nude mice. The study aimed to compare the efficacy of the targeted polymer-drug conjugate to free Docetaxel and a control group. Subjects were administered two doses of the targeted polymer-drug conjugate (14 mg / kg), free DTX (14 mg / kg), or a control intravenously on days 17 and 27, adhering to predetermined concentrations. The tumor growth dynamics of mice harboring Huh7 tumors are depicted in Figure 22 and Figure 23. As can be seen from the graphs, a polymer-drug conjugate as shown in Formula IX treatment decreases tumor growth, promotes tumor regression and prevents toxic effects in mice.

[0286] When the drug ratio exceeds a certain level, intermolecular hydrophobic interactions increase in the system. Nanoparticle formation within the scope of the present invention occurs to minimize the energy of the system. This leads to the formation of more stable, organized nanoparticle structures.

[0287] In one embodiment of the invention, the percentage of gemcitabine in the polymer-drug conjugate varies between 16% and 20% (w / w), and can be for example 18% (w / w). At these ratios by weight, drug interactions and ratios with the polymer matrix can influence nanoparticle formation.

[0288] The nanoparticles presented within the scope of the invention are stable structures. Since they are well stabilized, they can remain stable in solution over wide concentration ranges and for long periods of time. Their stability is increased by surface modifications.

[0289] The applicant also developed RGD receptor-targeted PEGMEMA nanoparticles for the targeted co-delivery of Gemcitabine in cancer therapy.

[0290] As another exemplary embodiment, nanoparticles made of a copolymer as shown in Formula XVI is provided for use in the treatment of solid tumors characterized with overexpression of integrins. By referring to Formula XVI, R is -CH3; Li comprises disulfide functional group, n is 3, Di is Gemcitabine, T is Cyclo(Arg-Gly-Asp-D-Phe-Lys) (SEQ ID NO: 4), B is fragment of a polymerization initiator that is a part of phenyl dithioester. According to another embodiment, n is 4. In accordance with these embodiments, the polymer-drug conjugates comprise an integrin binding ligand comprising Cyclo(Arg-Gly-Asp-D-Phe-Lys) peptide (SEQ ID NO: 4) at the chain end. Moreover, the Formula XVI is arranged as the end-chain functionality of the polymer. Formula XVI can be defined as RGD-end- functionalized polymers as the main part of the targeted drug delivery systems. According to this embodiment, x is a number between 15-200; y is a number between 1-100; and, Formula XVI is a random copolymer. Formula XVI is as follows: Formu a XVI

[0291] As another exemplary embodiment, nanoparticles made of a copolymer as shown in formula XVII are provided for use in the treatment of solid tumors characterized with overexpression of integrins. As referring to formula XVII, R is -CH3; Li comprises disulfide functional group, n is 3, Di is Gemcitabine, T is iRGD (i.e. iRGD = Cys-Arg-Gly-Asp-Lys-Gly-Pro-Asp-Cys (disulfide bridge Cysl-Cys-9) (SEQ ID NO: 3), B is fragment of a polymerization initiator that is a part of phenyl dithioester. According to another embodiment, n is 4. In accordance with these embodiments, the polymer-drug conjugates comprise an integrin binding ligand comprising iRGD peptide at the chain end. Moreover, the Formula XVI is arranged as the end-chain functionality of the polymer.

[0292] Formula XVI can be defined as RGD-end- functionalized polymers as the main part of the targeted drug delivery systems. According to this embodiment, x is a number between 15-200; y is a number between 1-100; and, Formula XVII is a random copolymer.

[0293] Formula XVII is as follows:

[0294] Formula XVII

[0295] The examples of nanoparticles made of the copolymers as shown in formula XVI and XVII are shown below: Example 36: Cytotoxicity Results of PEGMEMA — RGD-NPs conjugate according to

[0296] Formula XVI, and free Gemcitabine for MDA-MB-231 Cells

[0297] Nontargeted PEGMEMA / GEM nanoparticles and RGD targeted PEGMEMA-GEM nanoparticles were developed by the co-solvent evaporation method using THF: water mixture.

[0298] The prepared formulations were characterized for their particle size, polydispersity index, and in vitro drug release.

[0299] Particle size analysis of nontargeted PEGMEMA-GEM nanoparticle by DLS is shown in Figure 24.

[0300] Table 18: Size and Distribution Characteristics of PEGMEMA — RGD-NPs

[0301] Nanoparticle formulations are tested under different dilution conditions. Dilution stability studies are performed to understand whether the nanoparticles are in a stable solution. Dilution Stability of Polymer-Based Nanoparticles Measured by Dynamic Light Scattering (DLS) is shown in Figure 25.

[0302] Particle size analysis of RGD targeted PEGMEMA-GEM nanoparticle by DLS is shown in table 19.

[0303] Table 19: Size and Distribution Characteristics of RGD Targeted PEGMEMA — RGD-NPs According to Table 19, the volumetric size of 183.6 nm is in the range of a size that is desirable in drug delivery systems. This size implies a nanoparticle size small enough to easily penetrate cells, but large enough not to be rapidly cleared by phagocytic cells while circulating in the blood. The size of RGD Targeted PEGMEMA — RGD-NPs is effective in drug delivery systems targeted to tumors, intravenous injections or slow release systems.

