Drug-loaded mesoporous silica nanoparticle for prevention and treatment of brain cancers or brain metastases and uses thereof

Abstract

This disclosure relates to a method for preventing or treating brain cancer or metastatic brain cancer using mesoporous silicon dioxide nanoparticles (MSNs) loaded with a taxane-based chemotherapeutic agent, particularly paclitaxel (PTX), cabazitaxel (CTX), or docetaxel (DTX), wherein the MSN is loaded with PTX, CTX, or DTX.

Description

Technical Field

[0001] This invention relates to a method for preventing or treating brain cancer or metastatic brain cancer using mesoporous silicon dioxide nanoparticles (MSNs) loaded with taxane-based chemotherapeutic agents (e.g., paclitaxel (PTX), cabazitaxel (CTX), or docetaxel (DTX)), and also to MSNs loaded with taxane-based chemotherapeutic agents (e.g., PTX, CTX, or DTX) and their applications. Prior Technology

[0002] Cancer is a leading cause of death worldwide, with nearly 10 million deaths reported by the World Health Organization in 2020. While all types of cancer can lead to death, brain cancer, though not the most common, is arguably the most troublesome. The human brain governs many aspects of life, and when focusing on treating tumors, many chemicals, including drugs, cannot penetrate the blood-brain barrier (BBB), particularly the blood-tumor barrier (BBTB), and therefore cannot provide therapeutic benefits.

[0003] Scientists and doctors have made tremendous efforts in searching for potential drugs to treat brain cancer. Examples include temozolomide (TMZ), benzutifan, carmustine, everolimus, and lomustine, which are believed to be able to penetrate the brain's biological barrier (BBB), especially the BTB, and reach the brain tumor site. For over a decade, TMZ has been a first-line chemotherapy drug for gliomas. However, some patients may have contraindications to TMZ, or it may be less effective in patients who are resistant to it. Therefore, new treatment strategies for brain cancer still need to be developed.

[0004] Another issue is metastatic brain cancer, which can cause more deaths than primary brain cancer. Patients with metastatic brain cancer have a higher mortality rate. Many common cancers, such as lung cancer, breast cancer, colon cancer, and prostate cancer, are particularly prone to metastasizing to the brain. Once primary cancer has metastasized to the brain, surgery and radiation therapy are limited options for patients / physicians, but neither method is particularly effective. Aside from surgery and radiation therapy, TMZ remains the only drug currently available for treating metastatic brain cancer.

[0005] Using drug delivery systems may be a more efficient, effective, and direct way to deliver drugs to individuals. For the treatment of brain cancer or metastatic brain cancer, vesicles (lipids, microcells, polymers, or cytosomes), linear polymers, metals (Au, Gd, graphene), carbon dots, nanoimplants, dendritic polymers, and other materials can be used as drug delivery systems. For example, mesoporous silica nanoparticles (MSNs) are considered to have great potential as a drug delivery system due to their unique physical / chemical properties (e.g., large pore volume, chemical / thermal stability, high loading capacity, tunable surface properties, and excellent biocompatibility). Nevertheless, no existing drug delivery system suitable for treating brain cancer appears to exist, and therefore, there is still a need to develop drug delivery systems loaded with potential drugs for treating brain cancer, such as optimized MSNs. Summary of the Invention

[0006] This disclosure relates to a method for preventing or treating brain cancer or metastatic brain cancer in an individual, comprising intravenously administering mesoporous silica nanoparticles loaded with a taxane-based chemotherapeutic agent (e.g., paclitaxel (PTX), cabazitaxel (CTX), or docetaxel (DTX)) to the individual; and also relates to the use of mesoporous silica nanoparticles loaded with a taxane-based chemotherapeutic agent in the preparation of a medicament for preventing or treating brain cancer or metastatic brain cancer in an individual, wherein the medicament is administered intravenously to the individual. In particular, the mesoporous silica nanoparticles have at least one of the following characteristics: (a) Surface modification using (i) organic molecules, oligomers or polymers and (ii) positively charged molecules, oligomers or polymers, wherein the molar ratio of (i) and (ii) is in the range of 60:1 to 4:1; (b) Modification of the pore surface using the terminal hydrocarbon group; (c) Average particle size of 60 nm or less as measured by TEM; (d) Average dynamic light scattering particle size of 60 nm or smaller, measured by dynamic light scattering in phosphate-buffered saline (PBS); and (e) Surface modification using (i) organic molecules, oligomers or polymers. This disclosure also relates to mesoporous silicon dioxide nanoparticles loaded with cabazitaxel (CTX), wherein the mesoporous silicon dioxide nanoparticles have at least one of the following characteristics: (a) Surface modification using (i) organic molecules, oligomers or polymers and (ii) positively charged molecules, oligomers or polymers, wherein the molar ratio of (i) and (ii) is in the range of 60:1 to 4:1; (b) Modification of the pore surface using the terminal hydrocarbon group; (c) Average particle size of 60 nm or less as measured by TEM; (d) Average dynamic light scattering particle size of 60 nm or smaller, measured by dynamic light scattering in phosphate-buffered saline (PBS); and (e) Surface modification using (i) organic molecules, oligomers or polymers. This disclosure also relates to mesoporous silicon dioxide nanoparticles loaded with docetaxel (DTX), wherein the mesoporous silicon dioxide nanoparticles have at least one of the following characteristics: (a) Surface modification using (i) organic molecules, oligomers or polymers and (ii) positively charged molecules, oligomers or polymers, wherein the molar ratio of (i) and (ii) is in the range of 60:1 to 4:1; (b) Modification of the pore surface using the terminal hydrocarbon group; (c) Average particle size of 60 nm or less as measured by TEM; (d) Average dynamic light scattering particle size of 60 nm or smaller, measured by dynamic light scattering in phosphate-buffered saline (PBS); and (e) Surface modification using (i) organic molecules, oligomers or polymers. This disclosure also relates to mesoporous silicon dioxide nanoparticles loaded with paclitaxel (PTX), wherein the mesoporous silicon dioxide nanoparticles have at least one of the following characteristics: (a) Surface modification using (i) organic molecules, oligomers or polymers and (ii) positively charged molecules, oligomers or polymers, wherein the molar ratio of (i) and (ii) is in the range of 60:1 to 4:1; (b) Modification of the pore surface using the terminal hydrocarbon group; (c) Average particle size of 60 nm or less as measured by TEM; (d) Average dynamic light scattering particle size of 60 nm or smaller, measured by dynamic light scattering in phosphate-buffered saline (PBS); and (e) Surface modification using (i) organic molecules, oligomers or polymers. Simple Explanation of the Diagram

[0007] Figure 1 shows fluorescent staining images of normal brain regions and brain tumor regions in one of the mice injected with fluorescently labeled MSN. Figure 2 shows the experimental details and results of DTX and DTX@MSN in a mouse model of orthotopic TMZ-resistant brain tumors. Figure 3 shows the H&E staining of mouse brain tissue injected with PBS (control group), DTX (5 mg / kg and 10 mg / kg), and DTX@MSN (5 mg / kg and 10 mg / kg), respectively. Figure 4 shows the experimental details and results of treating mice with an orthotopic TMZ-resistant brain tumor using DTX or DTX@MSN in combination with TMZ. Figure 5 shows the experimental details and results of treating mice with an orthotopic TMZ-resistant brain tumor using CTX or CTX@MSN in combination with TMZ. Implementation

[0008] To aid in understanding this disclosure, the terms used herein are defined as follows.

[0009] In the context of this disclosure and the claims, unless specifically stated otherwise, the singular forms "a / an" and "the" include multiple indicators, and vice versa. Unless otherwise stated, any and all instances or exemplary language (e.g., "as") provided herein are for the purpose of better illustrating the invention and not for limiting its scope.

[0010] It should be understood that any numerical range described in this specification is intended to include all sub-ranges covered therein. For example, the range "50 to 70°C" includes all sub-ranges and specific values ​​between the minimum value of 50°C and the maximum value of 70°C, including, for example, 58°C to 67°C, and 53°C to 62°C, 60°C, or 68°C. Because the disclosed numerical ranges are continuous, they contain every value between the minimum and maximum values. Unless otherwise stated, the various numerical ranges indicated in this specification are approximate.

[0011] In this invention, the term "about" refers to an acceptable deviation from a given value as measured by a person skilled in the art, depending in part on how the value is measured or determined.

[0012] In this invention, unless specifically stated otherwise, the prefix "nanometer" as used herein refers to a size of about 300 nm or smaller. Unless specifically stated otherwise, the initial "medium" as used herein differs from the definition proposed by IUPAC and refers to a size of about 50 nm or smaller. In some embodiments, the prefix "medium" may refer to a smaller size, for example, about 20 nm or smaller, 10 nm or smaller, or 5 nm or smaller.

[0013] In this invention, as used herein, the term "silane" refers to a SiH4 derivative. Typically, at least one of the four hydrogens is replaced by a substituent such as an alkyl, alkoxy, or amino group, as described below. As used herein, the term "alkoxysilane" refers to a silane having at least one alkoxy substituent directly bonded to a silicon atom. As used herein, the term "organoalkoxysilane" refers to a silane having at least one alkoxy substituent directly bonded to a silicon atom and at least one hydrocarbon substituent. As used herein, the term "silate source" refers to a substance that can be considered as a salt or ester form of orthosilicic acid, such as sodium orthosilicate, sodium metasilicate, tetraethyl orthosilicate (tetraethoxysilane, TEOS), tetramethyl orthosilicate, or tetrapropyl orthosilicate. Optionally, the hydrocarbon substituent may be further heteroatom substituted or intercalated.

[0014] In this invention, as used herein, the term "hydrocarbon group" refers to a monovalent group derived from a hydrocarbon. As used herein, the term "hydrocarbon" refers to a molecule consisting only of carbon and hydrogen atoms. Examples of hydrocarbons include, but are not limited to, (cyclo)alkanes, (cyclo)olefins, dienes, aromatic hydrocarbons, etc. When the hydrocarbon group is further substituted as mentioned above, the substituent can be a halogen, amino group, hydroxyl group, thiol group, etc. When the hydrocarbon group is interspersed with heteroatoms as mentioned above, the heteroatoms can be S, O, or N. In this invention, the hydrocarbon group preferably contains 1 to 30 carbon atoms.

[0015] In this invention, the term "alkyl" refers to a saturated straight-chain or branched alkyl group, preferably comprising 1-30 carbon atoms and more preferably 1-20 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, dibutyl, isobutyl, tributyl, 2-ethylbutyl, n-pentyl, isopentyl, 1-methylpentyl, 1,3-dimethylbutyl, n-hexyl, 1-methylhexyl, n-heptyl, isoheptyl, 1,1,3,3-tetramethylbutyl, 1-methylheptyl, 3-methylheptyl, n-octyl, 2-ethylhexyl, 1,1,3-trimethylhexyl, 1,1,3,3-tetramethylpentyl, nonyl, decyl, undecyl, 1-methylundecyl, dodecyl, 1,1,3,3,5,5-hexamethylhexyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, or the like.

[0016] In this invention, the term "alkylene / alkylene group" refers to a divalent alkyl group as mentioned above. The term "short chain" means that the free radical or repeating unit contains up to 6 carbon atoms in the main chain, preferably up to 4 carbon atoms.

[0017] In this invention, as used herein, the term "alkoxyl" or "alkoxy" means a group having the formula "-O-alkyl", wherein "alkyl" in the formula has the meaning of "alkyl" as described above.

[0018] In this invention, as used herein, the term "cycloalkyl" means a saturated or partially unsaturated cyclic carbon group containing 3 to 10 cyclic carbon atoms, more preferably 3 to 8 cyclic carbon atoms, which optionally contains an alkyl substituent on the ring. Examples of cycloalkyl groups include (but are not limited to) cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-1-yl, and the like.

[0019] In this invention, the term "halogen" or "halogen(group)" means fluorine, chlorine, bromine or iodine.

[0020] In this invention, as used herein, the term "amine" refers to the functional group of the formula -NR1R2, wherein R1 and R2 each independently represent hydrogen or a hydrocarbon group as defined above.

