Pharmaceutical composition of lipid-polymer hybrid nanoparticles for the combined administration of chemotherapeutic agents and immunomodulatory agents.

Abstract

A pharmaceutical composition comprising lipid-polymer hybrid nanoparticles, wherein the composition includes the following: a polymeric core present in an amount of 20 to 45 wt. % of the total nanoparticle mass; a lipid shell present in an amount of 25 to 50 wt. % of the total nanoparticle mass; at least one chemotherapeutic agent present in an amount of 1 to 15 wt.% of the total nanoparticle mass; and at least one immunomodulatory agent present in an amount of 0.1 wt. % to 10 wt. % of the total nanoparticle mass.

Description

Technical field of the invention

[0001] The present disclosure relates to the field of pharmaceutical nanotechnology and cancer therapy, in particular a pharmaceutical composition comprising lipid-polymer hybrid nanoparticles configured for the co-administration of chemotherapeutic agents and immunomodulators. Background of the invention

[0002] Conventional cancer therapies are predominantly based on the systemic administration of chemotherapeutic agents. However, these often exhibit limited tumor specificity, rapid systemic clearance, dose-limiting toxicity, and the development of resistance. While chemotherapeutic agents are effective in inducing cytotoxic effects on rapidly dividing cancer cells, their non-selective biodistribution leads to side effects in healthy tissue, thus limiting their therapeutic efficacy. In parallel, immunotherapy has emerged as a promising approach to enhancing the antitumor immune response through immune checkpoint modulation, cytokine release, or activation of innate immune pathways. However, immunomodulatory agents alone often show only limited efficacy due to unfavorable pharmacokinetics, insufficient tumor accumulation, and immunosuppressive tumor microenvironments.

[0003] Combining chemotherapy and immunotherapy with conventional delivery systems has presented challenges such as differing solubilities, incompatible pharmacokinetic profiles, uncontrolled release, and systemic immune activation. While lipid-based carriers are biocompatible, they often exhibit limited structural stability and drug release, whereas polymeric nanoparticles, despite their mechanical robustness, can show reduced cellular uptake and limited membrane interaction. These limitations led to the development of lipid-polymer hybrid nanoparticles, which combine the mechanical strength of polymeric cores with the biological functionality of lipid shells.However, existing systems often lack precise composition control, defined mass ratios of the functional components, and reproducible combined loading with chemotherapeutic and immunomodulatory agents in clinically relevant proportions.

[0004] Therefore, there is still a need for a pharmaceutical composition that provides structurally stable lipid-polymer hybrid nanoparticles with controlled mass distribution of polymer core, lipid shell, chemotherapeutic agent and immunomodulator, thus enabling synchronized release, improved tumor targeting and optimized therapy outcomes.

[0005] Historically, the development of effective cancer therapies has relied on the systemic administration of chemotherapeutic agents designed to inhibit cell division or induce apoptosis in rapidly proliferating tumor cells. Although these substances have demonstrated clinical efficacy in a variety of malignancies, their therapeutic power is significantly limited by nonspecific biodistribution, rapid clearance from the bloodstream, poor tumor accumulation, and severe, dose-limiting toxicities that damage healthy tissue. Conventional low-molecular-weight chemotherapeutic agents often exhibit a narrow therapeutic index, necessitating careful dose adjustment and frequently compromising treatment effectiveness.Furthermore, repeated exposure to chemotherapeutic agents often leads to the development of multi-resistance mechanisms, including overexpression of efflux pumps and altered intracellular drug metabolism, which further reduces long-term treatment success.

[0006] Alongside chemotherapy, cancer immunotherapy has established itself as a promising approach that utilizes the body's own immune system to recognize and eliminate malignant cells. Immunomodulatory agents such as immune checkpoint inhibitors, cytokines, immunoadjuvants, and Toll-like receptor agonists have been shown to activate cytotoxic T lymphocytes, improve antigen presentation, and overcome tumor-induced immunosuppression. Despite these advances, immunotherapy as a sole treatment has some limitations. Many immunomodulatory agents have short systemic half-lives, are not very stable in the physiological environment, and have limited penetration into solid tumors. Furthermore, the systemic administration of immune-activating agents can cause severe immune-related side effects such as cytokine release syndrome and autoimmune toxicities, which restricts the dosage and suitability of certain patients.