[0304] Particle size analysis of targeted PEGMEMA-GEM nanoparticle by DLS is shown in Figure 26. When the Figure 26 is analyzed, the presence of a single prominent peak indicates that the nanoparticles are highly homogeneous in size. This graph indicates that it is a monodisperse system, meaning that the particles are largely similar in size. This is suitable for drug delivery systems where the PDI (polydispersity index) value is low because the homogeneous size distribution allows for more controlled drug release. The PDI as low as 0.109 indicates that the nanoparticles are highly homogeneous in size. Homogeneous distribution allows nanoparticles to exhibit stable behavior in biological systems and provides better control of drug release.

[0305] Moreover, dilution stability studies are performed to understand whether the nanoparticles are in a stable solution. Dilution Stability of Targeted Polymer-Based Nanoparticles Measured by Dynamic Light Scattering (DLS) is shown in Figure 27.

[0306] Example 37: Cytotoxicity Results of PEGMEMA — iRGD-NPs conjugate according to Formula XVII, and free Gemcitabine for MDA-MB-231 Cells

[0307] Human breast adenocarcinoma (MDA-MB-231 Cells) were treated with conjugates as depicted in Formula XVII and free GEM for 48 hours in DMEM medium. CCK-8 assay was performed to measure cell viability. The EC50 values of the polymer-drug conjugates and free GEM are shown in Table 20 and Figure 28.

[0308] Table 20: EC50 values of Free DTX , PEGMEMA-GEM-cRGD and PEGMEMA- GEM-iRGD conjugates for MDA-MB-231 cells

[0309] A dose-response study shown in Table 20 was performed to provide the concentration of the compounds that gives half-maximal response.

[0310] Figure 28 illustrates the cell viability of MDA-MB-231 cells treated with polymer-drug conjugates of the present disclosure compared with the free GEM and confirmed that polymer-drug conjugates present an enhanced effect of killing adenocarcinoma cells.

[0311] As referring to above examples, applicants provide polymeric assemblies or nanoparticles formed with polymer-drug conjugates of formula XVI and XVII, wherein the drugs as nanoparticles as mentioned in the examples above, the anti-cancer agent is protected from environmental conditions. This is because the anti-cancer agent is encapsulated within the nanoparticle structure. Thus, undesirable drug release that may occur in the plasma is minimised by nanoparticle formation. It can also physically encapsulate a second drug when the drug is a nanoparticle (i.e. NPs). In addition, nanoparticles provide a more controlled drug release profile and increase the circulation time of the drug in the plasma.

[0312] In one embodiment of the invention, the percentage of total docetaxel and gemcitabine in the polymer-drug conjugate varies between 16% and 25% (w / w), and can be for example 18% or 20% or 22% (w / w). At these ratios by weight, drug interactions and ratios with the polymer matrix can influence nanoparticle formation.

[0313] As another exemplary embodiment, nanoparticles made of a copolymer as shown in Formula XI are provided for use in the treatment of solid tumors characterized with overexpression of integrins. According to this embodiment, x is a number between 15-200; y is a number between 1-100; z is a number between 1-100; w is a number between 1-100; t is a number between 0.5-10; and, n is a number between 2-20.

[0314] Formula XI is as follows:

[0315] Formula XI

[0316] As another exemplary embodiment, nanoparticles made of a copolymer as shown in Formula XVIII are provided for use in the treatment of solid tumors characterized with overexpression of integrins. By referring to Formula XVIII, R is -CH3; Li comprises disulfide functional group, n is 3, Di is Docetaxel and D2 is Gemcitabine, B is fragment of a polymerization initiator that is a part of phenyl dithioester. According to another embodiment, n is 3 or 4 (i.e: for an average paramaeter n: 3.5). According to this embodiment, x is a number between 15-200; y is a number between 2- 100; and, z is a number between 2-100. Formula XVIII is a random copolymer. Nanoparticles containing GEM and DTX, both of which are formed by the polymer covalently bonded to the polymer, are within the scope of the invention.

[0317] Formula XVIII is as follows:

[0318] Formula XVIII

[0319] Nanoparticles made of a copolymer as shown in formula XIX are provided for use in the treatment of solid tumors characterized with overexpression of integrins. As referring to formula XIX, R is -CH3; Li comprises disulfide functional group, n is 3, Di is Docetaxel and D2 is Gemcitabine, B is fragment of a polymerization initiator. According to another embodiment, n is 4. In accordance with these embodiments, the polymer-drug conjugates comprise an integrin binding ligand comprising cRGD peptide at the chain end. Moreover, the Formula XIX is arranged as the endchain functionality of the polymer. Formula XIX can be defined as RGD-end-functionalized polymers as the main part of the targeted drug delivery systems. According to this embodiment, x is a number between 15-200; y is a number between 2-100; and, z is a number between 2-100. Formula XIX is a random copolymer.

[0320] Formula XIX is as follows:

[0321]

[0322] Formula XIX Particle size analysis of nanoparticle by DLS is shown in table 21. According to table 21, the volumetric size of 150.7 nm, PDI: 0.053 and Z-average 147.6 are in the range of the values that is desirable in drug delivery systems. This size implies a nanoparticle size small enough to easily penetrate cells, but large enough not to be rapidly cleared by phagocytic cells while circulating in the blood.