[0021] In this invention, the term "inner surface" refers to the surface that defines the "wall" of a hole, and the term "outer surface" refers to the surface of the outermost layer, wall, or structure of a nanoparticle.

[0022] In this invention, the term "therapeutic agent" as used herein refers to a substance that has a therapeutic effect in an organism. Examples of therapeutic ingredients include (but are not limited to) small molecule drugs, proteins (such as enzymes and protein drugs), antibodies, vaccines, antibiotics, or nucleotide drugs.

[0023] In this invention, as used herein, the terms "taxane-based chemotherapeutic agent" or "taxane-based chemotherapeutic agent" or "taxane-based chemotherapeutic agent" refer to chemically and therapeutically active compounds having a taxane core structure or derived from a taxane core structure (such as dehydrogenation). Examples of taxane-based chemotherapeutic agents / taxane-based chemotherapeutic agents include (but are not limited to) paclitaxel (PTX), cabazitaxel (CTX), and docetaxel (DTX). [Brain cancer or metastatic brain cancer] []

[0024] Despite significant recent advances in diagnosis and treatment, brain cancer remains a devastating disease due to its high recurrence rate and fatal outcomes. Brain cancer can originate in the brain (primary brain tumor) or spread to the brain from other parts of the body (metastatic tumor). The prognosis for both primary and metastatic brain cancer is generally poor. The median survival after initiating treatment (including surgery, radiation, chemotherapy, and combinations thereof) is less than one year. For example, glioblastoma (a form of primary brain cancer) can recur in the peritumoral area even when the BBB (body border of tumor) is intact, especially if the BBTB (body border of tumor tissue) remains intact. This significantly limits the effectiveness of chemotherapy in eliminating the remaining invasive cancer cells. Temozolomide (TMZ) is a first-line chemotherapy agent for glioblastoma (GBM), a high-grade glioma. Unfortunately, more than 50% of GBM patients do not respond to TMZ therapy. Tolerance to TMZ often becomes a limiting factor in effective treatment, and almost all patients experience disease progression. Effective chemotherapy is urgently needed to treat GBM and TMZ-refractory GBM. To date, only a few drugs are approved for the treatment of brain cancer. Furthermore, cancer can spread to the brain even if the patient has a non-primary brain tumor. The most likely cancers to cause metastatic brain cancer are lung cancer, breast cancer, prostate cancer, colon cancer, kidney cancer, melanoma, and thyroid cancer. The incidence of metastatic brain cancer is five times that of primary brain cancer, and the three most common metastatic cancers are lung cancer (20-56% of patients), breast cancer (5-20%), and melanoma (7-16%). Once the tumor has metastasized to the brain, surgery and radiation therapy are not particularly effective, and patient survival rates drop sharply (median overall survival is 6 months). Systemic chemotherapy is a treatment option for metastatic brain cancer, but due to BBB (especially BBTB), the efficacy of traditional chemotherapy agents is limited. To a large extent, addressing the BBB, especially BBTB, will be more important than considering whether brain tumor cells have inherent resistance to it, as BBB / BBTB prevents the entry of most chemotherapy agents. []

[0025] The blood-brain barrier (BBB) ​​is a crucial physiological barrier in the central nervous system, restricting the movement of ions and molecules from the circulating blood to the brain and protecting it from pathogens and toxins. However, the BBB also presents challenges for treating brain diseases, as most drugs are blocked by it. For the treatment of brain cancer, the problem of crossing the BBTB must be specifically considered. Existing methods for overcoming the BBB, especially the BBTB, remain limited. For example, multifunctional nanoparticles with smaller sizes and functionalized surfaces could be considered an option for crossing the BBB, especially the BBTB; however, the impact of these different characteristics of nanoparticles on modulating BBB, especially BBTB, penetration remains unclear.

[0026] Surprisingly, the inventors have discovered that MSNs with specific characteristics can effectively deliver chemotherapeutic agents to major tumors and peritumoral regions of the brain. For the use of MSNs across the brain border (BBB), especially the brain tumor (BBTB), and for the treatment of brain tumors or CNS diseases, fine control over the particle size (TEM and DLS) and surface properties (charge, functional groups, etc.) of the nanoparticles becomes crucial. In this invention, the inventors disclose MSNs with specific in-pore surface modifications and optimized particle surface modifications, exhibiting excellent loading of taxane-based chemotherapeutic agents, such as PTX, DTX, and CTX, good dispersibility under buffered or physiological conditions, and good stability under storage or physiological conditions, for use in the penetration of the BBB (especially the BBTB), treatment of brain cancer, and metastatic brain cancer. Furthermore, drug-loaded MSNs can exhibit unique anti-cell migration activity for the prevention, inhibition, or suppression of cancer metastasis, providing a new remedy for the treatment of metastatic brain cancer. In one specific embodiment, drug-loaded MSNs can be used for the prevention or treatment of brain cancer or metastatic brain cancer. In one specific embodiment, the drug-loaded MSN can be used to prevent or treat a single form of brain cancer, a single form of metastatic brain cancer, multiple forms of brain cancer, multiple forms of metastatic brain cancer, or any combination thereof. In one specific embodiment, the drug-loaded MSN can be used to prevent or treat a single form of metastatic brain cancer. In one specific embodiment, the drug-loaded MSN can be used to prevent or treat multiple forms of brain cancer. In one specific embodiment, the drug-loaded MSN can be used to prevent or treat multiple forms of metastatic brain cancer. In one specific embodiment, the drug-loaded MSN can be used to prevent or treat multiple forms of brain cancer, multiple forms of metastatic brain cancer, or combinations thereof. In one or more specific embodiments, the drug-loaded MSN can be used to prepare a medicament for the prevention or treatment of one or more of the aforementioned conditions. []

[0027] In one specific embodiment, the brain cancer is resistant to existing drugs, as indicated, for example, in information released by the National Cancer Institute, such as the 2021 website page "Drugs Approved for Brain Tumors". In one specific embodiment, the brain cancer is resistant to drugs selected from the group consisting of: temozolomide (TMZ), bevacizumab, bezutifan, carmustine, everolimus, lomustine, and naxitamab-gqgk. [] [Taxane-based chemotherapy drugs] [(taxane-based chemotherapeutic drugs)] [;] Paclitaxel [(PTX)] [、] [Dorseyat] [(DTX)] [and Cabatha] [(CTX)]

[0028] As discussed in this article, some patients with brain cancer may not be effectively treated with existing drugs (such as TMZ) because the rapid development of drug resistance often limits the clinical usefulness of existing drugs. PTX, DTX, and CTX are effective against glioma cells in vitro, but have shown little or no activity in clinical trials. To address the problems mentioned above, the inventors propose three potential drugs for the treatment of brain cancer: PTX, DTX, and CTX.

[0029] The commonly used chemotherapy drug PTX is approved for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and AIDS-related Kaposi sarcoma, but not for the treatment of brain cancer. PTX is a substrate of the multidrug resistance protein P-glycoprotein (P-gp), which is abundantly expressed in certain cancer cells and brain endothelial cells and acts as an efflux pump to prevent drug accumulation in tumors or the brain. Inefficient penetration and accumulation of PTX in brain tumors have resulted in no or limited efficacy in clinical trials for recurrent malignant glioblastoma. Docetaxel is approved for the treatment of breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, and head and neck cancer, but not for the treatment of brain cancer.

[0030] Furthermore, although DTX was found to effectively inhibit the growth of glioma cells in vitro, it exhibited poor intrinsic blood-brain tumor barrier (BBTB) penetration and off-target cytotoxicity, which led to unsuccessful or significantly limited success in the treatment of recurrent malignant glioblastoma in clinical trials.

[0031] Therefore, there is still a need to develop technologies that can effectively and efficiently deliver PTX or DTX to treat brain tumors.

[0032] On the other hand, CTX has been approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC), but not for the treatment of brain cancer. CTX's methylation reduces its affinity for P-glycoprotein (P-gp) and it has been used to treat paclitaxel- or docetaxel-resistant cancers. Furthermore, CTX may have the potential to cross the blood-brain barrier. However, recent studies have shown that CTX has only limited efficacy in patients with TMZ-refractory glioblastoma (GBM).

[0033] Despite the findings mentioned above, current experimental results indicate that PTX and DTX are ineffective against recurrent malignant glioblastoma, and CTX has shown only limited efficacy. However, they still hold potential for treating brain cancer if the challenges of crossing the blood-brain barrier (BBB) ​​or blood-tumor barrier (BBTB) can be overcome. PTX, DTX, and CTX have poor water solubility, and the addition of surfactants (such as polyoxyethylene castor oil (Cremophor EL) and polysorbate 80) to their formulations has been linked to various systemic adverse reactions (such as hypersensitivity, non-allergic severe anaphylaxis, and rash). Therefore, an inconvenient multi-step dilution process is required before use. [Mesoporous silicon dioxide nanoparticles loaded with taxane-based chemotherapeutic agents] (MSN)

[0034] Publicly available information on loading drugs, particularly taxane-based chemotherapeutic agents, onto MSNs or other nanodelivery systems for the treatment of brain cancer is limited. Several intravenously injectable nanoformulations of PTX, DTX, and CTX have been developed for the treatment of brain cancer and have shown varying degrees of effectiveness in animal studies. For example, polymeric microcells / nanoparticles (e.g., dextran-based), PLGA-coated MSNs, and lipid-coated MSNs loaded with PTX, as well as polymeric microcells / nanoparticles (e.g., PLA-PEG, PLGA-PEG nanoparticles), solid lipid nanoparticles, albumin-lipid nanoparticles loaded with DTX, and polymeric nanoparticles and liposomes loaded with CTX have been used in in vivo animal models of brain tumors. However, research on taxane-based chemotherapeutic agents, including MSNs loaded with PTX, DTX, and CTX, for the treatment of brain cancer appears to be limited. As mentioned above, most nanoparticles have a hydrodynamic size (measured in aqueous or physiological media) exceeding 100 nm and may require targeting ligands to facilitate BBB / BBTB penetration. However, these nanoparticles or nanoformulations may present issues that affect efficacy. In particular, particles with larger hydrodynamic sizes may exhibit less or no efficiency in penetrating BBB / BBTB. Furthermore, when exposed to biofluids, serum proteins may adsorb onto the outer surface of nanoparticles, forming a biomolecular layer and generating new physicochemical properties known as a "protein crown." Moreover, nanoparticles with targeting ligands on their outer surface attract proteins to their surface more readily than nanoparticles simply shielded with ordinary polyethylene glycol modification. This biomolecular layer (crown) surrounding the nanoparticles can interfere with the targeting molecules on the nanoparticle surface, potentially leading to clumping and increased opsonization, resulting in mistargeting or accidental clearance by the liver, kidneys, or spleen, thus exhibiting potential, undesirable side effects or reduced efficacy. As mentioned above, nano-formulations with large particle hydrodynamic dimensions and surface-targeted ligands may encounter obstacles, resulting in insufficient or minimal efficacy in brain cancer treatment, and may not be able to successfully transition from laboratory to in vivo or clinical applications. In fact, none of these have yet received market approval.

[0035] To prevent or address these problems, the inventors deduced that, through certain surface modifications, MSNs may have the potential to provide desired pharmacological effects, such as EPR effects and BBB (especially BBTB) penetration properties, and could be used to load taxane-based chemotherapeutic agents, such as PTX, DTX, and CTX. Specifically, mesoporous silica nanoformulations of taxane-based chemotherapeutic agents (e.g., DTX) for use in injectable suspensions (DTX@MSN) offer several benefits, including (but not limited to): (1) improved "solubility" of DTX without the use of surfactants associated with many systemic adverse reactions of currently clinically used DTX formulations; (2) reduced drug-related adverse reactions; and (3) increased BBTB penetration and tumor targeting ability of DTX. Therefore, DTX@MSN could prolong remission and survival in patients with malignant glioblastoma multiforme. Various MSNs can be used in this invention for drug loading. MSNs can also be modified with various surface functional groups to improve their biocompatibility and design for different purposes. For example, the inventors use MSNs with surface modifications of (i) organic molecules, oligomers, or polymers and (ii) positively charged molecules, oligomers, or polymers, and with end-capped hydrocarbon groups for in-pore surface modification to load taxane-based chemotherapeutic drugs, such as PTX, CTX, or DTX. In one specific embodiment, MSNs with specific surface modifications (e.g., PEGylation, positive charge modification, etc.) exhibit smaller particle sizes, particularly smaller hydrodynamic dimensions in aqueous solutions and physiological solutions, and customized surface charges, which can reduce protein corona adsorption and prolong circulation time and brain tumor targeting ability to improve the therapeutic effect of brain cancer. Accordingly, the MSNs used in the claimed invention do not have any "targeting ligands" for receptors on brain cancer or tumors or cell membranes. Targeting ligands include (but are not limited to) targeting peptides, targeting nucleotides, targeting proteins, targeting antibodies, targeting antigens, etc.

