Functionalized nanoparticle composition with 5-fluorouracil to improve anticancer efficacy

Abstract

Functionalized nanoparticle composition comprising 5-fluorouracil for enhanced anticancer activity, the composition comprising: a. 5-Fluorouracil at a quantity of 10.00% w / w, configured as an active anticancer agent; b. Poly(lactic acid-co-glycolic acid) at a quantity of 60.00% wt / w, configured to encapsulate the 5-fluorouracil and form a biodegradable nanoparticle matrix; c. Polyethylene glycol (PEG-2000) in an amount of 10.00% (w / w) configured to functionalize the surface of the nanoparticles and improve stability and bioavailability; d. Chitosan at a quantity of 5.00% (wt / wt), configured to effect surface modification and improve cellular uptake and targeting accuracy; e. Polyvinyl alcohol in an amount of 3.00% wt / wt, configured as a stabilizing and emulsifying agent during nanoparticle formation; f. Tween 80 at a concentration of 2.00% w / w, configured to improve dispersion stability and control particle size; and g. Mannitol at a quantity of 10.00% w / w, configured as a cryoprotectant to enhance stability during lyophilization and storage; the composition offering improved drug incorporation efficiency, delayed drug release, improved bioavailability, and enhanced anticancer activity compared to non-functionalized formulations of 5-fluorouracil.

Description

[0001] The present invention relates to the field of pharmaceutical compositions, in particular nanotechnology-based drug delivery systems for cancer therapy. More specifically, the invention relates to a functionalized nanoparticle composition comprising 5-fluorouracil and pharmaceutically acceptable excipients for improved therapeutic efficacy. The invention further relates to improved targeted release, bioavailability, and anticancer activity of 5-fluorouracil using surface-modified nanoparticles.

[0002] Cancer remains one of the leading causes of death worldwide, and chemotherapeutic agents such as 5-fluorouracil (5-FU) are frequently used to treat various cancers, including colorectal, breast, and gastrointestinal cancers. However, the conventional administration of 5-fluorouracil is subject to significant limitations, such as rapid systemic degradation, a short biological half-life, poor tumor selectivity, and nonspecific distribution throughout the body. These drawbacks result in reduced therapeutic efficacy and increased systemic toxicity, thus limiting the overall clinical effectiveness of 5-fluorouracil.

[0003] To overcome these limitations, various approaches have been developed, including modified formulations, prodrugs, and controlled-release systems. However, these existing delivery systems often fail to adequately protect the drug from premature degradation and do not ensure efficient accumulation at the tumor site. Furthermore, the lack of targeted delivery leads to damage to healthy tissues, resulting in undesirable side effects such as gastrointestinal toxicity, myelosuppression, and mucosal damage. Therefore, there remains an urgent need for an improved drug delivery system that can enhance the stability, bioavailability, and tumor-specific delivery of 5-fluorouracil.

[0004] Nanoparticle-based drug delivery systems have emerged as a promising strategy due to their ability to improve drug stability, enable controlled release, and enhance targeted drug delivery. However, conventional, non-functionalized nanoparticles often exhibit limited targeting accuracy and insufficient interaction with cancer cells. Accordingly, there is a need for a functionalized nanoparticle composition containing 5-fluorouracil that can improve drug delivery efficiency, enhance anticancer activity, reduce systemic toxicity, and overcome the limitations associated with conventional formulations.

[0005] One objective of this disclosure is to provide a functionalized nanoparticle composition comprising 5-fluorouracil for enhanced anticancer activity. The functionalized nanoparticles improve drug stability and therapeutic performance compared to conventional formulations.

[0006] Another objective of this disclosure is to improve the targeted delivery of 5-fluorouracil to cancerous tissue. This targeted delivery minimizes exposure to healthy tissue and reduces systemic side effects.

[0007] Another objective of this disclosure is to improve the bioavailability of 5-fluorouracil through nanoparticle-based encapsulation. The nanoparticle system protects the drug from premature degradation and extends its circulation time.

[0008] A further objective of the present disclosure is to provide a controlled and sustained release of 5-fluorouracil from the nanoparticle composition. This controlled release maintains an optimal therapeutic drug concentration over a longer period.