[0323] Table 21: Size and distribution characteristics of the polymer-drug conjugate

[0324] Particle size analysis of the nanoparticle by DLS is shown in Figure 29. Example 38: Cytotoxicity Results of free DTX, free DTX+GEM, nanoparticles including PEGMEMA-Docetaxel (DTX)-Gemcitabine-Nps according to Formula XVIII for MCF-7 Cells Breast cancer (MCF-7) cells were treated with conjugates as depicted in Formula XVIII (i.e. cRGD peptide at the chain end), free DTX or free DTX+Gemcitabin for 48 hours in RPMI-1640 medium. Moreover, MCF-7 cells were treated with nanoparticles (i.e. NPs) including PEGMEMA-DTX- Gemcitabin conjugate (without RGD). CCK-8 assay was performed to measure cell viability. The results are shown in Table 22 below.

[0325] Example 39: Cytotoxicity Results of free DTX, free DTX+GEM, Nanoparticles including PEGMEMA-Docetaxel (DTX)-Gemcitabine (with S-S linker)-cRGD Nps according to Formula XIX and PEGMEMA-DTX-Gemcitabin conjugate (without RGD) for MCF-7 Cells

[0326] Breast cancer (MCF-7) cells were treated with conjugates as depicted in Formula XIX (i.e. cRGD peptide at the chain end), free DTX or free DTX+Gemcitabin for 48 hours in RPMI-1640 medium.

[0327] Moreover, MCF-7 cells were treated with nanoparticles (i.e. NPs) including PEGMEMA-DTX- Gemcitabin-cRGD conjugate. CCK-8 assay was performed to measure cell viability. The results are shown in Table 22 below. Table 22: EC50 values of free DTX, free Gemcitabin, free DTX+Gemcitabin, nanoparticles including PEGMEMA-DTX-GEM and nanoparticles including

[0328] PEGMEMA-DTX-GEM-cRGD conjugates for MCF-7

[0329] Figure 30 is a graph showing cell viability of MCF-7 cell lines when the cells were treated with free DTX, free Gemcitabin, free DTX+Gemcitabin, nanoparticles including PEGMEMA-DTX- GEM and nanoparticles including PEGMEMA-DTX-GEM-cRGD conjugates for MCF-7.

[0330] The nanoparticles presented within the scope of the invention are stable structures. Since they are well stabilized, they can remain stable in solution over wide concentration ranges and for long periods of time. Their stability is further increased by surface modifications.

[0331] In a possible embodiment, R is selected from -H or -CH3; x is a number between 15-200; y is a number between 2-100; n is a number between 2-20; Li is a cleavable linker comprising GFLG; Di is Docetaxel; T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD; B is an end group that is a polymerization initiator or a fragment thereof.

[0332] In another possible embodiment, R is selected from -H or -CH3; x is a number between 15-200; y is a number between 2-100; n is a number between 2-20; t is a number between 0.5-10; Li is a cleavable linker comprising GFLG; Di is a first therapeutic agent that is Docetaxel; T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD; A is an end group that is a polymerization initiator or a fragment thereof; B is an end group that is a polymerization initiator or a fragment thereof.

[0333] In a possible embodiment, R is selected from -H or -CH3; x is a number between 1-100; y is a number between 2-20; z is a number between 2-20, Li is a cleavable linker comprising GFLG; L2 is a second cleavable linker; Di is a first therapeutic agent that is Docetaxel; D2 is a second therapeutic agent that is Gemcitabine or Combretastatin A4; B is an end group that is a polymerization initiator or a fragment thereof.

[0334] In another possible embodiment, R is selected from -H or -CH3; x is a number between 2-100; y is a number between 2-20; n is a number between 2-20; Li is a cleavable linker; Di is a therapeutic agent, B is an end group that is a polymerization initiator or a fragment thereof; and, Formula XII is a random copolymer.

[0335] Formula XII is as follows:

[0336] Formula XII

[0337] In another possible embodiment, R is selected from -CH3; x is a number between 2-100; y is a number between 2-20; n is a number between 2-20; Li is a cleavable linker comprising GFLG; Di is a first therapeutic agent that is Docetaxel; D2 is a second therapeutic agent that is Gemcitabine; B is an end group that is a polymerization initiator or a fragment thereof.

[0338] According to another aspect of the present invention, a polymer-drug conjugate has the Formula XIII wherein x is a number between 15-200; y is a number between 1-100, A is an end group that is a polymerization initiator or a fragment thereof, B is an end group that is a polymerization initiator or a fragment thereof such that the one or both of the end groups is a polymerization initiator of a fragment thereof.

[0339] Formula XIII is as follows:

[0340]

[0341] Formula XIII

[0342] In an in vitro study, P(OEGMA / GEM), a polymer-drug conjugate, demonstrated superior anticancer activity with IC50 values of 4.89 x 10'5and 2.32 x 10'6against Capan-1 and BcPC-3 cancer cell lines, respectively, compared to free gemcitabine (GEM), which exhibited IC50 values of 2.51 x 1 O'8and 1.67 x 10'7for the same cell lines. According to another aspect of the present invention, a polymer-drug conjugate has the Formula XIV wherein x is a number between 15-200; y is a number between 1-100.