[0036] Examples of organic molecules, oligomers, or polymers (i) include, but are not limited to, short-chain poly(alkyl glycols) (PAGs), such as poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), PEG-PPG copolymers, etc. Other (organic) modifiers may be introduced to modify the properties of MSN (e.g., surface properties); examples include (but are not limited to) mercaptopropyltrimethoxysilane, chloromethyltrimethoxysilane, ethyltriethoxysilane (ETAS), N-(trimethoxysilylpropyl)ethylenediaminetriacetic acid (EDTAS), (3-trihydroxysilyl)propylmethylphosphonate (THPMP), methyltriethoxysilane (MTAS), (3-mercaptopropyl)trimethoxysilane (MPTMS), zwitterionic silanes, etc.

[0037] Examples of positively charged molecules, oligomers, or polymers (ii) include (but are not limited to) polyethyleneimine (PEI); alkoxysilane-terminated (poly)alkylamines, such as N-[3-(trimethoxysilyl)propyl]-N,N,N-trimethylammonium chloride (TA), N-[3-(trimethoxysilyl)propyl]ethylenediamine (EDPTMS), N1-(3-trimethoxysilylpropyl)diethylenetriamine, etc.; organic-alkoxysilanes, such as 3-aminopropyltrimethoxysilane (APTMS), 3-aminopropyltriethoxysilane, etc.

[0038] In some cases, it is necessary to use positively charged molecules, oligomers, or polymers (ii) shorter than the organic molecules, oligomers, or polymers (i) in the preparation of surface modifications, which are believed to reduce non-target, non-specific binding.

[0039] Examples of terminal hydrocarbon moieties include, but are not limited to, terminal aromatic moieties, terminal (cyclic)aliphatic moieties, or combinations thereof. The term "terminal" means that the hydrocarbon moieties are directly attached to the silicon atoms of the silicon dioxide nanoparticles. In some embodiments, the terminal aromatic moieties are substituted with lower alkyl groups or halogens. In another embodiment, the terminal aromatic moieties are derived from trimethoxyphenylsilane (TMPS). In some embodiments, the terminal (cyclic)aliphatic moieties comprise (cyclic)alkyl, (cyclic)alkenyl, or combinations thereof, which may optionally be substituted with lower alkyl groups or halogens. In one specific embodiment, the terminal aliphatic portion is derived from a long-chain alkylsilane having 4 to 18 carbon atoms, including but not limited to butyltrimethoxysilane, butyltriethoxysilane, hexyltrimethoxysilane, hexyltriethoxysilane, octyltrimethoxysilane, octyltriethoxysilane, isooctyltrimethoxysilane, isooctyltriethoxysilane, decyltrimethoxysilane, decyltriethoxysilane, dodecyltrimethoxysilane, dodecyltriethoxysilane, tetradecyltrimethoxysilane, tetradecyltriethoxysilane, hexadecyltrimethoxysilane, hexadecyltriethoxysilane, octadecyltrimethoxysilane, and octadecyltriethoxysilane, preferably trimethoxy C6-8 alkylsilane.

[0040] The inventors have discovered that certain problems should be better addressed when loading taxane-based chemotherapeutic agents (e.g., PTX, CTX, or DTX) onto MSNs. For example, if the degree of surface modification mentioned above (i) and (ii) is too high, the loading efficiency will be severely affected. Another challenge is the suspendability and stability of the nanoparticles with terminal hydrocarbon moieties modified within the pores. The inventors then unexpectedly discovered that the molar ratio of (i) to (ii) of MSNs with surface modifications mentioned above (i) and (ii) is within the range of 60:1 to 4:1, for example, 55:1 to 4.5:1, 50:1 to 5:1, 45:1 to 5.5:1, 40:1 to 5.5:1, 35:1 to 5.5:1, 30:1 to 5.5:1, 25:1 to 5.5:1. Mohr ratios of 0.5:1, 20:1 to 5.5:1, 15:1 to 5.5:1, 12.5:1 to 4.5:1, 10:1 to 5:1, 8.5:1 to 5.5:1, 7.5:1 to 6.5:1, or about 7:1, or any numerical range consisting of the above endpoints, such as 55:1 to 7:1, 20:1 to 6.5:1, 45:1 to 7:1, etc., can greatly improve the problem. The molar ratios of (i) and (ii) can be determined by elemental analysis or by the reagents used to prepare MSN. In addition, the inventors have found that the amount of the terminal hydrocarbon moiety (on the pore surface) should be large enough to improve the loading efficiency of taxane-based chemotherapeutic agents (e.g., PTX, DTX, or CTX). In one specific embodiment, pore surface modification can be achieved by using silane without a terminal hydrocarbon moiety and silane with at least one terminal hydrocarbon moiety, wherein the terminal hydrocarbon moiety is derived from silane with at least one terminal hydrocarbon moiety. In one specific embodiment, the amount of terminal hydrocarbon moiety used to prepare MSN, expressed as the molar ratio of silane without a terminal hydrocarbon moiety to silane with at least one terminal hydrocarbon moiety, is at least 50:1, or at least 40:1, at least 35:1, at least 30:1, at least 25:1, at least 20:1, at least 15:1, at least 10:1, at least 5:1, or any numerical range consisting of the aforementioned endpoints, such as 5:1 to 50:1, 15:1 to 50:1, 20:1 to 40:1, etc. In one specific embodiment, the number of silanes with at least one terminal hydrocarbon moiety per particle can be calculated and / or measured.

[0041] In one particular embodiment, when used to load taxane-based chemotherapeutic drugs (e.g., PTX, CTX, or DTX), the inventors have found that MSNs can be modified with (i) organic molecules, oligomers, or polymers for external surface modification and with terminal hydrocarbon groups for internal pore surface modification, but not with (ii) positively charged molecules, oligomers, or polymers for external surface modification, and the drug-loaded MSNs can still exhibit the desired properties.

[0042] In one specific embodiment, the average particle size of the mesoporous silica nanoparticles of this disclosure, measured by TEM, is 60 nm or less, 50 nm or less, 40 nm or less, 30 nm or less, or 20 nm or less. In another specific embodiment, the pore size of the mesoporous silica nanoparticles of this disclosure is 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, 25 nm or less, 20 nm or less, 15 nm or less, 10 nm or less, 5 nm or less, or 3 nm or less, or any numerical range consisting of the aforementioned endpoints, such as 3 nm to 50 nm, 5 nm to 35 nm, 10 nm to 45 nm, etc. In one specific embodiment, the average dynamic light scattering particle size of the mesoporous silica nanoparticles of this disclosure, measured by dynamic light scattering in phosphate-buffered saline (PBS), is 60 nm or less, 50 nm or less, 40 nm or less, or 30 nm or less. Without being bound by theory, the average DLS size of (drug-loaded) mesoporous silica nanoparticles of 60 nm or smaller in PBS would facilitate intravenous administration of nanoformulations and penetration of BBB / BBTB.

[0043] In some specific embodiments, the zeta potential of the MSN (at pH 7.4) can be within a reasonable range of values, such as -22 to +25 mV, -20 to +20 mV, -15 to +15 mV, or -10 to +10 mV, or the endpoints mentioned herein, for example, -15 to +20 mV, -10 to +25 mV, -15 to +10 mV, etc. In one specific embodiment, the BET surface area of ​​the mesoporous silicon dioxide nanoparticles is 1000 m² / g or less, 750 m² / g or less, 500 m² / g or less, or 250 m² / g or less.

[0044] In one specific embodiment, the taxane-based chemotherapeutic agent is selected from the group consisting of: paclitaxel (PTX), cabazitaxel (CTX), and docetaxel (DTX) and any combination thereof. In one specific embodiment, the taxane-based chemotherapeutic agent is selected from the group consisting of: CTX, DTX, and combinations thereof. In one specific embodiment, the taxane-based chemotherapeutic agent is selected from the group consisting of: PTX, CTX, and combinations thereof. In one specific embodiment, the taxane-based chemotherapeutic agent is DTX. In one specific embodiment, the taxane-based chemotherapeutic agent is PTX. In one specific embodiment, the taxane-based chemotherapeutic agent is CTX.

[0045] Mesoporous silicon dioxide nanoparticles have at least one of the following characteristics: (a) Surface modification using (i) organic molecules, oligomers or polymers and (ii) positively charged molecules, oligomers or polymers, wherein the molar ratio of (i) and (ii) is in the range of 60:1 to 4:1; (b) Modification of the pore interior surface using the terminal hydrocarbon group; (c) Average particle size of 60 nm or less as measured by TEM; (d) Average dynamic light scattering particle size of 60 nm or smaller, measured by dynamic light scattering in phosphate-buffered saline (PBS); and (e) Surface modification using (i) organic molecules, oligomers or polymers.

[0046] In one specific implementation, MSN has features (a) and (b); features (e) and (b); or features (b) and (d); preferably features (a), (b) and (c); preferably features (e), (b) and (c); preferably features (a), (b) and (d); preferably features (e), (b) and (d); preferably features (b), (c) and (d); more preferably features (a), (b), (c) and (d); and even more preferably features (e), (b), (c) and (d).

[0047] MSNs loaded with taxane-based chemotherapeutic agents (e.g., PTX, CTX, or DTX) exhibiting BBB (especially BBTB) penetration capabilities will demonstrate advantages as a high-potential drug delivery system for treating brain-related cancers. All examples, components, reaction conditions, or parameters described herein are for illustrative purposes only and are not intended to limit the materials or preparation methods by the exemplary embodiments described herein.

[0048] Mesoporous silica nanoparticles (MSNs) possess a well-defined structure and a high density of surface silanol groups, which can be modified with a wide range of organic functional groups. MSNs of different sizes were prepared using an amine-base catalytic method. The particle size was controlled by adjusting the amine concentration, amount, and concentration of the silane source, as well as the reaction temperature.

[0049] In order to achieve the desired characteristics (e.g., loading amount, dispersibility, and stability) of MSNs for loading taxane-based chemotherapeutic drugs (e.g., PTX, DTX, or CTX), the inventors conducted important experiments to modify the synthesis procedure of MSNs, including (but not limited to) (1) introducing the concept of sequential addition of silane source and internal surface modifier; specifically, introducing the internal surface modifier before adding the silane source; (2) adjusting the ratio and amount of silane source / internal surface modifier (internal surface modification); (3) adjusting the ratio and amount of (i) organic molecules, oligomers or polymers and (ii) positively charged molecules (external surface modification); and (4) adjusting hydrothermal conditions, including temperature, heating time, etc.

[0050] Without being bound by theory, modifications (1) and (4) can improve the structural stability and aqueous dispersibility / suspension stability of MSN; modifications (1) and (2) can increase drug loading and particle stability; and modifications (3) can improve the dispersibility of particles in aqueous solutions (especially physiological media) and reduce pore blockage caused by, for example, positively charged molecules (which can cause a decrease in drug loading).

[0051] In this disclosure, the drug can thus be loaded within the pores rather than attached to the outer surface of the MSN, resulting in no significant difference in the DLS size of the MSN before and after drug loading. In summary, this invention overcomes the unintended drawbacks of existing MSNs by providing smaller hydrodynamic dimensions, better dispersibility, and stability of the drug-loaded MSN. This is crucial for MSNs used as carriers for taxane-based chemotherapeutic drugs (e.g., PTX, DTX, and CTX), especially in the application of intravenously administered nanomedicines.