[0009] Another objective of this disclosure is to improve the cellular uptake of 5-fluorouracil by cancer cells. The functionalized surface enhances the interaction between nanoparticles and tumor cells, thereby improving therapeutic efficacy.

[0010] Another objective of this disclosure is to reduce the required dosage of 5-fluorouracil while maintaining or improving its therapeutic efficacy. This dosage reduction helps to minimize dose-dependent toxicity and side effects.

[0011] A further objective of the present disclosure is to improve the physicochemical stability of the nanoparticle composition during storage and administration. The functionalized nanoparticles prevent leakage and degradation of the drug.

[0012] Another objective of this disclosure is to provide a safe, effective, and efficient platform for administering cancer treatment drugs. The composition improves overall treatment outcomes and patient compliance compared to conventional drug delivery systems.

[0013] The present invention relates generally to a functionalized nanoparticle composition containing 5-fluorouracil to enhance anticancer activity and improve drug release. The invention relates in particular to biodegradable and surface-functionalized nanoparticles configured to improve the stability, bioavailability, and controlled release of the drug. The present invention further provides a pharmaceutical composition that overcomes the limitations associated with conventional 5-fluorouracil therapy, including rapid degradation, poor targeting, and systemic toxicity.

[0014] One embodiment of the present invention provides a functionalized nanoparticle composition comprising 10.00 wt% 5-fluorouracil encapsulated in 60.00 wt% poly(lactic acid-co-glycolic acid) (PLGA), forming a biodegradable polymer matrix. The composition further comprises polyethylene glycol (PEG-2000) and chitosan, configured to functionalize the nanoparticle surface, thereby enhancing stability, cellular uptake, and targeting accuracy. The nanoparticles are configured to provide a uniform particle size and improved therapeutic performance.

[0015] Another embodiment of the invention relates to the production of functionalized nanoparticles using an emulsion solvent evaporation technique. The production process includes the encapsulation of 5-fluorouracil in the polymer matrix, followed by surface functionalization and stabilization using pharmaceutically acceptable excipients, including polyvinyl alcohol, Tween 80, and mannitol. The resulting nanoparticles are further processed and lyophilized to obtain a stable pharmaceutical formulation suitable for administration.

[0016] Another embodiment of the invention relates to a nanoparticle composition with a particle size in the range of 150 nm to 180 nm, a high drug delivery efficiency in the range of 85% to 95%, and a delayed drug release of up to 48 hours. The controlled release properties improve therapeutic efficacy and reduce the dosing frequency. Furthermore, the functionalized nanoparticles exhibit improved physicochemical stability and enhanced storage properties.

[0017] Another embodiment of the invention aims to improve the efficacy of 5-fluorouracil against cancer by enhancing cellular uptake and targeted delivery. The functionalized surface of the nanoparticles improves interaction with cancer cells, resulting in increased cytotoxicity and reduced burden on healthy tissue. This targeted approach improves treatment efficacy and reduces side effects.

[0018] Another embodiment of the invention aims to provide a safe, stable, and effective pharmaceutical composition suitable for treating various types of cancer. Compared to conventional formulations, the invention offers improved bioavailability, extended circulation time, and enhanced therapeutic outcomes. The functionalized nanoparticle system provides an advanced drug delivery platform to improve cancer therapy.

[0019] The present invention relates to a functionalized nanoparticle composition containing 5-fluorouracil for improved delivery of cancer drugs. The invention provides biodegradable, polymer-based nanoparticles configured to encapsulate and protect the pharmaceutical active ingredient. The surface of the nanoparticles is functionalized with polyethylene glycol and chitosan to enhance stability, bioavailability, and cellular uptake. The composition further comprises pharmaceutically acceptable excipients to facilitate the formation, stabilization, and storage of the nanoparticles. The invention provides a controlled and targeted drug delivery system to improve the therapeutic efficacy of 5-fluorouracil in cancer treatment. EXAMPLE 1: Composition

[0020] The functionalized nanoparticle composition comprises 10.00% w / w 5-fluorouracil as the active anticancer agent. The composition further includes 60.00% w / w poly(lactic acid-co-glycolic acid) (PLGA), configured to form a biodegradable polymeric nanoparticle matrix for drug encapsulation. Additionally, 10.00 w / w polyethylene glycol (PEG-2000) is included as a surface functionalization agent to enhance stability, circulation time, and bioavailability, and 5.00 w / w chitosan is included as a surface modification and targeting agent to improve cellular uptake and therapeutic efficacy.