[0343] Formula XIV is as follows:

[0344]

[0345] Formula XIV

[0346] According to another aspect of the present invention, a polymer-drug conjugate has the Formula XV wherein x is a number between 15-200; y is a number between 1-100.

[0347] Formula XV is as follows:

[0348]

[0349] Formula XV

[0350] The therapeutic agent(s) can also be selected from a sub group comprising, but not limited to, nucleoside analogs, antifolates, other metabolites, topoisomerase I inhibitors, anthracyclines, podophyllotoxins, taxanes, vinca alkaloids, alkylating agents, platinum compounds, antihormones, radiopharmaceutics, monoclonal antibodies, tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, retinoids, immunomodulatory agents, histonedeacetylase inhibitors and other agents. Nucleoside analogs can be selected from a group comprising, but not limited to, azacitidine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, fluorouracil (5-FU), gemcitabine, mercaptopurine, nelarabine, pentostatin, tioguanine, trifluridine, tipiracil. Antifolates can be selected from a group comprising, but not limited to, methotrexate, pemetrexed, pralatrexed, raltitrexed. Other metabolites can be selected from a group comprising, but not limited to, hydroxy carbamide. Topoisomerase I inhibitors can be selected from a group comprising, but not limited to, irinotecan and topotecan. Anthracyclines can be selected from a group comprising, but not limited to, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin. Podophyllotoxins can be selected from a group comprising, but not limited to, etoposide and teniposide. Taxanes can be selected from a group comprising, but not limited to, cabazitaxel, docetaxel, paclitaxel. Vinca alkaloids can be selected from a group comprising, but not limited to, vinblastine, vincristine, vindesine, vinflunine, vinorelbine. Alkylating agents can be selected from a group comprising, but not limited to, bendamustine, chlorambucil, dacarbazine, melphalan, streptozotocin, trabectedin. Antihormone compounds can be selected from a group comprising, but not limited to, abiraterone, bicalutamide, cyproterone, degarelix, exemestane, fulvestrant, goserelin, histrelin, leuprolide, mifepristone, triptorelin. Tyrosine kinase inhibitors can be selected from a group comprising, but not limited to, afatinib, axitinib, bosutinib, cobimetinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, pazopanib, ruxolitinib, sunitinib, vandetanib. Mammalian target of rapamycin (mTOR) inhibitors can be selected from a group comprising, but not limited to everolimus, temsirolimus. Retinoids can be selected from a group comprising, but not limited to, alitretinoin, bexarotene, isotretinoin, tamibarotene, tretinoin. Immunomodulatory agents can be selected from a group comprising, but not limited to, lenalidomide, pomalidomide, thalidomide. Histone deacetylase inhibitors can be selected from a group comprising, but not limited to, belinostat, panobinostat, valproate, vorinostat. Other agents can be selected from a group comprising, but not limited to, anagrelide, ceritinib, dabrafenib, idelalisib, ibrutinib, palbociclib, vemurafenib, bleomycin, bortezomib, dactinomycin, eribulin, estramustine, ixabepilone, mitomycin, procarbazine, alectinib, fluxymesterone, iobenguane, imiguimod, interferon, ixazomib, lanreotide, lentinan, octreotide, omacetaxine, tegafur, gimerazil, oteracil, uracil, combretastatin, chloroquine.

[0351] In a possible embodiment of the invention, the therapeutic agent(s) is selected from taxanes, antifolates, tyrosine kinase inhibitors, anthracyclines, nucleoside analogs or other agents. The therapeutic agent(s) can be selected from a group comprising docetaxel, combretastatin, gemcitabine and fluorouracil (5-FU).

[0352] Herein the term "agent(s)" refer to at least one or more therapeutic agents. In an embodiment of the invention the therapeutic agent is docetaxel. In an embodiment of the invention the therapeutic agent is pemetrexed. In an embodiment of the invention the therapeutic agent is chloroquine. In an embodiment of the invention the therapeutic agent is combretastatin. In an embodiment of the invention the therapeutic agent is gemcitabine. In an embodiment of the invention the therapeutic agent is 5-FU. In an embodiment of the invention the therapeutic agent is lapatinib. In an embodiment of the invention the therapeutic agent is a combination of two or more therapeutic agents selected from the group comprising docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicine, 5-FU and any other agents listed above. As such, therapeutic agent(s) that are a combination of two or more therapeutic agents can be selected from the main groups or specific members of the main groups listed above. The therapeutic agent can be present in an amount in between 1% to 40% by weight of the polymer-drug conjugate, preferably in an amount between 2% to 35% by weight of the drug-polymer conjugate and most preferably in an amount between 3% to 30% by weight of the drug-polymer conjugate. The therapeutic agent can be present in an amount in the range of for example; 4% to 25% or 5% to 24% or 6% to 23% or 7% to 22% or 8% to 20% by weight of the drug-polymer conjugate.