[0052] In one specific embodiment, the difference in DLS size (e.g., measured in PBS at 37°C) of the drug-loaded MSN after overnight incubation (e.g., 15 to 24 hours) will be less than 10 nm, preferably less than 5 nm.

[0053] In one state, MSNs can be prepared by a method comprising the following steps: (a) providing an alkaline solution containing a surfactant concentration sufficient to form microcells; (b) introducing a silane source into the solution; (c) introducing (i) an organic molecule, oligomer, or polymer and optionally (ii) a positively charged molecule, oligomer, or polymer into the solution; (d) hydrothermally treating the solution; (e) collecting the product; (f) removing residual surfactant from the product; and optionally (g) purifying or washing the product. In one specific embodiment, the method comprises step (b-1) as step (b), introducing a silane having a hydrocarbon moiety (silane having at least one terminal hydrocarbon moiety), followed by the introduction of a silane source, preferably step (b-1-1) sequentially introducing the silane having a hydrocarbon moiety (silane having at least one terminal hydrocarbon moiety), a first portion of the silane source, and a second portion of the silane source. In one embodiment, the method includes step (c-1) as step (c), introducing components (i) and (ii) indicated in step (c) above. In another embodiment, the method includes step (d-1), as in step (d), sequentially hydrothermally treating the solution at a first temperature during a first time period and at a second temperature during a second time period. In various specific embodiments, the method includes steps (a) to (g); steps (a), (b-1) / (b-1-1), (c) to (f); steps (a), (b-1) / (b-1-1), (c) to (g); steps (a), (b), (c-1) to (f); steps (a), (b), (c-1), (d) to (g); steps (a) to (c), (d-1), (e), (f); steps (a) to (c), (d-1), (e) to (g); steps (a), (b-1) / (b-1-1), (c-1), (d) to (f); steps (a), (b-1) / (b-1-1), ( c-1), (d) to (g); steps (a), (b-1) / (b-1-1), (c), (d-1), (e), (f); steps (a), (b-1) / (b-1-1), (c), (d-1), (e) to (g); steps (a), (b), (c-1), (d-1), (e), (f); steps (a), (b), (c-1), (d-1), (e) to (g); steps (a), (b-1) / (b-1-1), (c-1), (d-1), (e), (f); or steps (a), (b-1) / (b-1-1), (c-1), (d-1), (e) to (g).

[0054] Typically, 0.2 to 0.5 g of surfactant is dissolved in a sealed beaker at the desired temperature (45 to 65 °C) in 150 to 250 mL of an alkaline aqueous solution (e.g., ammonium hydroxide solution (0.1 to 0.25 M)). After stirring for 10 to 30 minutes, 15 to 135 μL of silane having at least one terminal hydrocarbon moiety is added to 60 to 500 μL of solvent (e.g., alcohol, such as ethanol), and stirring is continued for 20 to 60 minutes. The sealing film is then removed, and subsequently, with stirring, 150 to 750 μL of silane without a terminal hydrocarbon moiety is added to the solution in 0.8 to 3 mL of solvent (e.g., alcohol, such as ethanol), preferably with vigorous stirring. After stirring for 0.5 to 1.5 hours, another 100 to 500 μL of silane without a terminal hydrocarbon moiety is added to 0.4 to 2 mL of solvent (e.g., alcohol, such as ethanol). After 2 to 4 hours of reaction, 825 to 1700 μL of PEG-silane (silane with a PEG moiety, such as (2-[methoxy(polyvinyloxy)6-9propyl]-trimethoxysilane)) and 0 to 455 μL of positively charged molecules, oligomers, or polymers (such as TA-silane, (N-[3-(trimethoxysilyl)propyl]-N,N,N-trimethylammonium chloride)) in 2.5 to 5.4 mL of solvent (e.g., alcohol, such as ethanol) are introduced into the reactants. Optionally, another 0 to 85 μL of TEOS in 0 to 500 μL of EtOH is then added immediately. After stirring the mixture for 0.5 to 1.5 hours, it is aged at the desired temperature (e.g., 45 to 65 °C) without stirring for at least 12 hours. The solution was then sealed and placed in an oven at 65 to 75°C for 40 to 60 hours, or subjected to hydrothermal treatment at 65 to 75°C and 85 to 95°C for 20 to 28 hours each. The synthesized product was washed and collected by centrifugation or a cross-flow system. To remove surfactant from the pores of the MSN, the synthesized product was incubated in 40 to 85 mL of an acidic solvent (e.g., alcohol, such as ethanol) containing an acid (e.g., hydrochloric acid (37%)) for 0.5 to 1.5 hours, extracted at 55 to 65°C, and incubated once or several times. The product was washed and collected by centrifugation or a cross-flow system, and finally stored in ethanol, preferably 85% or higher. For the synthesis of MSN-PEG with different functional groups, different positively charged molecules, oligomers, or polymers, such as TA-silane, EDPTMS-silane, or other functional silanes, were used. In one example, the molar ratio of TEOS / octyltriethoxysilane varies from 50:1 to 5:1, for example, from 35:1 to 8:1, 30:1, 20:1, 15:1 and 10:1, and the ratio of PEG-silane / TA-silane varies from 18:1 to 4:1, for example, from 15:1, 10:1, 7:1, 4:1 and n:0 (i.e., PEG only) to provide different degrees of modification.

[0055] In one specific embodiment, the silane source comprises tetraethoxysilane (TEOS), tetramethoxysilane (TMOS), sodium silicate, or a mixture thereof. Surface modifiers can be used to adjust the properties of the MSN. In one specific embodiment, the (organic) modifier includes (but is not limited to) propyltriethoxysilane, butyltrimethoxysilane, octyltrimethoxysilane, diphenyldiethoxysilane, n-octyltriethoxysilane, mercaptopropyltrimethoxysilane, chloromethyltrimethoxysilane, isobutyltriethoxysilane, ethyltrimethoxystyrenesilane, methyltriethoxysilane, phenyltriethoxysilane (PTEOS), phenyltrimethoxysilane (PTMOS), methyltrimethoxysilane (MTMOS), ethyltriethoxysilane (ETAS), N... -(trimethoxysilylpropyl)ethylenediaminetriacetic acid (EDTAS), (3-trihydroxysilyl)propylmethylphosphonate (THPMP), methyltriethoxysilane (MTAS), (3-mercaptopropyl)trimethoxysilane (MPTMS), zwitterionic silanes, (N-[3-(trimethoxysilyl)propyl-N,N,N-trimethylammonium chloride), N-[3-(trimethoxysilyl)propyl]ethylenediamine, polyethyleneimine (PEI), alkoxysilane-terminated (poly)alkyl (poly)amines or organo-alkoxysilanes with amino groups, etc.

[0056] Examples of surfactants suitable for preparing MSN include, but are not limited to, cationic, anionic, and nonionic surfactants. Appropriate surfactants are selected based on reaction conditions such as pH, ionic strength, temperature, reactants, and products. Examples of cationic surfactants include, but are not limited to, pH-dependent primary, secondary, or tertiary amines with long-chain hydrocarbon groups, whose terminal amine groups carry a positive charge below a specific pH value, such as primary, secondary, or tertiary amines becoming positively charged at pH < 10, for example, oteninidine dihydrochloride; and permanently charged quaternary ammonium salts, such as cetrimonium bromide (CTAB), hexadecylpyridine chloride (CPC), benzylaminocabromide chloride (BAC), benzyl chloride (BZT), dimethyl di(octadecyl)ammonium chloride, and di(octadecyl)dimethylammonium bromide (DODAB). Examples of anionic surfactants include, but are not limited to, sulfates, sulfonates, and phosphates or esters; such as ammonium lauryl sulfate, sodium lauryl sulfate (sodium dodecyl sulfate, SLS, or SDS) and related alkyl ether sulfates, sodium laureth sulfate (sodium lauryl ether sulfate or SLES) and sodium myristyl ether sulfate, docusate (sodium dioctyl sulfosuccinate), perfluorooctyl sulfonate (PFOS), perfluorobutane sulfonate, alkyl aryl ether phosphates, and alkyl ether phosphates. Examples of nonionic surfactants include, but are not limited to, poly(ethylene oxide) nonylphenyl ether, polyethylene glycol sorbitan alkyl ester, polyethylene glycol alkyl ether, glucoside alkyl ether, polyethylene glycol octylphenyl ether, polyethylene glycol alkylphenyl ether, glyceryl alkyl ester, polypropylene glycol alkyl ether, block copolymers, poloxamer, cocoamide MEA, cocoamide DEA, lauryl dimethylamine oxide, or polyethoxylated animal fat amines. MSN's size

[0057] MSNs of different sizes can be prepared using an amine-base catalytic method. MSNs are prepared in a single sample under highly diluted conditions and low surfactant levels. In this disclosure, the MSNs preferably have an average diameter of less than 40 nm, as measured by TEM. The size of the MSNs can be controlled by adjusting the concentration, amount, and concentration of the alkoxysilane amine, the reaction temperature, etc. Without being bound by theory, the size of the MSN can be increased when the amine concentration is higher, and vice versa; the size of the MSN can also be increased when the amount of alkoxysilane is higher, and vice versa. In various specific embodiments, 0.14-0.5 g of CTAB is used in 150 mL of ammonium hydroxide solution, the amine concentration is in the range of 0.05 to 1.5 M, preferably 0.1 to 0.5 M, more preferably 0.1 to 0.25 M; the amount of alkoxysilane added to 150 mL of ammonium hydroxide solution is in the range of 1 mL to 5 mL, preferably 1 mL to 3 mL, more preferably 2 mL to 2.5 mL of ethanol TEOS (i.e., TEOS in ethanol, about 0.862 to 1.2 M); and the reaction temperature is in the range of 30°C to 60°C, preferably 40°C to 60°C, more preferably 50°C to 60°C; any combination of these conditions may be used as a specific embodiment of this disclosure. Additional surfactants

[0058] For the treatment of a disease, at least one additional bioactive ingredient (active agent) may be loaded onto and / or into the MSN, for example, distributed within the spaces of the MSN, on the surface of the MSN, etc. The additional bioactive ingredient can be appropriately selected based on its size and the associated symptom / disease. In some specific embodiments, the additional bioactive ingredient is co-administered with a taxane-based chemotherapeutic agent loaded onto the MSN, either before or after the administration of the taxane-based chemotherapeutic agent loaded onto the MSN. Examples of additional bioactive ingredients include (but are not limited to) everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-I0l, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, and EGFR inhibitors. TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, CdK inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, focal adhesion kinase inhibitors, Map kinase (mek) inhibitors, VEGF-inducing antibodies, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovoma b) Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, Romidesin, ADS-I00380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomes, 5'-Deoxy-5-Fluorouracil, Vincristine, Temozolomide, ZK-304709, Seliciclib; PD0325901, AZD-6244, Capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7 ... -Dihydro-4-oxo-1-H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methylsulfonylurea-piperidinemethyl)-indolyl]-quinolone, valanib, AG-013736, AVE-0005, goserelin acetate, leuprolide Acetate, triptorelinpamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetateAcetate), raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanibcanertinib dihydrochloride, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifamib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A A) FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-aspartate aminotransferase, Bacillus Calmette-Guerin.(BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, and other medications. daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide (l) Euprolide, levamisole, lomustine, dichloromethyldiethylamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin tostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanineMustard, uracilmustard, estramustine, altretamine, fluxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastatin (neovastat), BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukindiftitox, gefitinib, bortezomib, paclitaxel, cetyl alcohol polyoxyethylene ether free paclitaxel, epoxilon B Epihilone B, BMS-247550, BMS-310705, Droloxifen, 4-Hydroxytamoxifen, Pipendoxifene, ERA-923, Arzoxifene, Fulvestrane, Acolbifene, Lasofoxifene, Idoxifene, TSE-424, HMR-3339, ZK186619, Topotecan, PTK787 / ZK 222584, VX-745, PD184352, Rapamycin, 40-O-(2-hydroxyethyl) Rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wortmarmin, ZM336372, L-779,450, PEG-filgrastim, Dabepoetin epoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-aspartate aminotransferase, lenalidomide, gemtuzumab zumab), hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritgumomabtiuxetan, androgens, decitabine, hexamethasone Hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal donomycin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK cells-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylpressonin, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin α and darbepoetin α, curcumin, curcumin analogues. In one specific implementation, a taxane-based chemotherapeutic agent-loaded MSN is administered in combination with (temozolomide) TMZ, for example, TMZ is administered together with the taxane-based chemotherapeutic agent-loaded MSN, or is administered before or after the administration of the taxane-based chemotherapeutic agent-loaded MSN. BBB / BBTB Penetration Effect