[0007] Given the complementary mechanisms of action of chemotherapy and immunotherapy, combination therapies have been extensively researched. Chemotherapy can induce immunogenic cell death, increase the release of tumor antigens, and modulate the tumor microenvironment to enhance the immune response. Immunotherapy, on the other hand, can induce long-term tumor suppression and prevent relapse. However, the conventional concurrent administration of chemotherapeutic agents and immunomodulators in separate formulations presents a significant challenge. Differences in solubility, stability, pharmacokinetics, and optimal dosing regimens often lead to asynchronous drug release, suboptimal drug concentrations in tumor tissue, and unpredictable systemic exposure. These problems often negate the potential synergistic benefits of combination therapy and can increase toxicity.

[0008] To address these challenges, nanotechnology-based drug delivery systems have been intensively researched for cancer therapy. Polymer nanoparticles have been developed to encapsulate chemotherapeutic agents, thereby enabling improved drug stability, controlled release, and increased tumor accumulation through the enhanced permeability and retention (EPR) effect. Biodegradable polymers such as poly(lactic-co-glycolic acid), polycaprolactone, and polylactic acid are widely used due to their favorable safety profiles and tunable degradation kinetics. However, polymer nanoparticles often exhibit limited cellular uptake, insufficient interaction with biological membranes, and rapid opsonization, leading to clearance by the mononuclear phagocyte system.Furthermore, the encapsulation of hydrophilic or biologically sensitive immunomodulators in polymeric matrices continues to pose a technical challenge and can lead to low loading efficiency or loss of biological activity.

[0009] Lipid-based nanocarriers, including liposomes and lipid nanoparticles, are frequently used for drug delivery due to their biocompatibility, their ability to encapsulate both hydrophilic and hydrophobic drugs, and their favorable interactions with cell membranes. Liposomal formulations of chemotherapeutic agents have achieved clinical success by reducing systemic toxicity and improving pharmacokinetics. However, lipid-based systems often exhibit limited structural stability, susceptibility to drug loss during storage or in the bloodstream, and difficulties in achieving a delayed-release profile. Furthermore, pure lipid systems may lack sufficient mechanical stability to allow the simultaneous loading of multiple therapeutic agents with differing physicochemical properties.

[0010] To overcome the respective limitations of polymer- and lipid-based carriers, hybrid drug delivery systems combining polymers and lipids have been developed. Lipid-polymer hybrid nanoparticles typically consist of a polymer core, which provides mechanical stability and controlled release, surrounded by a lipid shell that enhances biocompatibility and cellular interaction. While such systems represent a promising platform for combination therapy, many existing approaches lack precise control over component composition and mass distribution. In some described systems, the relative proportions of polymer, lipid, and therapeutic agents are not precisely defined, leading to batch variability, inconsistent drug loading, and unpredictable release behavior. These shortcomings compromise scalability, reproducibility, and regulatory approval.

[0011] Another significant limitation of existing hybrid nanoparticle systems is the inadequate spatial distribution of multiple therapeutic agents within the nanoparticle structure. Often, both chemotherapeutic agents and immunomodulators are randomly distributed or confined to a single compartment, resulting in uncontrolled release kinetics and reduced therapeutic synergy. The lack of defined association relationships between therapeutic agents and specific nanoparticle components complicates the targeted management of immediate and sustained biological effects. Furthermore, surface modification strategies to improve circulation time or targeting efficiency are often employed without clear quantitative control, leading to excessive surface functionalization that can compromise nanoparticle stability or complicate fabrication.