[0353] In another embodiment A and B are both fragments of a polymerization initiator, however they are structurally different from one another. In other words, A and B are different fragments of the same initiator. In another embodiment A and B are both fragments of a polymerization initiator and they have the same chemical structure. In one embodiment, A and / or B is selected from the group consisting of 4,4'-Azobis(4-cyanovaleric acid), 4,4'-Azobis(4-cyanovaleric acid), 1,1'- Azobis(cyclohexanecarbonitrile), 2,2'-Azobis(2-methylpropionamidine) dihydrochloride, 2,2'- Azobis(2-methylpropionitrile) (also known as AIBN), Ammonium persulfate, hydroxymethanesulfinic acid monosodium salt dihydrate, potassium persulfate, sodium persulfate, tert-Butyl hydroperoxide, tert-Butyl peracetate, Cumenehydroperoxide, 2,5-Di(tert-butylperoxy)- 2,5-dimethyl-3-hexyne, Dicumyl peroxide, 2,5-Bis(tert-butylperoxy)-2,5-dimethylhexane, 1,1- Bis(tert-butylperoxy)-3,3,5-trimethylcyclohexane, 1 , 1 -Bis(tert-amylperoxy)cyclohexane,

[0354] Benzoyl peroxide, 2-Butanone peroxide, tert-Butyl peroxide, Di-tert-amyl peroxide, Lauroyl peroxide, tert-Butyl per oxy benzoate, tert-Butylperoxy 2-ethylhexyl carbonate, tert-Butyl hydroperoxide, 2- Azidoethyl 2-bromoisobutyrate, Bis[2-(2-bromoisobutyryloxy)undecyl] disulfide, Bis[2-(2'-bromoisobutyryloxy)ethyl]disulfide, 2-Bromoisobutanoic acid N- hydroxysuccinimide ester, 2-Bromoisobutyric anhydride, a-Bromoisobutyryl bromide, 2-(2- Bromoisobutyryloxy)ethyl methacrylate, tert-Butyl a-bromoisobutyrate, 3-Butynyl 2- bromoisobutyrate, Dipentaerythritolhexakis(2-bromoisobutyrate), Dodecyl 2-bromoisobutyrate, Ethyl a-bromoisobutyrate, Ethylene bis(2-bromoisobutyrate), 2-Hydroxyethyl 2- bromoisobutyrate, 1-(DL-1,2-Isopropylideneglyceryl) 2-bromoisobutyrate, Methyl a- bromoisobutyrate, Octadecyl 2-bromoisobutyrate, Pentaerythritoltetrakis(2-bromoisobutyrate), 1 - (Phthalimidomethyl) 2-bromoisobutyrate, Poly(ethylene glycol) bis(2-bromoisobutyrate), Propargyl 2-bromoisobutyrate, 1,1,1 -Tris(2-bromoisobutyryloxymethyl)ethane, 10-Undecenyl 2- bromoisobutyrate, N-tert-Butyl-O-[l-[4-(chloromethyl)phenyl]ethyl]-N-(2-methyl-l- phenylpropyl)hydroxylamine, N-tert-Butyl-N-(2-methyl-l-phenylpropyl)-O-(l- phenylethyl)hydroxylamine, TEMPO, TEMPO methacrylate, 2,2,5-Trimethyl-4-phenyl-3- azahexane-3-nitroxide, 3,5-Bis(2-dodecylthiocarbonothioylthio-l - oxopropoxy)benzoic acid, 3- Butenyl 2-(dodecylthiocarbonothioylthio)-2-methylpropionate, 4-Cyano-4-

[0355] [(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid, 4-Cyano-4-

[0356] [(dodecylsulfanylthiocarbonyl)sulfanyl]pentanol, Cyanomethyl dodecyl, Cyanomethyl [3- (trimethoxysilyl)propyl] trithiocarbonate, 2-Cyano-2-propyl dodecyl trithiocarbonate, S,S- Dibenzyl trithiocarbonate, 2-(Dodecylthiocarbonothioylthio)-2-methylpropionic acid, 2- (Dodecylthiocarbonothioylthio)-2-methylpropionic acid, 3 -azido- 1 -propanol ester, 2- (Dodecylthiocarbonothioylthio)-2-methylpropionic acid N-hydroxysuccinimide ester, 2- (Dodecylthiocarbonothioylthio)-2-methylpropionic acid pentafluorophenyl ester, 2- (Dodecylthiocarbonothioylthio)propionic acid, Methyl 2-(dodecylthiocarbonothioylthio)-2- methylpropionate, Pentaerythritol tetrakis[2-(dodecylthiocarbonothioylthio)-2- methylpropionate], Phthalimidomethyl butyl trithiocarbonate, 1,1,1-

[0357] Tris[(dodecylthiocarbonothioylthio)-2-methylpropionate]ethane, benzyl benzodithioate, Cyanomethyl benzodithioate, 4-Cyano-4-(phenylcarbonothioylthio)pentanoic acid, 4-Cyano-4- (phenylcarbonothioylthio)pentanoic acid N-succinimidyl ester, 2-Cyano-2-propyl benzodithioate, 2-Cyano-2-propyl 4-cyanobenzodithioate, Ethyl 2-(4-methoxyphenylcarbonothioylthio)acetate, Ethyl 2-methyl-2-(phenylthiocarbonylthio)propionate, Ethyl 2-(phenylcarbonothioylthio)-2- phenylacetate, Ethyl 2-(phenylcarbonothioylthio)propionate, 1 -(Methoxy carbonyl)ethyl benzodithioate, 2-(4-Methoxyphenylcarbonothioylthio)ethanoic acid, 2-Nitro-5-(2- propynyloxy)benzyl, 4-cyano-4-(phenylcarbonothioylthio)pentanoate, 2-