[0059] The blood-brain barrier (BBB) ​​restricts the delivery of most therapeutic drugs into the brain; when focusing on treating brain cancer, crossing the blood-brain tumor barrier (BBTB) must be given special consideration. Nanoparticles can be tuned in size, shape, surface charge, and / or conjugated ligands to increase penetration through the BBB or BBTB. Nanoparticles conjugated with targeting ligands that bind to receptors on endothelial cells (such as transferrin, lactoferrin, glutathione, and low-density lipoprotein receptors) can also facilitate penetration through the BBB or BBTB. This invention provides a balance between BBB (especially BBTB) penetration effects and the loading efficiency of taxane-based chemotherapeutic agents (e.g., PTX, CTX, or DTX) to achieve optimal outcomes in the treatment of brain cancer. Inhibiting cancer metastasis to prevent brain cancer

[0060] Cancer metastasis leads to high mortality rates in patients with cancer. Furthermore, treatment becomes even more difficult if the cancer is metastatic and has spread to the brain. Therefore, this disclosure also relates to the prevention of brain cancer by intravenous administration of mesoporous silicon dioxide nanoparticles loaded with an agent of this disclosure, such as a taxane-based chemotherapeutic agent (e.g., PTX, DTX, or CTX), to an individual suffering from metastatic cancer occurring outside the brain, thereby preventing the metastatic cancer from spreading to the brain. In one specific embodiment, the metastatic cancer includes lung cancer, breast cancer, prostate cancer, colon cancer, kidney cancer, melanoma, thyroid cancer, or any combination thereof.

[0061] The following examples are provided to enable those skilled in the art to better understand the invention, but are not intended to limit the scope of the invention. [Example] [Materials, Methods, and Test Models] Transmission electron microscopy (TEM)

[0062] Transmission electron microscopy (TEM) was used to directly examine and verify the appearance of silicon dioxide nanoparticles. TEM images were taken on a Hitachi H-7100 TEM microscope operating at an accelerating voltage of 100 kV. Samples dispersed in ethanol were dropped onto a carbon-coated copper grid and air-dried for TEM observation. Dynamic light scattering (DLS) and zeta potential

[0063] Size measurements of silicon dioxide nanoparticles in different solution environments were performed using dynamic light scattering (DLS) on a Malvern Zetasizer nanoparticle ZS (Malvern, UK). The (solvated) particle size formed in the following solutions was analyzed at room temperature: H₂O and PBS buffer solution (pH 7.4). The surface charge (zeta potential) of silicon dioxide nanoparticles at a particle concentration of 0.1 mg / mL in PBS (0.01×, pH 7.4) was measured using the Malvern Zetasizer nanoparticle ZS. Pyrolysis gravimetric analysis and elemental analysis

[0064] Pyrolysis gravimetric analysis (TGA) was performed from 40 °C to 800 °C on a thermal analyzer with a heating rate of 10 °C min⁻¹ and an air purging of 40 mL min⁻¹. The mass percentages of carbon, nitrogen, oxygen, and hydrogen in the silicon dioxide nanoparticles were determined by an elemental analyzer (elementar Vario EL cubic type for NCSH, Germany). Multiphoton fluorescence microscopy

[0065] Multiphoton microscopy (Olympus FVMPE-RS) was used to observe the distribution of fluorescein-labeled MSNs in brain tissue regions and cerebral blood vessels within brain tumor regions of U87 orthotopic xenograft tumor mice. Mice were anesthetized for craniotomy. Images of the particle distribution were captured from the brain surface (i.e., at a depth of approximately 150 μm) using a two-photon microscope at an excitation wavelength of 850 nm and a water immersion objective. U87 Glioma Animal Model

[0066] U87-LUC glioma cells were cultured at 37°C in a humidified 5% CO2 atmosphere in minimum essential medium (MEM) supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin (Invitrogen) or in Durbecco's Modified Eagle Medium (DMEM). Cells were collected by trypsin digestion, washed once with phosphate-buffered saline (PBS), and resuspended (1 × 10⁵ cells / μL; 3 × 10⁵ cells / 3 μL) in MEM or PBS before being implanted into the striatum of mice. Pathogen-free male NU / NU mice (5 to 7 weeks old) or Balb / c nude mice (5 to 7 weeks old, male) were purchased from Lesco Biotechnology Co., Ltd. Mice were housed in a controlled environment, and all procedures were performed according to laboratory animal care guidelines. For implantation of U87-LUC tumor cells, animals were anesthetized with 2% isoflurane gas or a mixture of Zoltil (20-40 mg / kg) and Xylazine (5-10 mg / kg) and fixed in a stereotactic frame. A sagittal incision was made in the skin covering the skullcap, and a hole was made 1.5 mm anterior to the exposed skull and 2 mm lateral to the anterior fontanelle using a 23G needle. Five or three microliters of U87-LUC glioma cell suspension were injected at a depth of 2 mm from the brain surface. The injection was performed over 3 minutes, and the needle was withdrawn over an additional 2 minutes. Brain tumor growth was optionally monitored by IVIS and MRI. TMZ-resistant glioma animal model

[0067] TMZ-resistant glioma cells (U87MG-R) were cultured at 37°C in a humidified 5% CO2 atmosphere in DMEM supplemented with 10% fetal bovine serum and 100 μg / mL penicillin / streptomycin. NOD-SCID male mice (8 weeks old) were purchased from Lesco Biotechnology Co., Ltd. For intracranial transplantation, experimental procedures were performed under sterile conditions. For TMZ-resistant glioblastoma transplantation, a cranial burr hole was made in the right frontal lobe. Cells (2 × 10⁵ cells or 5 μL of TMZ-resistant glioma cell suspension (U87MG-R, 6 × 10⁵ cells / 5 μL) were injected into the cortex to a depth of 3 mm using a stereotactic guided, microprocessor-controlled single injector (Harvard Apparatus, Holliston, MA, USA). [Example] [1]

[0068] Mesoporous silica nanoparticles modified with TEOS and octyltriethoxysilane (C8-silane) in different ratios on the sidewalls of the pores were prepared, as well as mesoporous silica nanoparticles modified with PEG and functional groups in different ratios on the surface of the nanoparticles.

[0069] Mesoporous silica nanoparticles (MSNs) possess a well-defined structure and a high density of surface silanol groups, which can be modified with a wide range of organic functional groups. MSNs of different sizes were prepared using an amine-base catalytic method under highly diluted and low surfactant conditions. The particle size was controlled by adjusting the amine concentration, the amount of TEOS added, and the reaction temperature. TA silane (N-[3-(trimethoxysilyl)propyl]-N,N,N-trimethylammonium chloride) was used as a charge modifier in this example to provide positively charged groups on the MSN surface, and octyltriethoxysilane was used as an internal surface modifier to provide aliphatic groups on the pore inner surface of the MSN. Typically, 0.29 to 0.49 g of CTAB was dissolved in 150 to 250 mL of ammonium hydroxide solution (0.1–0.25 M) in a sealed beaker at the desired temperature (50–60 °C). After stirring for 15 minutes, add 15.6–130.5 μL of the terminal hydrocarbon moiety (octyltriethoxysilane) and 60–500 (e.g., 200) μL of ethanol, and stir for 30 minutes. Then, remove the sealing film, and subsequently add 150–750 μL of TEOS in 0.8–3.0 mL of ethanol to the solution with vigorous stirring. After stirring for 1 hour, add an additional 100–500 μL of TEOS in 0.4–2.0 (e.g., 0.6–1.3) mL of ethanol. After reacting for 3 hours, PEG-silane (2-[methoxy(polyvinyloxy)6-9propyl]-trimethoxysilane) (850 to 1700 μL, e.g., 1000 μL) in 2.6 to 5.4 mL (e.g., 3.2 mL) of ethanol and TA-silane (N-[3-(trimethoxysilyl)propyl]-N,N,N-trimethylammonium chloride) (0 to 455 μL, e.g., 155.8 μL) are introduced into the reactants. In some cases, another portion of up to 85 μL of TEOS in up to 500 μL of EtOH is added immediately. After stirring for 1 hour, the mixture is aged without stirring at the desired temperature (e.g., 50°C–60°C) for at least 12 hours until the final reaction volume is reduced to 40 to 85 mL. The solution was then sealed and placed in an oven at approximately 70°C for 40 to 48 hours, or at approximately 70°C for 18 to 24 hours followed by hydrothermal treatment at approximately 90°C for 22 to 24 hours. The synthesized product was washed and collected by centrifugation or a transverse flow system. To remove surfactant from the pores of the MSN, the synthesized product was incubated in 40 to 85 mL (e.g., 50 to 85 mL) of acidic ethanol containing 678 to 1442 μL (e.g., 848 μL) (first time) and 40 to 85 μL (e.g., 50 to 85 μL) (second time) of hydrochloric acid (37%), and extracted at 60°C for 1 hour.The washed product was collected by centrifugation or a cross-flow system and ultimately stored in more than 90% ethanol or in (pure) H₂O. For the synthesis of MSN-PEG with different functional group modifications, EDPTMS-silane or other functionalized silanes were used to replace TA-silane. To obtain different degrees of modification, the molar ratio of TEOS / octyltriethoxysilane varied from 50:1, 40:1, 30:1, 20:1, 15:1, 10:1, and 5:1, and the PEG-silane / TA-silane ratio varied from 15:1, 10:1, 7:1, 4:1, and n:0 (i.e., PEG only). Taxane-based chemotherapy drugs (docetaxel and cabazitaxel) are loaded in MSN.

[0070] C8-MSN-PEG / TA particles (approximately 1.6 g) were dispersed in 16 to 50 mL (e.g., 16 to 32 mL) of H₂O. A stock solution of DTX or CTX at a concentration of 50 mg / mL in DMSO (1.161 to 1.862 mL) was used for drug loading, and this solution was slowly added dropwise to the particle solution under vigorous stirring. After complete mixing, the mixture was further diluted with H₂O (48 to 50 mL) to reduce the DMSO concentration. To remove trace amounts of free drug aggregates, the mixture was filtered through a 0.22 μm filter. The mixture was then washed with 7 to 10 times its volume of H₂O using a transverse flow system. Finally, the product was stored in H₂O. [Reference Example] [1]

[0071] Internal surface modification of MSNs has been used to load drugs for delivery, such as anticancer agents, such as curcumin analogs. However, particles known in the art are unsuitable for delivery of taxane-based chemotherapeutic agents (e.g., paclitaxel, docetaxel, and cabazitaxel), especially for in vivo applications, due to poor drug loading efficiency, dispersibility in aqueous solutions, and stability under storage and physiological conditions. Preliminary studies by the inventors show that the dispersibility of C8-silane-introduced particles in PBS is affected by the TEOS / C8-silane ratio during synthesis. For example, particles synthesized at a TEOS:C8-silane ratio of 20:1 exhibit similar hydrodynamic dimensions (DLS) in water and PBS. However, when we attempted to increase the C8-silane ratio (to a TEOS:C8-silane ratio of 15:1) to enhance drug loading capacity, the DLS size of MSNs in PBS was twice that of MSNs in water. When we further increased the C8-silane ratio to a TEOS:C8-silane ratio of 10:1, severe particle aggregation was observed in PBS, with a DLS size of approximately 1 μm. Furthermore, after overnight incubation in PBS at 37°C, the particles exhibited unstable dispersion and aggregation and were therefore considered unstable, as evidenced by the significantly increased DLS size, implying that the particle structure or surface modification of the MSN could be degraded or destroyed. However, the inventors were also concerned that reducing the proportion of internal organic modification (in this example, C8-silane) could affect drug loading efficiency. [] [Taxane-based chemotherapy drugs] [@MSN] [,especially] [DTX@MSN] [and] [CTX@MSN] [Improvements in drug loading, dispersibility, and stability of nanoformulations] []

[0072] In order to address the problems arising from optimizing these factors (e.g., loading, dispersibility, and stability), as illustrated in Example 1, the inventors attempted to adjust the MSN synthesis, including (but not limited to) the TEOS / C8-silane ratio, hydrothermal conditions, and surface modification. In particular, to increase drug loading and particle stability, we not only increased the amount of C8-silane during synthesis to achieve a TEOS:C8-silane ratio of 15:1, but also adjusted the order of addition of TEOS and C8-silane, for example, adding C8-silane first and then TEOS; the hydrothermal treatment conditions were adjusted from about one day at 70°C to about two days at 70°C, or about one day at 70°C and another day at 90°C; to improve particle dispersibility in aqueous solutions, especially physiological solutions, and to reduce pore blockage caused by TA-silane, we increased the amount of PEG-silane and decreased the amount of TA-silane, so that the PEG-silane:TA-silane ratio varied from 2:1 to 7:1; we also conducted an example of using PEG-silane alone as an external surface modification.