[0012] From a formulation perspective, many existing nanoparticle-based combination therapies face challenges in manufacturing the final dosage form. Incorporating nanoparticles into injectable or infused drugs requires careful control of excipients, osmolarity, and colloidal stability. Insufficient stabilization during storage and administration can lead to aggregation, sedimentation, or loss of the therapeutic agent. Furthermore, current delivery systems and handling methods are often not optimized for nanoparticle formulations, exposing them to shear forces, temperature fluctuations, or impurities that can compromise nanoparticle integrity prior to administration.

[0013] Despite extensive research efforts, there remains a lack of standardized, compositionally defined lipid-polymer hybrid nanoparticle systems capable of reliably releasing chemotherapeutic agents and immunomodulators in controlled and clinically relevant proportions. Existing solutions often focus on feasibility studies rather than scalable, reproducible compositions for pharmaceutical development. The absence of clearly specified weight fractions for the core structural components, therapeutic agents, stabilizers, and excipients limits the ability to correlate formulation parameters with biological efficacy and clinical outcomes.

[0014] Therefore, there remains a need for a pharmaceutical composition that combines the structural advantages of polymeric cores with the biological functionality of lipid shells, while simultaneously allowing precise control of the loading of chemotherapeutic and immunomodulatory agents. Such a system should ensure synchronized release, balanced immediate and long-term effects, improved stability, and compatibility with common dosage forms and delivery systems. Addressing these challenges is crucial for advancing combination therapies against cancer toward consistent clinical application and improved treatment outcomes for patients. Summary of the invention

[0015] The present disclosure relates to a pharmaceutical composition consisting of lipid-polymer hybrid nanoparticles with a polymer core and a lipid shell. The nanoparticles are configured to simultaneously release at least one chemotherapeutic agent and at least one immunomodulator in defined weight percentages based on the total mass of the nanoparticles. The composition enables simultaneous cytotoxic and immunomodulatory effects while ensuring nanoparticle stability, controlled release, and compatibility with pharmaceutically acceptable excipients. The disclosure further relates to a device for handling and administering the pharmaceutical composition, which stores, preserves, and administers it while maintaining the integrity of the nanoparticles.

[0016] The main objective of the present invention is to provide a pharmaceutical composition of structurally stable and compositionally defined lipid-polymer hybrid nanoparticles that enables the simultaneous administration of at least one chemotherapeutic agent and at least one immunomodulator in a single nanoscale carrier system. A further objective of the invention is the controlled embedding of a polymer core and a lipid shell in predefined weight ratios to combine mechanical stability with biocompatibility, thereby improving bloodstream stability, cellular interaction, and therapeutic reliability.

[0017] A further objective of the invention is to provide a nanoparticle composition that enables precise control of the loading with chemotherapeutic agents and immunomodulators in defined weight percentages based on the total mass of the nanoparticles, thus ensuring reproducible drug ratios, predictable pharmacokinetic behavior, and consistent therapeutic outcomes. A further objective of the invention is the spatial distribution of the immunomodulators between the lipid shell and the polymer core to enable both an immediate immune response and sustained immunostimulatory effects after administration.

[0018] A further aim of the invention is to reduce the systemic toxicity and undesirable immune reactions associated with conventional chemotherapy and immunotherapy by improving the targeted delivery and controlled release of active substances from the lipid-polymer hybrid nanoparticles. A related aim is to increase the accumulation of active substances in the tumor and their intracellular release while simultaneously minimizing premature loss and degradation of the active substances during circulation.

[0019] A further objective of the invention is to provide a nanoparticle composition that is compatible with surface stabilizers, steric shielding agents, and targeted ligands in defined amounts, thereby improving colloidal stability, prolonging systemic circulation time, and enabling selective interaction with tumor-associated tissue or receptors. A further objective of the invention is to ensure that the combined therapeutic payload of chemotherapeutic agents and immunomodulators remains within a controlled range that supports a synergistic antitumor effect without compromising the integrity of the nanoparticles.

[0020] A further objective of the invention is to provide a pharmaceutical dosage form in which the lipid-polymer hybrid nanoparticles are uniformly dispersed together with pharmaceutically compatible excipients, thereby facilitating the formulation of injectable or infused dosage forms for clinical use. A further objective of the invention is to ensure the physical stability, biological activity, and therapeutic efficacy of the nanoparticle composition during storage, handling, and administration.