[0358] (Phenylcarbonothioylthio)propanoic acid, 2-Phenyl-2-propyl benzodithioate, Cyanomethyl methyl(4-pyridyl)carbamodithioate, Cyanopropan-2-yl N-methyl-N-(pyridin-4- yl)carbamodithioate, Methyl 2-[methyl(4-pyridinyl)carbamothioylthio]propionate, 1- Succinimidyl-4-cyano-4-[N-methyl-N-(4-pyridyl)carbamothioylthio]pentanoate or any fragment of the initiators listed herein. In a possible embodiment, the polymer-drug conjugate of invention comprises GFLG as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicine, 5-FU.

[0359] In a possible embodiment, the polymer-drug conjugate of invention comprises Val-Cit as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicine, 5-FU.

[0360] In a possible embodiment, the polymer-drug conjugate of invention comprises Phe-Lys as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, 5-FU.

[0361] In a possible embodiment, the polymer-drug conjugate of invention comprises Vai- Ala as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, 5-FU.

[0362] In a possible embodiment, the polymer-drug conjugate of invention comprises Ala-Leu- Ala-Leu as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, 5-FU.

[0363] In a possible embodiment, the polymer-drug conjugate of invention comprises a C1-C10 hetero substituted hydrocarbon comprising at least one disulfide functional group as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, 5-FU.

[0364] In a possible embodiment, the polymer-drug conjugate of invention comprises a C1-C10 hetero substituted hydrocarbon comprising at least one acetal functional group as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, 5-FU.

[0365] In a possible embodiment, the polymer-drug conjugate of invention comprises C1-C10 hetero substituted hydrocarbon comprising at least one ester functional group as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, 5-FU.

[0366] In a possible embodiment, the polymer-drug conjugate of invention comprises a C1-C10 hetero substituted hydrocarbon comprising at least one imine functional group as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, 5-FU, 5'-Deoxy 5-Fluorocytidine (5'-DFCR) and lapatinib.

[0367] In a possible embodiment, the polymer-drug conjugate of invention comprises a C1-C10 hetero substituted hydrocarbon comprising at least one amide functional group as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, 5-FU, 5'-Deoxy 5-Fluorocytidine (5'-DFCR) and lapatinib.

[0368] In a possible embodiment, the polymer-drug conjugate of invention comprises a C1-C10 hetero substituted hydrocarbon comprising at least one carbonate functional group as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, 5-FU.

[0369] In a possible embodiment, the polymer-drug conjugate of invention comprises a C1-C10 hetero substituted hydrocarbon comprising at least one carbamate functional group as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, 5-FU.

[0370] In a possible embodiment, the polymer-drug conjugate of invention comprises a C1-C10 hetero substituted hydrocarbon comprising at least one hydrazone functional group as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, 5-FU.

[0371] In a possible embodiment, the polymer-drug conjugate of invention comprises a C1-C10 substituted or hetero substituted hydrocarbon comprising two or more functional groups selected from the group comprising acetal, ester, imine, amide, disulfide, carbonate, carbamate, hydrazone as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, 5-FU. In a possible embodiment, the polymer-drug conjugate of invention comprises a combination of a C1-C10 substituted hydrocarbon comprising at least one functional group selected from the group comprising acetal, ester, imine, amide, disulfide, carbonate, carbamate, hydrazone and a peptide chain selected from the group comprising GFLG, Val-Cit, Vai-Ala, Ala-Leu-Ala-Leu or Phe-Lys as the linker and a therapeutic agent selected from the group docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU.

[0372] In a possible embodiment, the polymer-drug conjugate of invention comprises a combination of a C1-C10 substituted hydrocarbon comprising one or more functional group selected from the group comprising acetal, ester, imine, amide, disulfide, carbonate, carbamate, hydrazone and a peptide chain selected from the group comprising GFLG as the linker and a therapeutic agent selected from the group docetaxel, combretastatin, gemcitabine or 5-FU.

[0373] In another embodiment the polymer-drug conjugate of the invention has an average molecular weight in between 20 kDa to 300 kDa, preferably between 30 kDa to 270 kDa, most preferably between 40 kDa to 250 kDa.

[0374] Another embodiment of the invention is a method for preparation of the polymer-drug conjugate of the invention which comprises polymerization of PEG (meth)acrylate monomer and at least one type of (meth)acrylate-L-D monomer. In another aspect, a method for preparation of the polymer- drug conjugate of the invention comprises (i) polymerization of PEG (meth)acrylate monomer and (meth)acrylate-L monomer and then (ii) reacting the sum of the reaction mix with at least one type of therapeutic agent to give polymer conjugate.