[0021] The composition further includes 3.00 wt% polyvinyl alcohol (PVA), configured as a surfactant and stabilizer to facilitate nanoparticle formation and prevent aggregation, and 2.00 wt% Tween 80, configured as an emulsifier to improve dispersion and control particle size. Additionally, 10.00 wt% mannitol is included as a cryoprotectant to enhance stability during lyophilization and storage. The overall composition is maintained at 100.00 wt% and forms a stable, functionalized nanoparticle system suitable for enhanced delivery of cancer drugs. EXAMPLE 2: Production

[0022] The functionalized nanoparticle composition containing 5-fluorouracil was prepared using an emulsion solvent evaporation technique. First, 60.00 wt% PLGA was dissolved in a suitable organic solvent, such as dichloromethane, under continuous magnetic stirring to obtain a clear polymer solution. Then, 10.00 wt% 5-fluorouracil was dispersed in the polymer solution under continuous stirring to form a homogeneous drug-polymer mixture. In a separate vessel, an aqueous phase was prepared by dissolving 3.00 wt% polyvinyl alcohol (PVA) and 2.00 wt% Tween 80 in distilled water under moderate stirring to obtain a homogeneous stabilizing solution.

[0023] The drug-polymer organic phase was then slowly added dropwise to the aqueous phase under high-speed homogenization to form a stable oil-in-water emulsion. The resulting emulsion was continuously stirred to allow evaporation of the organic solvent, leading to the formation of drug-loaded nanoparticles. Subsequently, 10.00 wt% polyethylene glycol (PEG-2000) and 5.00 wt% chitosan were added to the nanoparticle dispersion under continuous stirring to functionalize the nanoparticle surface and improve targeting accuracy, stability, and cellular uptake.

[0024] Finally, 10.00% w / w mannitol was added as a cryoprotectant to stabilize the nanoparticles during drying. The resulting nanoparticle suspension was centrifuged to collect the nanoparticles and then washed with distilled water to remove any unencapsulated drug and excess surfactant. The purified nanoparticles were then lyophilized to obtain a dry, free-flowing powder of functionalized nanoparticles containing 5-fluorouracil, suitable for pharmaceutical delivery and enhanced anticancer activity. EXAMPLE 3: Analysis of particle size and polydispersity index (PDI)

[0025] The particle size and polydispersity index (PDI) of the functionalized nanoparticles were determined by dynamic light scattering (DLS). Approximately 10 mg of lyophilized nanoparticles containing 5-fluorouracil were dispersed in 10 ml of distilled water to achieve a concentration of 1 mg / ml, followed by 5 minutes of ultrasonic treatment at 25 °C to ensure uniform dispersion. The sample was analyzed using a particle size analyzer at a scattering angle of 90°, at ambient pressure (1 atm) and temperature (25 ± 2 °C). The mean particle size and PDI values ​​were recorded to assess the uniformity and stability of the nanoparticle formulation.

[0026] The results show that the functionalized nanoparticles exhibited an average particle size of 162.4 ± 3.2 nm with a polydispersity index (PDI) of 0.182 ± 0.015, indicating a uniform size distribution. The narrow PDI value confirms the formation of a homogeneous and stable nanoparticle formulation suitable for drug delivery. EXAMPLE 4: Measuring the Zeta Potential

[0027] The zeta potential of the nanoparticles was measured to determine their surface charge and stability. A 10 mg sample of nanoparticles was dispersed in 10 ml of 1 mM potassium chloride solution to achieve a concentration of 1 mg / ml. The dispersion was ultrasonically treated for 5 minutes at 25 °C and transferred to a zeta potential measurement cell. The analysis was performed at 25 °C under standard atmospheric pressure using a zeta analyzer. The zeta potential values ​​were recorded in millivolts (mV) and indicate the electrostatic stability of the functionalized nanoparticle system.