[0021] A further objective of the invention is to provide a device for storing, preserving, and administering the pharmaceutical composition while maintaining nanoparticle integrity and dosing accuracy. A related objective is the controlled handling and administration of the nanoparticle composition without exposing it to excessive mechanical stress, thermal fluctuations, or contamination.

[0022] Overall, the invention aims to provide a robust, reproducible and clinically transferable lipid-polymer hybrid nanoparticle composition and an associated delivery system that together overcome the limitations of existing combined cancer therapies and improve the safety, efficacy and reliability of the combined administration of chemotherapeutic agents and immunomodulators. Detailed description of the invention

[0023] Fig.Figure 1 shows a block diagram of a pharmaceutical composition comprising lipid-polymer hybrid nanoparticles. The system 100 comprises: a polymer core (102) present in an amount of 20 to 45 wt.% of the total nanoparticle mass; a lipid shell (104) present in an amount of 25 to 50 wt.% of the total nanoparticle mass; at least one chemotherapeutic agent (106) present in an amount of 1 wt.% to 15 wt.% of the total nanoparticle mass; and at least one immunomodulatory agent (108) present in an amount of 0.1 wt.% to 10 wt.% of the total nanoparticle mass.

[0024] In one embodiment, the polymer core (102) comprises a biodegradable polymer selected from poly(lactic acid-co-glycolic acid), polycaprolactone, polylactic acid or polyethylene glycol-functionalized derivatives thereof, wherein the polymer core constitutes 25 to 40 wt.% of the total nanoparticle mass.

[0025] In one embodiment, the lipid shell (104) comprises one or more phospholipids in an amount of 15 to 35 wt.% and cholesterol or a cholesterol derivative in an amount of 5 to 15 wt.% based on the total mass of the nanoparticle.

[0026] In one embodiment, the chemotherapeutic agent (106) is selected from doxorubicin, paclitaxel, docetaxel, cisplatin, carboplatin or combinations thereof, wherein the chemotherapeutic agent is present in an amount of 2 wt.% to 10 wt.% of the total nanoparticle mass.

[0027] In one embodiment, the immunomodulatory agent (108) is selected from immune checkpoint inhibitors, cytokines, Toll-like receptor agonists, immunoadjuvants or combinations thereof, wherein the immunomodulatory agent is present in an amount of 0.5 wt.% to 5 wt.% of the total nanoparticle mass.

[0028] In one embodiment, the immunomodulator (108) is associated with the lipid shell in an amount of 40 to 80 wt. % of the total immunomodulator content and with the polymer core in an amount of 20 to 60 wt. % of the total immunomodulator content.

[0029] In one embodiment, the lipid-polymer hybrid nanoparticles further comprise a surface stabilizer or a steric shielding agent present in an amount of 0.5 wt.% to 10 wt.% of the total nanoparticle mass.

[0030] In one embodiment, the surface stabilizer or steric shielding agent comprises polyethylene glycol-conjugated lipids present in an amount of 1 wt.% to 7 wt.% of the total nanoparticle mass.

[0031] In one embodiment, the lipid-polymer hybrid nanoparticles further comprise a targeting ligand present in an amount of 0.01 wt.% to 3 wt.% of the total nanoparticle mass.

[0032] In one embodiment, the total content of the chemotherapeutic agent (106) and the immunomodulator (108) is 3 to 20 wt. % of the total nanoparticle mass.

[0033] In one embodiment, the composition further comprises pharmaceutically acceptable excipients in an amount of 1 wt.% to 15 wt.% selected from buffers, isotonic agents or stabilizers.

[0034] In one embodiment, the lipid-polymer hybrid nanoparticles constitute 5 to 30 wt. % of a final pharmaceutical dosage composition.