[0375] In an embodiment of the invention said PEG (meth)acrylate has an average molecular weight in between 200-2000 g / mol or between 250-1500 g / mol or 300-1100 g / mol.

[0376] In a possible embodiment, the polymer-drug conjugate of invention comprises carbamate and dithiolane functional group as the linker and a therapeutic agent is gemcitabine.

[0377] The polymer-drug conjugate of the invention can be prepared by any of the known polymerization methods. Any suitable initiators and / or catalysts known in the art can be used for the preparation of the polymer-drug conjugate of the present invention. Where a polymerization initiator is used, the initiator or a fragment thereof may be present in the resulting polymer-drug conjugate.

[0378] “Comprising” in the context of the present specification is intended to meaning “including”. Where technically appropriate, embodiments of the invention may be combined.

[0379] The active targeting permits selective release of the therapeutic agent adjacent to or inside the cell. The polymer-drug conjugates are much less toxic than the free drugs or drug combinations.

[0380] Even if a polymer-drug conjugate shows a similar EC50 value compared to the free drug, it can still offer several significant advantages. The polymer conjugates according to the present invention is able to circulate in the body for a longer period, enhancing the drug's effectiveness and potentially requiring less frequent administration. The present invention is designed to target specific cells, such as tumor cells, allowing the drug to reach the target cells directly while minimizing harm to healthy tissues, thereby reducing side effects. Additionally, the polymer conjugates disclosed are more stable than free drugs, remaining effective in the body for a longer duration without degradation or inactivation. This controlled and targeted drug delivery can result in lower side effects, making the treatment more tolerable for patients. Despite having a similar EC50 value, these advantages can significantly improve overall treatment efficacy and patient outcomes, making polymer-drug conjugates of the invention an attractive option for commercialization.

[0381] The present invention provides one or more polymer-drug conjugates which achieves the selective binding of RGD to integrins on cancer cells so as to enhance the specificity of drug delivery, the receptor-mediated endocytosis of RGD-modified carriers leads to increased uptake of anti-cancer agents by cancer cells, and reduced side effects which reduces the exposure of healthy tissues to cytotoxic drugs, minimizing adverse effects.

[0382] The present invention also provides a method for the treatment of cancer characterized in treating via isolated organ perfusion a subject in need thereof with a therapeutically effective amount of the polymer-drug conjugates disclosed above. The isolated organ is selected from the group consisting of liver, lung, pelvis, ovaria, pancreas, brain and breast.

[0383] The endometrial cancers, ovarian cancer, prostate cancer, breast cancer, liver cancer, pancreatic cancer, head and neck cancer, colon adenocarcinoma or lung cancer is characterized by high integrin expression.

[0384] The present invention also provides a method of treating lung cancer in humans. Said method comprising administering the polymer-drug conjugate of the invention to said humans. The present invention also provides the usage of the polymer-drug conjugates for the manufacture of a medicament for the treatment of the endometrial cancer, ovarian cancer, prostate cancer, breast cancer, liver cancer, pancreatic cancer, head and neck cancer, colon adenocarcinoma or lung cancer in patients.

Claims

CLAIMS1. A polymer-drug conjugate for use in the treatment of solid tumors characterized with overexpression of integrins comprising a (meth)acrylate based polymer backbone, and at least two side chains wherein one side chain is a PEG chain and the other side chain comprises at least one anti-cancer agent which is Docetaxel covalently bonded to at least one cleavable linker; wherein the polymer-drug conjugate further comprises an integrin binding ligand (T) comprising cyclic RGD or linear RGD or iRGD and wherein the polymer-drug conjugate is a random copolymer.

2. The polymer-drug conjugate having Formula I for use according to claim 1 in the treatment of solid tumors with overexpression of integrins:Formula I wherein- R is selected from -H or -CH3;- x is a number between 15-200;- y is a number between 1-100;- n is a number between 2-20;- Li is a first cleavable linker comprising GFLG;- Di is a first anti-cancer agent that is Docetaxel;- T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD;- B is an end group that is a polymerization initiator or a chain transfer agent or a fragment thereof; and- Formula I is a random copolymer.

3. The polymer-drug conjugate having Formula II for use according to claim 1 in the treatment of solid tumors with overexpression of integrins:Formula II wherein- R is selected from -H or -CH3;- x is a number between 15-200;- y is a number between 1-100;- n is a number between 2-20;- t is a number between 0,5- 10;- Li is a first cleavable linker comprising GFLG;- Di is a first therapeutic agent that is Docetaxel;- T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD;- A is an end group that is a polymerization initiator or a chain transfer agent or a fragment thereof;- B is an end group that is a polymerization initiator or a chain transfer agent or a fragment thereof; and- Formula II is a random copolymer.

4. The polymer-drug conjugate having Formula III for use according to claim 1 or claim 2 in the treatment of solid tumors with overexpression of integrins:Formula III wherein- R is selected from -H or -CH3;- x is a number between 15-200;- y is a number between 1-100;- z is a number between 1-100;- n is a number between 2-20;- t is a number between 0,5- 10;- Li is a first cleavable linker comprising GFLG;- Di is a first therapeutic agent that is Docetaxel;- T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD;- A is an end group that is a polymerization initiator or a chain transfer agent or a fragment thereof;- B is an end group that is a polymerization initiator or a chain transfer agent or a fragment thereof; and,- Formula III is a random copolymer.