[0073] With these adjustments, MSN particles exhibited good dispersibility (DLS size of MSN < 60 nm) under PBS and physiological conditions, high suspension stability (DLS size of MSN or DTX@MSN < 60 nm after overnight incubation at 37°C), high drug loading (loading efficiency of DTX and CTX > 80% or 70% respectively), and long-term stability of drug-loaded MSN. []

[0074] Comparison of the dispersion of MSN in previous studies and this disclosure: [] Table 1 C8-MSN-PEG / TA TEOS: Internal Modifier Ratio (in moles) PEG:TA ratio (in moles) DLS (d, nm) in a medium H 2O PBS Reference _MSN (a) 20:1 (C8-silane) 2:1 31.5 40.0 Reference: MSN (b) 15:1 (C8-silane) 2:1 29.8 76.2 Reference: MSN (c) 10:1 (C8-silane) 2:1 39.3 Approximately 1,000 Reference: MSN (d) 20:1 (TMPS) 2:1 36.5 43.1 Reference _MSN (e) 15:1 (TMPS) 2:1 48.9 785.1 This disclosure (1) 15:1 (C8-silane) 2:1 45.9 45.0 This disclosure (2) 15:1 (C8-silane) 4:1 42.9 42.2 NTT2_200 (This disclosure) (3)*** 15:1 (C8-silane) 7:1 44.3 43.5 NTT2_200 (This Publication) (3-1)*** 15:1 (C8-silane) 7:1 46.4 46.5 NTT2_206 (This disclosure) (4) 10:1 (C8-silane) 7:1 42.7 41.5 NTT2_200m (This disclosure) (5) 15:1 (C8-silane) ** 44.5 42.1 This disclosure (6) 20:1 (TMPS) 7:1 57.8 56.6 This disclosure (7) 15:1 (TMPS) 7:1 52.8 50.9 **(PEG-silane is used only for external surface modification) ***The synthesis conditions and reagents for different batches of NTT2_200 are the same.

[0075] Based on the data presented in Table 1, it can be found that even with a high degree of internal surface (pore surface) modification (i.e., a low TEOS:internal modifier ratio), MSNs optimized for loading taxane-based chemotherapeutic drugs can still exhibit ideal DLS sizes in PBS. []

[0076] To assess stability under application conditions, MSN with C8-silane internal modification and suitable characteristics was used for evaluation. MSNs were cultured overnight in PBS at 37°C (as an analogy to human body temperature), and their DLS size was measured before and after culture. Comparisons of MSN DLS size with PDI in previous studies and this disclosure are shown in Table 2 below. [] Table 2 [] C8-MSN-PEG / TA DLS (d, nm) / PDI in PBS Before treatment After spending the night at 37°C Reference _MSN (a-1)*** 43.6 / 0.160 55.9 / 0.206 Reference: MSN (a-2)*** 35.1 / 0.235 77.1 / 0.213 (This disclosure) (1) 45.0 / 0.126 44.9 / 0.138 (This disclosure) (2) 42.2 / 0.105 44.0 / 0.127 NTT2_200 (This disclosure) (3) 43.5 / 0.065 44.2 / 0.084 NTT2_200 (This disclosure) (3-1) 46.4 / 0.103 46.5 / 0.103 NTT2_206 (This disclosure) (4) 41.5 / 0.176 41.8 / 0.156 NTT2_200m (This disclosure) (5) 42.1 / 0.080 43.3 / 0.112 ***The different batches of reference MSN have the same synthesis conditions and reagents as reference MSN(a).

[0077] Clearly, after overnight incubation in PBS at 37°C, the DLS size of reference MSNs (a-1) and (a-2) increased significantly, possibly even exceeding 60 nm, while the DLS size of the optimized MSN remained almost unchanged. The results show that the optimized MSN remains stable under analog application conditions. MSNs with internal TMPS modification were also evaluated.

[0078] To further evaluate the suitability of the drug-loaded MSNs under application conditions, MSNs with suitable properties from Table 2 were used to load DTX, and the DTX@MSNs were incubated overnight in PBS at 37°C, while their DLS size was measured. Table 3 below shows a comparison of the DLS size and PDI of the DLS size of the DTX-loaded MSNs: Table 3. C8-MSN-PEG / TA DLS (d, nm) / PDI in PBS Before treatment After spending the night at 37°C DTX@Reference_MSN (a-3)*** 31.4 / 0.209 68.4 / 0.203 DTX@(This disclosure) (1) 43.2 / 0.097 42.9 / 0.123 DTX@(This Publication) (2) 41.5 / 0.099 42.4 / 0.111 DTX@NTT2_200 (This disclosure) (3) 43.6 / 0.075 45.0 / 0.116 DTX@NTT2_206 (This disclosure) (4) 38.4 / 0.086 39.7 / 0.091 DTX@NTT2_200m (This disclosure) (5) 44.1 / 0.078 45.3 / 0.121 ***The different batches of reference MSN have the same synthesis conditions and reagents as reference MSN(a).

[0079] Clearly, after overnight incubation in PBS at 37°C, the DLS size of the reference DTX@MSN (a-3) significantly increased, even exceeding 60 nm, while the DLS size of the present invention's DTX@MSN showed almost no change. The results demonstrate that the present invention's DTX@MSN remains stable under analog application conditions. MSNs with internal TMPS modification were also evaluated. [Example] [2]

[0080] TEM and DLS measurements were performed on MSNs loaded with DTX or CTX that were synthesized in Reference Example 1 and exhibited good dispersibility and high suspension stability. The results are shown in Table 4 below. Table 4 Average size (nm) (TEM) DLS (d, nm) / PDI in PBS Load capacity Loading efficiency DTX@MSN (This Publication) (1) 25.1 ± 4.9 43.2 / 0.097 3.47% 64.6% DTX@MSN (This Publication) (2) 26.8 ± 3.8 41.5 / 0.099 4.37% 81.4% DTX@NTT2_200 (This disclosure) (3) 30.2 ± 5.0 43.6 / 0.075 4.42% 94.9% DTX@NTT2_200 (This disclosure) (3-1) 30.4 ± 4.5 47.4 / 0.076 4.56% 86.8% DTX@NTT2_200m (This disclosure) (5) 28.1 ± 5.1 44.1 / 0.078 7.01% 81% CTX@NTT2_200 (This disclosure) (3-1) 30.4 ± 4.5 47.2 / 0.089 5.28% 89.8%

[0081] Loading capacity is represented by the weight ratio of drug to drug@MSN. Loading efficiency is represented by the weight ratio of the amount of drug loaded on the MSN to the total amount of drug used for loading. The inventors unexpectedly discovered that external surface modification can affect the loading capacity and efficiency of taxane-based chemotherapeutic agents (DTX and CTX). Specifically, the difference between the optimized MSNs (1), (2), and (3) is solely the ratio of the external surface modifier, i.e., PEG-silane:TA-silane = 2:1, 4:1, and 7:1, respectively. In the case of DTX@MSN, when the PEG / TA-silane ratio increases (i.e., the amount of positively charged modifier is lower), the loading capacity can increase by approximately 26% to 31%, and the loading efficiency can increase by approximately 26% to 47%. MSNs with internal TMPS modification were also evaluated for loading taxane-based chemotherapeutic agents. Long-term (storage) stability

[0082] The drug-loaded MSNs were stored in different media to assess long-term stability via the properties shown in Table 5: Table 5 [Stability Factors] [Analysis Methods] [property] Integrity and size TEM Morphology, particle size and size distribution Suspension / Gathering DLS Particle size in H₂O and PBS Drug loading capacity HPLC Drug loading capacity Drug degradation HPLC Total amount of drug with drug integrity in the medicine Leakage of the loaded drug HPLC Drug loading and free drug ratio

[0083] Test conditions: NTT2_200 (optimized MSN(3) in Table 1) was used to load DTX and disperse it in each medium. The storage concentration of DTX@NTT2_200 was approximately 150 mg / mL, and it was stored at 4°C for at least 3 months. The TEM size, DLS size (in H2O or PBS), and entrained DTX of DTX@NTT2_200 were measured, and the solution / dispersion state was visually assessed. The results are summarized below. During storage, the stock solution DTX concentration (i.e., the total DTX concentration in the dispersion (free DTX and DTX@MSNs (entrained DTX))) was measured as an indicator of DTX degradation. The percentage of entrained DTX was obtained by centrifuging or filtering a sample of the dispersion to separate free DTX from DTX@MSNs. Table 6 [] [Storage Media] [TEM] [size] [(nm)] [DLS] [size] [(d.nm) / PDI] [Stock solution] [DTX] [concentration] [(mg / mL)] [Smuggled in] [DTX] [Solution State] H 2O (initial) 26.0 ± 3.1 41.9 / 0.146 (in H₂O) 42.0 / 0.068 (in PBS) 6.24 ~99% clarify H 2O (3 months) 26.2 ± 3.0 41.6 / 0.152 (in H₂O) 40.6 / 0.084 (in PBS) 6.81++ ~99% clarify brine (initial) 28.5 ± 5.6 47.1 / 0.079 (in H₂O) 48.7 / 0.081 (in PBS) 6.52 ~99% clarify brine (3 months) 27.4 ± 4.9 47.0 / 0.080 (in H₂O) 48.0 / 0.103 (in PBS) 6.74++ ~99% clarify 5% Dextrose (initial) 29.6 ± 4.3 47.0 / 0.135 (in H₂O) 47.3 / 0.082 (in PBS) 6.63 ~99% clarify 5% Dextrose (3 months) 26.5 ± 5.3 46.1 / 0.151 (in H₂O) 47.1 / 0.084 (in PBS) 6.66++ ~99% clarify Citrate buffer (5mM, pH 6.5) (initial) 25.9 ± 3.8 43.4 / 0.119 (in H₂O) 43.8 / 0.111 (in PBS) 5.77 ~99% clarify Citrate buffer (5mM, pH 6.5) (3 months) 26.4 ± 3.3 42.8 / 0.109 (in H₂O) 43.3 / 0.134 (in PBS) 6.48 ++ ~99% clarify Acetate buffer (5mM, pH 4.5) (initial) 25.6 ± 3.1 43.8 / 0.140 (in H₂O) 42.3 / 0.082 (in PBS) 5.77 ~99% clarify Acetate buffer (5mM, pH 4.5) (3 months) 27.3 ± 2.7 43.4 / 0.150 (in H₂O) 42.5 / 0.101 (in PBS) 6.24++ ~99% clarify ++: The increase in DTX concentration in the stock solution may be a result of solvent evaporation.