[0035] The present invention relates to a pharmaceutical composition of lipid-polymer hybrid nanoparticles for the combined administration of chemotherapeutic agents and immunomodulators. The structure, loading ratios, and internal distribution of the components are defined according to the claims. The invention further comprises a control logic for the nanoparticle composition, the distribution of the therapeutic agent, stabilization, and dosage consistency. This ensures reproducibility and functionality throughout the entire manufacturing and administration phase.

[0036] According to the invention, the formulation process begins with the determination of the target parameters of the nanoparticle composition, including the total mass of the nanoparticles and the predefined weight fractions of the polymer core, the lipid shell, the chemotherapeutic agent, the immunomodulator, and optional surface modifiers. Initially, a proportion of 20 to 45 wt.% of the total mass of the nanoparticles is allocated to the polymer core, with a value between 25 and 40 wt.% being selected in preferred embodiments based on the desired degradation kinetics and release profile. Biodegradable polymers such as poly(lactic acid-co-glycolic acid), polycaprolactone, polylactic acid, or polyethylene glycol-functionalized derivatives are selected as core materials. The molecular weight and composition of the polymer are correlated with the desired release duration and mechanical stability.

[0037] After selecting the core parameters, the process assigns a lipid shell comprising 25 to 50 wt% of the total mass of the nanoparticles. The lipid composition is optimized by allocating phospholipids at a rate of 15 to 35 wt% and cholesterol or cholesterol derivatives at a rate of 5 to 15 wt%. The ratio of phospholipid to cholesterol is determined by correlating membrane stiffness, permeability, and stability in the bloodstream. The lipid shell is computationally modeled to uniformly envelop the polymer core, forming a continuous boundary layer that reduces surface energy and stabilizes the nanoparticle structure.

[0038] The loading of the chemotherapeutic agent is then technically determined in the range of 1 to 15 wt.% of the total mass of the nanoparticles, with preferred embodiments selecting a range between 2 and 10 wt.%. The selection of the chemotherapeutic agent, such as doxorubicin, paclitaxel, docetaxel, cisplatin, carboplatin, or combinations thereof, is based on its physicochemical compatibility with the polymer core and the therapeutic indication. The process primarily binds the chemotherapeutic agent to the polymer core matrix and models diffusion coefficients and the kinetics of polymer degradation to achieve sustained intracellular release after internalization of the nanoparticles.

[0039] The immunomodulatory agent is subsequently incorporated at a concentration of 0.1 to 10 wt% of the total mass of the nanoparticles, with concentrations between 0.5 and 5 wt% being selected in preferred embodiments. Immune checkpoint inhibitors, cytokines, Toll-like receptor agonists, immunoadjuvants, or combinations thereof serve as immunomodulatory agents. The process controls the spatial distribution of the immunomodulatory agent such that 40 to 80 wt% of the total content is bound to the lipid shell, thus enabling early activation of the immune system after administration, while 20 to 60 wt% is embedded in the polymer core to ensure sustained immune stimulation. This dual-association model is optimized by iterative simulations that correlate the timing of drug release with the enhancement of the immune response.

[0040] Surface stabilization is subsequently achieved by the targeted addition of surface stabilizers or steric shielding agents in an amount of 0.5 to 10 wt% of the total mass of the nanoparticles. In preferred embodiments, polyethylene glycol-conjugated lipids are incorporated in an amount of 1 to 7 wt% to reduce protein adsorption and uptake by macrophages. If targeted binding is required, targeting ligands are incorporated in an amount of 0.01 to 3 wt%, with the ligand density being optimized to maximize receptor-mediated binding while ensuring colloidal stability.

[0041] The system also ensures that the combined content of chemotherapeutic agent and immunomodulator is between 3 and 20 wt% of the total mass of the nanoparticles. This restriction guarantees therapeutic synergy without compromising the structural integrity of the nanoparticles or release control. After all composition restrictions have been met, the procedure validates the stability of the nanoparticles by evaluating the predicted zeta potential, hydrodynamic diameter, and drug encapsulation efficiency against predefined acceptance thresholds.