5. The polymer-drug conjugate having Formula IV for use according to any one of the preceding claims in the treatment of solid tumors with overexpression of integrins:Formula IV wherein- R is selected from -H or -CH3;- x is a number between 15-200;- y is a number between 1-100;- z is a number between 1-100;- n is a number between 2-20;- Li is a first cleavable linker comprising GFLG;- Di is a first therapeutic agent that is Docetaxel;- L2 is a second cleavable linker;- D2 is a second therapeutic agent that is Gemcitabine or Combretastatin A4;- T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD;- B is an end group that is a polymerization initiator or a chain transfer agent or a fragment thereof; and- Formula IV is a random copolymer.

6. The polymer-drug conjugate having Formula V for use according to any one of the preceding claims in the treatment of solid tumors with overexpression of integrins:Formula V wherein- R is selected from -H or -CH3;- x is a number between 15-200;- y is a number between 1-100;- z is a number between 1-100;- n is a number between 2-20;- t is a number between 0,5- 10;- Li is a first cleavable linker comprising GFLG;- Di is a first therapeutic agent that is Docetaxel;- L2 is a second cleavable linker;- D2 is a second therapeutic agent that is Gemcitabine or Combretastatin A4;- T is an integrin binding ligand comprising cyclic RGD or linear RGD or iRGD;- A is an end group that is a polymerization initiator or a chain transfer agent or a fragment thereof;- B is an end group that is a polymerization initiator or a chain transfer agent or a fragment thereof; and- Formula V is a random copolymer.

7. The polymer-drug conjugate having Formula VI for use according to any one of the preceding claims in the treatment of solid tumors with overexpression of integrins:Formula VI wherein- x is a number between 15-200;- n is a number between 2-20;- y is a number between 1-100.

8. The polymer-drug conjugate having Formula VII for use according to any one of the preceding claims in the treatment of solid tumors with overexpression of integrins:Formula VII wherein- x is a number between 15-200;- y is a number between 1-100;- z is a number between 1-100;- n is a number between 2-20;- t is a number between 0,5- 10.

9. The polymer-drug conjugate having Formula VIII for use according to any one of the preceding claims in the treatment of solid tumors with overexpression of integrins:Formula VIII wherein- x is a number between 15-200;- y is a number between 1-100;- z is a number between 1-100;- n is a number between 2-20.

10. The polymer-drug conjugate having Formula IX for use according to any one of the preceding claims in the treatment of solid tumors with overexpression of integrins:Formula IX wherein- x is a number between 15-200;- y is a number between 1-100;- z is a number between 1-100;- n is a number between 2-20.

11. The polymer-drug conjugate having Formula X for use according to any one of the preceding claims in the treatment of solid tumors with overexpression of integrins:Formula X wherein- x is a number between 15-200;- y is a number between 1-100;- z is a number between 1-100;- t is a number between 0,5- 10.- n is a number between 2-20.

12. The polymer-drug conjugate having Formula XI for use according to any one of the preceding claims in the treatment of solid tumors with overexpression of integrins:Formula XI wherein- x is a number between 15-200;- y is a number between 1-100;- z is a number between 1-100;- w is a number between 1-100;- t is a number between 0,5- 10.- n is a number between 2-20.

13. The polymer-drug conjugate for use according to claim 5 or claim 6 in the treatment of solid tumors with overexpression of integrins, wherein the second cleavable linker (L2) comprises one or more functional group that is selected from acetal, ester, imine, amide, disulfide, carbonate or carbamate.

14. A polymer-drug conjugate for use in the treatment of solid tumors with overexpression of integrins according to any one of the claims 1 to 12 wherein the solid tumor is breast cancer.

15. A polymer-drug conjugate for use in the treatment of solid tumors with overexpression of integrins according to any one of the claims 1 to 12 wherein the solid tumor is ovarian cancer.

16. A polymer-drug conjugate for use in the treatment of solid tumors with overexpression of integrins according to any one of the claims 1 to 12 wherein the solid tumor is lung cancer.

17. A polymer-drug conjugate for use in the treatment of solid tumors with overexpression of integrins according to any one of the claims 1 to 12 wherein the solid tumor is liver cancer.

18. A polymer-drug conjugate for use in the treatment of solid tumors with overexpression of integrins according to any one of the claims 1 to 12 wherein the solid tumor is head and neck cancer.

19. A polymer-drug conjugate for use in the treatment of solid tumors with overexpression of integrins according to any one of the claims 1 to 12 wherein the solid tumor is prostate cancer.

20. A polymer-drug conjugate for use in the treatment of solid tumors with overexpression of integrins according to any one of the claims 1 to 12 wherein the solid tumor is colon adenocarcinoma.

21. A polymer-drug conjugate for use in the treatment of solid tumors with overexpression of integrins according to any one of the claims 1 to 12 wherein the solid tumor is brain cancer.

22. A polymer-drug conjugate for use in the treatment of solid tumors with overexpression of integrins according to any one of the claims 1 to 12 wherein the solid tumor is pancreatic cancer.

Images