[0084] Based on the above results, the TEM and DLS sizes of DTX@MSN did not change significantly after 3 months of storage. This may indicate that MSN retains its intact structure and surface modification and good dispersibility after long-term storage, without aggregation in the storage medium. Furthermore, almost no free DTX was observed in the dispersion after storage, and the DTX concentration in the stock solution did not decrease. This suggests that the DTX@MSN of the present invention exhibits long-term stability in various storage media, and at least no DTX release or degradation was observed. MSN with TMPS internal modification was also evaluated. Elemental analysis and pyrolysis gravimetric analysis

[0085] In the synthesis of C8-MSN-PEG / TA, C8-silane (aliphatic molecules) is used to modify the pore surface of MSN. PEG silane ((i) organic molecules, oligomers, or polymers) and TA silane ((ii) positively charged molecules, oligomers, or polymers) react at different molar ratios to adjust the PEG / TA ratio on the outer surface of the MSN. To quantify the functional groups on the C8-MSN-PEG / TA nanoparticles, the elemental composition of the C8-MSN-PEG / TA particles was measured using an elemental analyzer. The number of C8 groups (by weight, mg or g) per particle was derived from the mass percentage of carbon in the C8-MSN (particles before the introduction of surface modifiers), the number of TA groups was derived from the mass percentage of nitrogen in the C8-MSN-PEG / TA particles, and the number of PEG groups was derived from the mass percentage of carbon, which was obtained by subtracting the mass percentage of carbon contributed by the C8 groups and TA groups of C8-MSN-PEG / TA from the total mass percentage of carbon.

[0086] In addition, the total organic group mass percentage was measured by pyrolysis gravimetric analysis. The total mass percentage of C8 groups, PEG groups, and TA groups was derived from the weight loss of C8-MSN-PEG / TA from 150°C to 800°C. Based on the above analysis and calculations, the number of C8 groups, TA groups, and PEG groups in NTT2_200 are approximately 0.831, 0.094, and 0.425 (mmol / g), respectively, and the total organic mass percentage of C8 groups, TA groups, and PEG groups in C8-MSN-PEG / TA is approximately 22.15%. [Example] [3] Dose-related efficacy of docetaxel (DTX) and cabazitaxel (CTX) in the treatment of TMZ-resistant brain tumors [, , ]

[0087] To evaluate the toxicity of DTX and CTX and the efficacy of direct administration of DTX and CTX in treating TMZ-resistant brain tumors, 36 mice with TMZ-resistant brain tumors were used in the experiment and divided into six groups of six mice each; dosage details are shown in Table 7 below: Table 7 Group number dose Median survival time (days) * 1 (Control Group) 20% DMSO + 10% Tween 80 in PBS solution or PBS solution (23) / 27 [26.5] 2 (Comparison Group) PBS + TMZ (10 mg / kg) (23) / 27 [26.5] 3 TMZ (10 mg / kg) + 10 mg / kg DTX (15) / 19 4 TMZ (10 mg / kg) + 20 mg / kg DTX (11) / 15 5 TMZ (10 mg / kg) + 10 mg / kg CTX (11) / 15 6 TMZ (10 mg / kg) + 20 mg / kg CTX (8) / 12 * (Number of days after the first injection) / Number of days after tumor cell implantation

[0088] The administration frequency was twice weekly until the end of the study. Mice were administered DTX, CTX, and PBS intravenously (IV) and TMZ intraperitoneally (IP). To assess overall survival, mice were monitored until they died spontaneously or were near death.

[0089] The results showed that mice in the control and comparison groups (groups 1 and 2) survived to the end of the test period ((15) / 19, (days after the first injection) / days after tumor cell implantation). However, according to the test results of groups 3 to 6, CTX and DTX exhibited high toxicity at doses of 10 mg / kg or higher, as evidenced by significant weight loss and low survival rates in mice during the test period (all mice died before the end of the test period). Furthermore, mice in groups 3 to 6 showed signs of discomfort and decreased activity several hours after drug administration.

[0090] To further investigate the toxicity of CTX, the inventors conducted additional studies, namely groups 2-1 and 7, as detailed in Table 8 below: Table 8 Group number Animal number dose 2-1 (Comparison Group) 4 TMZ (10 mg / kg) 7 5 TMZ (10 mg / kg) + CTX (5 mg / kg)

[0091] The results showed that in comparison group 2-1, all mice survived for 30 days; however, in group 7, only one mouse survived for more than (15) / 19, ((days after the first injection) / days after tumor cell implantation). The sole surviving mouse in group 7 was continuously administered the drug at the same frequency until week 5; brain and pathological biopsies were performed on this mouse.

[0092] Given the above, direct administration of DTX at doses of 10 mg / kg or higher, or CTX at doses of 5 mg / kg or higher, may not be suitable for the treatment of brain cancer due to the high toxicity at these dose levels. [Example] [4] BBTB penetration and tumor targeting of MSN for DTX delivery

[0093] The penetration and tumor-targeting capabilities of BBTB are fundamental and crucial for altering the ineffective therapeutic activity of DTX or CTX by introducing MSN nanocomposites. In an animal model, mice with orthotopic xenograft brain tumors were intravenously injected with fluorescently labeled MSN (fluorescently labeled NTT2_200), and the distribution of particles in brain tissue regions and cerebral blood vessels in brain tumor regions was obtained using multiphoton fluorescence microscopy. Specifically, on the second day after injection, mouse brains were collected and fixed to prepare frozen sections. Sections stained with 4',6-dimethylamidine-2-phenylindole (DAPI) (blue signal) were used to observe cell nuclei to assess brain morphology and identify tumor tissue, and the distribution of rhodamine B isothiocyanate (RITC) conjugated MSNs was observed under fluorescence microscopy using a red signal. Compared with normal brain tissue, brain tumor regions show a significant accumulation of MSNs (Figure 1), indicating that MSNs can circulate in the blood vessels and accumulate and remain around the brain tumor site, thereby achieving higher efficacy and lower drug-related toxicity. [Example] [5] Dose-related efficacy of docetaxel (DTX) and DTX@MSN in the treatment of TMZ-resistant brain tumors

[0094] As noted above, resistance to TMZ often becomes a limiting factor for effective treatment. Given this, the TMZ-resistant orthotopic xenograft GBM model is a good model for validating the effectiveness of therapeutic agents. Mice with orthotopic TMZ-resistant brain tumors were intravenously injected with DTX alone and DTX in a nano-formulation (DTX@MSN, MSN type NTT2_200) on days 5, 9, 13, 26, 30, and 34. Animal weight and survival time were monitored until spontaneous death. Compared to the control group and the DTX-only group, DTX@MSN demonstrated effective tumor suppression and significantly prolonged overall survival. The high-dose DTX@MSN group showed an approximately 83.7% increase in lifespan compared to the control group, and the survival improvement with DTX@MSN was dose-dependent. In contrast, the median survival time in the DTX-only group was similar to or shorter than that in the control group due to the lower efficacy and higher toxicity of DTX alone, consistent with clinical observations. In addition, mice treated with DTX alone exhibited mobility impairment, interaction difficulties, and greater weight loss compared to mice treated with DTX@MSN due to toxicity (Figure 2).

[0095] Histological micrographs of tissue sections from brain tumors were also collected to assess tumor size after treatment (see Figure 3). Tumor size in the DTX@MSN treatment group, regardless of the dose level (5 mg / kg or 10 mg / kg), was significantly smaller than that in the DTX-only treatment group and the control group. Conversely, tumor size in the DTX-only treatment group was similar to that in the control group, indicating that DTX alone was ineffective against brain tumor growth (Figure 3). Furthermore, the expression levels of apoptosis biomarkers in brain tissue (caspase-3 and cleaved PARP apoptosis markers associated with DTX-induced cancer cell death) were positively correlated with the antitumor efficacy of DTX@MSN and DTX alone, demonstrating that DTX is delivered to brain tumors via MSN and induces cancer cell death. [Example] [6] Dose-related efficacy of docetaxel@MSN (DTX@MSN) in combination with TMZ for the treatment of TMZ-resistant brain tumors.

[0096] To evaluate the toxicity of DTX and the efficacy of direct administration of DTX loaded in mesoporous silicon dioxide nanoparticles (NTT2_200 shown in Example 1) for the treatment of TMZ-resistant brain tumors, mice with orthotopic TMZ-resistant brain tumors were used in the experiment, with one group consisting of four mice (control group) and other groups each consisting of six mice. Because the inventors recognized that dose levels of 10 mg / kg or higher may exhibit high toxicity, the dose levels used in this experiment were adjusted. Details of the dose and mean survival time are indicated in Table 9 below: Table 9 Group number dose Median survival time (days) * 1 (Control Group) 20% DMSO + 10% Tween 80 in PBS solution or PBS solution 27 [26.5] 2 (Comparison Group) PBS + TMZ (10 mg / kg) 27 [26.5] 8 TMZ (10 mg / kg) + 5 mg / kg DTX@MSN A total of six doses

[43] 9 TMZ (10 mg / kg) + 10 mg / kg DTX@MSN A total of five doses [41 [40.5]] * Number of days after tumor cell implantation [, , ]

[0097] During administration, mice in groups 8 and 9 did not exhibit decreased activity or other abnormalities, only weight loss. The median survival time (time to 50% fractional survival) in groups 8 and 9 was significantly longer than in groups 1 and 2. Specifically, mice treated with TMZ alone (group 2) had similar survival times to the control group (group 1), indicating tumor cell resistance to TMZ. The combination of DTX in the MSN nanocomposite (DTX@MSN) with TMZ significantly increased the overall survival rate in both the control group (PBS and TMZ) and the DTX + TMZ combination treatment group (Figure 4). It should be noted that TMZ plus DTX has high toxicity and may limit efficacy and cause post-treatment mobility impairment, interaction disorders, significant weight loss, and premature death in mice; therefore, it should be used with caution.

[0098] All results indicate that MSN nanocomposites, whether used alone or in combination with TMZ, can deliver DTX across the BBTB to targeted brain tumors, enabling DTX@MSN to effectively inhibit cancer cell proliferation and induce apoptosis, reduce drug-related toxicity, and significantly increase overall survival. Therefore, it has a superior effect than DTX alone in the treatment of brain cancer or cancer that has metastasized to the brain. [Example] [7] Dose-related efficacy of cabazitaxel@MSN (CTX@MSN) in combination with TMZ for the treatment of TMZ-resistant brain tumors.

[0099] To evaluate the toxicity of the CTX-TMZ combination therapy and the efficacy of intravenous administration of the CTX-TMZ combination loaded in mesoporous silicon dioxide nanoparticles (NTT2_200 shown in Example 1 of this paper) for the treatment of TMZ-resistant brain tumors, mice with orthotopic TMZ-resistant brain tumors were used in the experiment, with one group consisting of four mice (control group) and other groups each consisting of six mice. Because the inventors recognized that dose levels of 10 mg / kg or higher may exhibit high toxicity, the dose levels in this experiment were adjusted. Details of the dosage and mean survival time are indicated in Table 10 below: Table 10 Group number dose Median survival time (days) * 1 (Control Group) 20% DMSO + 10% Tween 80 in PBS solution or PBS solution 27 [26.5] 2 (Comparison Group) PBS + TMZ (10 mg / kg) 27 [26.5] 10 TMZ (10 mg / kg) + 5 mg / kg CTX@MSN A total of six doses

[40] 11 TMZ (10 mg / kg) + 10 mg / kg CTX@MSN A total of five doses 19 * Number of days after tumor cell implantation [, , ]

[0100] The combination of CTX and TMZ exhibited high toxicity at a dose of 10 mg / kg, as evidenced by significant weight loss and premature death in mice during the test. Although the combination of CTX@MSN and TMZ reduced toxicity and prolonged survival in mice compared to the CTX group, the dose of 10 mg / kg was still too high for the mice to tolerate. Reducing the dose of CTX@MSN to 5 mg / kg, the tolerable dose in mice, resulted in the efficacy of the combination of CTX@MSN and TMZ being demonstrated and survival time being prolonged (see Figure 5).