[0028] The results show that the zeta potential of the functionalized nanoparticles was -32.6 ± 2.4 mV, indicating good electrostatic stability. The high negative surface charge prevents nanoparticle aggregation and improves the stability of the formulation. EXAMPLE 5: Drug Inclusion Efficiency (EE%) and Drug Loading Capacity

[0029] The inclusion efficiency of 5-fluorouracil was determined using a centrifugation method. Approximately 50 mg of nanoparticles were dispersed in 10 ml of phosphate-buffered saline (PBS, pH 7.4) and centrifuged for 30 minutes at 15,000 rpm and 4 °C. The supernatant was collected and analyzed using a UV-Vis spectrophotometer at a wavelength of 266 nm to determine the amount of free drug. The inclusion efficiency and drug loading capacity were calculated by comparing the amount of free drug with the total amount of drug initially added (10 mg 5-fluorouracil per 100 mg of composition).

[0030] The results show that the encapsulation efficiency of 5-fluorouracil in the functionalized nanoparticles was 89.3 ± 2.1%, while the drug loading capacity was 14.8 ± 1.3%.

[0031] The high encapsulation efficiency confirms the effective encapsulation of the active ingredient in the polymer matrix. EXAMPLE 6: In vitro drug release

[0032] The in vitro drug release profile was evaluated using a dialysis diffusion method. Approximately 20 mg of drug-loaded nanoparticles were suspended in 5 ml of phosphate-buffered saline (PBS, pH 7.4) and placed in a dialysis membrane (molecular weight limit 12,000 Da). The dialysis membrane was immersed in 100 ml of PBS, which was maintained at 37 ± 0.5 °C with continuous stirring at 100 rpm and atmospheric pressure. At predetermined time intervals (1, 2, 4, 8, 12, 24, and 48 hours), 5 ml of the release medium was withdrawn and replaced with fresh buffer. The amount of 5-fluorouracil released was analyzed by UV-Vis spectrophotometry at 266 nm.

[0033] The nanoparticle formulation demonstrated sustained drug release, with a release of 28.5 ± 2.0% after 4 hours and 91.7 ± 2.6% after 48 hours. These results confirm a controlled and prolonged release compared to conventional drug formulations. EXAMPLE 7: Morphological characterization (SEM analysis)

[0034] The morphology of the nanoparticles was investigated using scanning electron microscopy (SEM). A small amount (5 mg) of lyophilized nanoparticles was mounted on an aluminum stub using double-sided adhesive tape and coated with a thin layer of gold under vacuum at a pressure of 0.01 mbar and a temperature of 25 °C. The sample was analyzed under an SEM at an accelerating voltage of 10–20 kV to determine the shape, surface morphology, and structural integrity of the nanoparticles.

[0035] SEM analysis revealed that the nanoparticles had a spherical shape with a smooth surface morphology and a particle size in the range of 150-180 nm. The nanoparticles showed no aggregation, confirming their structural integrity and uniformity. EXAMPLE 8: Stability Study

[0036] The nanoparticle formulation was evaluated under various storage conditions. Approximately 100 mg of lyophilized nanoparticles were stored in sealed glass vials at 4 °C ± 2 °C (refrigerator conditions) and 25 °C ± 2 °C at 60% relative humidity under atmospheric pressure. Samples were taken at intervals of 0, 1, 2, and 3 months and evaluated for particle size, drug uptake efficiency, and physical appearance to assess the stability of the formulation.