[0042] The lipid-polymer hybrid nanoparticles produced using this system are subsequently incorporated into a pharmaceutical dosage form. The process determines the nanoparticle concentration such that the lipid-polymer hybrid nanoparticles constitute 5 to 30 wt% of the finished dosage form. Pharmaceutically acceptable excipients, including buffers, isotonics, and stabilizers, are selected in amounts of 1 to 15 wt% to ensure the physiological tolerability and stability of the suspension. The excipient composition is formulated to prevent aggregation, sedimentation, or premature release of the active ingredient during storage and administration.

[0043] During administration, the system extends to dosage control within an application system designed as a pharmaceutical handling machine. This system controls storage temperature, mixing intensity, and dosing volume to ensure uniform nanoparticle dispersion and precise therapeutic release. Feedback from concentration sensors and flow controllers is processed to ensure consistency between the intended and administered nanoparticle composition, thus maintaining the therapeutic ratios defined in the instructions for use.

[0044] According to the present disclosure, the pharmaceutical composition comprises lipid-polymer hybrid nanoparticles, the polymer core of which constitutes 20 to 45 wt.% and the lipid shell of which constitutes 25 to 50 wt.% of the total mass of the nanoparticles. The polymer core consists of biodegradable polymers such as poly(lactic acid-co-glycolic acid), polycaprolactone, polylactic acid, or their polyethylene glycol-functionalized derivatives, thus ensuring mechanical stability, controlled degradation, and delayed drug release. In certain embodiments, the proportion of the polymer core to the total mass of the nanoparticles is 25 to 40 wt.% to achieve an optimal ratio between drug loading and structural integrity.

[0045] The lipid shell surrounds the polymer core and consists of one or more phospholipids in an amount of 15 to 35 wt% of the total mass of the nanoparticle, as well as cholesterol or cholesterol derivatives in an amount of 5 to 15 wt%. The lipid shell improves biocompatibility, facilitates interaction with cell membranes, and contributes to prolonged systemic circulation. The lipid-polymer interface enables the stable encapsulation of active ingredients while preventing premature release.

[0046] At least one chemotherapeutic agent is contained within the nanoparticles in an amount of 1 to 15 wt% of the total mass of the nanoparticles, particularly in an amount of 2 to 10 wt%. Suitable chemotherapeutic agents include, for example, doxorubicin, paclitaxel, docetaxel, cisplatin, carboplatin, or combinations thereof. These agents can be primarily bound to the polymer core to enable sustained intracellular release after cellular uptake.

[0047] At least one immunomodulatory agent is present in an amount of 0.1 to 10 wt% of the total mass of the nanoparticles, particularly in an amount of 0.5 to 5 wt%. The immunomodulatory agent may be an immune checkpoint inhibitor, a cytokine, a Toll-like receptor agonist, an immunoadjuvant, or a combination thereof. The immunomodulatory agent is distributed between the lipid shell and the polymer core such that 40 to 80 wt% of the total agent content is bound to the lipid shell and 20 to 60 wt% to the polymer core. This enables both an immediate immune response and sustained immune stimulation.

[0048] The lipid-polymer hybrid nanoparticles can additionally contain surface stabilizers or steric shielding agents in amounts of 0.5 to 10 wt% of the total mass of the nanoparticles, including polyethylene glycol-conjugated lipids in amounts of 1 to 7 wt%. These stabilizers reduce opsonization, prolong circulation time, and improve colloidal stability. Additionally, targeted ligands can be incorporated in amounts of 0.01 to 3 wt% to enable selective binding to tumor-associated receptors.

[0049] The total content of chemotherapeutic agent and immunomodulator ranges from 3 to 20 wt% of the total mass of the nanoparticles. The nanoparticles can be processed into a final pharmaceutical formulation in which the lipid-polymer hybrid nanoparticles constitute 5 to 30 wt%, while the remainder consists of pharmaceutically acceptable excipients such as buffers, isotonic agents, and stabilizers in an amount of 1 to 15 wt%. REFERENCES 100 A pharmaceutical composition comprising lipid-polymer hybrid nanoparticles. 102 Polymer core 104 Lipid shell 106 Chemotherapeutic agent 108 Immunomodulatory agent

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