[0101] Brain biopsies (not shown) were performed on mice in groups 1–3, 5, and 8–11 to evaluate the therapeutic efficacy against brain cancer. Brains were removed after natural death and subsequently stained with hematoxylin and eosin (H&E staining). Significant tumor growth was observed in mice in groups 1 and 2. In mice in groups 3 and 5, although the mice died before the end of the testing period, the tumor size was smaller than in groups 1 and 2. On the other hand, data from mice in groups 8–11 were promising. Specifically, the tumor size in mice in groups 8–11 was significantly smaller than that in mice in groups 1 or 2, and the tumor in mice in group 11 almost disappeared (although these mice died earlier). Furthermore, tumor shrinkage was dose-dependent, as the tumor size in group 9 (TMZ (10 mg / kg) + 10 mg / kg DTX@MSN) and group 11 (TMZ (10 mg / kg) + 10 mg / kg CTX@MSN) mice was smaller than that in group 8 (TMZ (10 mg / kg) + 5 mg / kg DTX@MSN) and group 10 (TMZ (10 mg / kg) + 5 mg / kg CTX@MSN), respectively. Additionally, CTX@MSN may be more effective than DTX@MSN. [Example] [8]

[0102] A Phase I / II study of docetaxel in MSN nanoformulation in adults with and without metastatic brain cancer, including those with recurrent or refractory advanced gliomas and solid tumors. instruct

[0103] As a treatment for recurrent or refractory advanced gliomas and advanced solid tumors with or without metastatic brain cancer. Research Objective

[0104] A phase I / II, multicenter, open-label trial was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of DTX or CTX in MSN nanoformations as monotherapy or combination therapy in the treatment of advanced gliomas and advanced solid tumors with and without metastatic brain cancer. Research Design

[0105] The study comprised three phases: Phase Ia (dose escalation with monotherapy) and Phase Ib (dose escalation with combination therapy with temozolomide (TMZ)) in high-grade gliomas. In Phase II, the maximum tolerated dose of the nanoformulation recommended in Phase Ia was tested in solid tumors with and without metastatic brain cancer. Treatment duration and study completion [Ia] [Expect] []

[0106] The nanocompound was tested in an iterative, accelerated dose-escalation manner. All patients received the nanocompound intravenously on day 1 of a 14- or 21-day cycle, or on day 1 and day 22 of a 28- or 42-day cycle, until disease progression, toxicity, withdrawal of consent, or study termination. [Ib] [Expect] []

[0107] The combination of nano-formulations with TMZ was tested using dose escalation designs of 3+3, 3+4, 4+3, or 4+4.

[0108] Dosage: The nano-component was administered on day 1 of a 14- or 21-day cycle, or on day 1 and day 22 of a 28- or 42-day cycle; TMZ administration: 75 mg / m² for 42 days concurrently with lesion radiotherapy, followed by TMZ administration once daily at an initial maintenance dose of 150 mg / m² for 6 cycles on days 1-5 of a 28-day cycle.

[0109] Study End: Until disease progression, toxicity, withdrawal of consent, or study termination. [II] [Expect] []

[0110] In multiple expanded groups for each cancer type studied, the maximum tolerated dose (MTD) recommended from stage Ia was used. Monotherapy with the nanoformulations was tested at fixed doses on HGGs, mBC, mNSCL, and mCRPC to determine clinical efficacy. Dosage sequence: Day 1 of a 14-day or 21-day cycle, or Day 1 and Day 22 of a 28-day or 42-day cycle. Duration: Infusion for 1 hour, 14 or 21 days per cycle. Study completion: until disease progression, toxicity, withdrawal of consent, or study termination. Study endpoints Phase Ia and Ib endpoints: tolerability, safety, and pharmacokinetics. Phase II: Primary endpoints: PFS, OS Secondary endpoint: Quality of life Research on treatment Phase Ia: Investigational drugs: DTX in MSN nanocomposites or CTX in MSN nanocomposites Dosage levels: 4 dosage levels One treatment cycle: All patients received the nano-formulation intravenously on day 1 of a 14-day or 21-day cycle, or on days 1 and 22 of a 28-day or 42-day cycle. Subjects may continue treatment until disease progression, toxicity, withdrawal of consent, or termination of the study. Phase Ib: Investigational drugs: combinations of DTX and TMZ in nanocomposites or combinations of CTX and TMZ in nanocomposites. Dosage levels: 2 dosage levels One treatment cycle: All patients received intravenous nano-mixture on day 1 of a 14- or 21-day cycle, or on day 1 and day 22 of a 28- or 42-day cycle; TMZ administration: 75 mg / m² for 42 days concurrently with lesion radiotherapy, followed by TMZ administration once daily at an initial maintenance dose of 150 mg / m² on days 1-5 of a 28-day cycle, for a total of 6 cycles. Subjects may continue treatment until disease progression, toxicity, withdrawal of consent, or termination of the study. Phase II: Investigational drugs: DTX in MSN nanocomposites or CTX in MSN nanocomposites Dosage level: From the maximum tolerated dose (MTD) recommended for Phase Ia. One treatment cycle: Day 1 of a 14-day or 21-day cycle, or Day 1 and Day 22 of a 28-day or 42-day cycle. Control drug. None, used for 14 or 21 days / cycle, 2 treatment cycles, real-world data.

[0111] In summary, the proposed taxane-based chemotherapeutic agents @MSN (e.g., CTX@MSN and DTX@MSN) offer superior efficacy compared to existing drugs in the treatment of brain tumors and metastatic brain cancers, especially drug-resistant brain tumors, with longer survival times and fewer side effects such as decreased mobility, injection site reactions (pain, redness, or swelling), nausea, vomiting, diarrhea, muscle pain, joint pain, burning sensation, tingling, numbness, and pain in the hands, arms, feet, or legs.

[0112] The components, reaction conditions, and parameters described in the examples are for illustrative purposes only and are not intended to limit the materials or preparation methods.

[0113] Those skilled in the art will understand that changes and modifications can be made to the teachings and disclosures of this invention without departing from the spirit and scope of this application. Based on the foregoing, this application intends to cover any variations and modifications thereof, provided that such variations and modifications fall within the scope defined by the appended claims or their equivalents.

Claims

1. Use of mesoporous silicon dioxide nanoparticles loaded with a taxane-based chemotherapeutic agent for the preparation of a medicament for the prevention or treatment of brain cancer or metastatic brain cancer in an individual, wherein the medicament is administered intravenously to the individual, wherein: The taxane-based chemotherapeutic agent is selected from the group consisting of cabazitaxel and docetaxel; and the mesoporous silicon dioxide nanoparticles have the following characteristics: (a) surface modification with (i) organic molecules, oligomers or polymers and (ii) positively charged molecules, oligomers or polymers, wherein the molar ratio of (i) and (ii) is in the range of 60:1 to 4:1; (b) intrapore surface modification with terminal hydrocarbon moiety, wherein the hydrocarbon moiety contains 1 to 30 C atoms; and (d) an average dynamic light scattering particle size of 60 nm or less, measured by dynamic light scattering in phosphate buffer brine.

2. As claimed in claim 1, wherein the taxane-based chemotherapeutic agent is docetaxel.

3. As claimed in claim 1, wherein the mesoporous silica nanoparticles further have at least one of the following characteristics: (a') characteristic (a) being surface modified with (i) an organic molecule, oligomer or polymer and (ii) a positively charged molecule, oligomer or polymer, wherein the molar ratio of (i) and (ii) is in the range of 10:1 to 5:1; (b') characteristic (b) being surface modified with a terminal hydrocarbon moiety, wherein the terminal hydrocarbon moiety is derived from a long-chain alkylsilane having 4 to 18 carbon atoms; (c) an average particle size of 60 nm or less as measured by TEM; and (d') characteristic (d) an average dynamic light scattering particle size of 50 nm or less as measured by dynamic light scattering in phosphate-buffered saline.

4. As claimed in claim 3, wherein the mesoporous silicon dioxide nanoparticles have the characteristics of (a') and (b') or (b') and (d').

5. As claimed in claim 3, wherein the mesoporous silicon dioxide nanoparticles have the features of (a), (b), (c) and (d) or (a'), (b'), (c) and (d).

6. As claimed in claim 1, wherein the brain cancer is resistant to drugs selected from the group consisting of: temozolomide, bevacizumab, bezutefal, carmustine, everolimus, lomustine, and nalcitumab.

7. As claimed in claim 1, wherein the prevention of the brain cancer or metastatic brain cancer is achieved by intravenous administration of the drug loaded with the drug to an individual suffering from metastatic cancer occurring outside the brain to prevent the metastatic cancer from metastasizing to the brain.

8. As requested in paragraph 7, wherein the metastatic cancer is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, colon cancer, kidney cancer, melanoma, thyroid cancer, and any combination thereof.

9. For the purposes of claim 1, wherein (1) the organic molecule, oligomer or polymer (i) is selected from poly(ethylene glycol), poly(propylene glycol), PEG-PPG copolymers and combinations thereof, (2) the positively charged molecule, oligomer or polymer (ii) is selected from (N-[3-(trimethoxysilyl)propyl]-N,N,N-trimethylammonium chloride), N-[3-(trimethoxysilyl)propyl]ethylenediamine, polyethyleneimine, alkoxysilane-terminated (poly)alkyl(poly)amine, organic alkoxysilanes having one or more amino groups and combinations thereof, or (3) both (1) and (2).

10. As claimed in claim 11, wherein the pore surface modification is achieved by using one or more silanes without terminal hydrocarbon moieties and one or more silanes having at least one terminal hydrocarbon moieties, and the molar ratio of the one or more silanes without terminal hydrocarbon moieties to the one or more silanes having at least one terminal hydrocarbon moieties is less than 50:

1.

11. As claimed in claim 1, wherein the terminal hydrocarbon moiety is selected from the group consisting of: terminal aromatic moiety, terminal aliphatic moiety, terminal cyclic aliphatic moiety, and combinations thereof.

12. As claimed in claim 1, wherein the drug is further administered with an additional active agent.

13. A mesoporous silicon dioxide nanoparticle loaded with a taxane-based chemotherapeutic agent, wherein: The taxane-based chemotherapeutic agent is selected from the group consisting of cabazitaxel and docetaxel; and the mesoporous silicon dioxide nanoparticles have a combination of characteristics (a), (b), and (d): (a) surface modification with (i) an organic molecule, oligomer, or polymer and (ii) a positively charged molecule, oligomer, or polymer, wherein the molar ratio of (i) and (ii) is in the range of 60:1 to 4:1; (b) pore surface modification with a terminal hydrocarbon moiety, wherein the hydrocarbon moiety contains 1 to 30 C atoms; and (d) an average dynamic light scattering particle size of 60 nm or less, measured in phosphate-buffered saline.

14. The mesoporous silicon dioxide nanoparticles of claim 13, wherein the mesoporous silicon dioxide nanoparticles further have characteristic (c): an average particle size of 60 nm or less as measured by TEM.

15. The mesoporous silicon dioxide nanoparticles of claim 13, wherein the taxane-based chemotherapeutic agent is docetaxel.

16. The mesoporous silicon dioxide nanoparticles of claim 13, wherein (1) the organic molecule, oligomer or polymer (i) is selected from poly(ethylene glycol), poly(propylene glycol), PEG-PPG copolymers and combinations thereof, (2) the positively charged molecule, oligomer or polymer (ii) is selected from (N-[3-(trimethoxysilyl)propyl]-N,N,N-trimethylammonium chloride), N-[3-(trimethoxysilyl)propyl]ethylenediamine, polyethyleneimine (PEI), alkoxysilane-terminated (poly)alkyl(poly)amine, organic alkoxysilanes having one or more amino groups and combinations thereof, or (3) both (1) and (2).

17. The mesoporous silicon dioxide nanoparticles of claim 13, wherein the pore surface modification is achieved by using one or more silanes without terminal hydrocarbon moieties and one or more silanes having at least one terminal hydrocarbon moieties, and the molar ratio of the one or more silanes without terminal hydrocarbon moieties to the one or more silanes having at least one terminal hydrocarbon moieties is less than 50:

1.

18. The mesoporous silicon dioxide nanoparticles of claim 13, wherein the terminal hydrocarbon group is selected from the group consisting of: terminal aromatic groups, terminal aliphatic groups, terminal cyclic aliphatic groups, and combinations thereof.

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