[0037] The nanoparticles remained stable with negligible changes in particle size (162.4 nm to 168.7 nm) and encapsulation efficiency (89.3% to 87.6%) after 3 months at 4 °C and 25 °C. The formulation showed no visible aggregation or degradation, confirming its excellent stability. EXAMPLE 9: In vitro cytotoxicity study (MTT assay)

[0038] The cytotoxicity of the functionalized nanoparticles was investigated using an MTT assay in cancer cell lines. The cells were cultured in a 96-well plate with a density of 1 × 10⁻⁶ 4Cells were seeded per well and incubated for 24 hours at 37 °C, 5% CO2, and 95% relative humidity. The cells were treated with nanoparticle formulations containing 10 µg / ml of 5-fluorouracil and incubated for 24 to 48 hours. Subsequently, 20 µl of MTT reagent (5 mg / ml) was added, and the cells were incubated for 4 hours at 37 °C, followed by dissolution in dimethyl sulfoxide (DMSO). Absorbance was measured at 570 nm using a microplate reader to determine cell viability.

[0039] The results show that the functionalized nanoparticle formulation exhibited increased cytotoxicity with a cell viability of 28.4 ± 2.3%, compared to 52.7 ± 3.1% for pure 5-fluorouracil at a concentration of 10 µg / ml. These results demonstrate a significantly improved anticancer activity of the nanoparticle formulation. Examples

[0040] Functionalized nanoparticle composition comprising 5-fluorouracil for enhanced anticancer activity, the composition comprising: a. 5-Fluorouracil at a quantity of 10.00% w / w, configured as an active anticancer agent; b. Poly(lactic acid-co-glycolic acid) at a quantity of 60.00% wt / w, configured to encapsulate the 5-fluorouracil and form a biodegradable nanoparticle matrix; c. Polyethylene glycol (PEG-2000) in an amount of 10.00% (w / w) configured to functionalize the surface of the nanoparticles and improve stability and bioavailability; d. Chitosan at a quantity of 5.00% (wt / wt), configured to effect surface modification and improve cellular uptake and targeting accuracy; e. Polyvinyl alcohol in an amount of 3.00% wt / wt, configured as a stabilizing and emulsifying agent during nanoparticle formation; f. Tween 80 at a concentration of 2.00% w / w, configured to improve dispersion stability and control particle size; and g. Mannitol at a quantity of 10.00% w / w, configured as a cryoprotectant to improve stability during lyophilization and storage;

Claims

[1] Functionalized nanoparticle composition comprising 5-fluorouracil for enhanced anticancer activity, wherein the composition comprises: a. 5-Fluorouracil at a quantity of 10.00% w / w, configured as an active anticancer agent; b. Poly(lactic acid-co-glycolic acid) at a quantity of 60.00% wt / w, configured to encapsulate the 5-fluorouracil and form a biodegradable nanoparticle matrix; c. Polyethylene glycol (PEG-2000) in an amount of 10.00% (w / w) configured to functionalize the surface of the nanoparticles and improve stability and bioavailability; d. Chitosan at a quantity of 5.00% (wt / wt), configured to effect surface modification and improve cellular uptake and targeting accuracy; e. Polyvinyl alcohol in an amount of 3.00% wt / wt, configured as a stabilizing and emulsifying agent during nanoparticle formation; f. Tween 80 at a concentration of 2.00% w / w, configured to improve dispersion stability and control particle size; and g. Mannitol at a quantity of 10.00% w / w, configured as a cryoprotectant to enhance stability during lyophilization and storage; the composition offering improved drug incorporation efficiency, delayed drug release, improved bioavailability, and enhanced anticancer activity compared to non-functionalized formulations of 5-fluorouracil. [2] The functionalized nanoparticle composition according to claim 1, wherein the nanoparticles have an average particle size in the range of 150 nm to 180 nm, a polydispersity index of 0.150 to 0.250 and a zeta potential in the range of -25 mV to -40 mV, thereby providing improved stability and uniformity. [3] The functionalized nanoparticle composition according to claim 1, wherein the composition has an active ingredient deposition efficiency in the range of 85% to 95% and enables sustained release of 5-fluorouracil for up to 48 hours, thereby improving therapeutic efficacy. [4] The functionalized nanoparticle composition according to claim 1, wherein the composition is in the form of a lyophilized powder and, after reconstitution, offers improved cellular uptake and improved anticancer activity with reduced systemic toxicity compared to conventional 5-fluorouracil formulations.