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Nanotechnology has emerged as a hope to deliver drugs at targeted site to obtain maximum therapeutic benefits. Lipid-polymer hybrid nanoparticles have provided the platform to deliver drugs in a controlled manner with enhanced stability and biocompatibility. LPHNPs have the dual advantages of polymeric and liposomal drug delivery system and can encapsulate both hydrophilic and hydrophobic drugs. The objective of this dissertation was to develop the lipid-chitosan hybrid nanoparticles for potential delivery of chemotherapeutic agents at tumor site to achieve maximum therapeutic benefits and decrease side effects associated with chemotherapeutic agents. Lipid-chitosan hybrid nanoparticles were prepared by using chitosan as a polymer and LIPOID S75 as a lipid using modified ionic gelation method. The prepared nanoparticles have size in range of 200-300nm with PDI values less than 0.3 and surface charge showed good stability in suspension form. The transmission electron microscopy images showed spherical nanoparticles having lipoplex like structure. All prepared nanoparticles showed high entrapment efficiency (>80%) and good drug loading. The FTIR analysis confirmed the compatibility among the excipients and XRD analysis showed no sharp peaks of cisplatin in formulation and cisplatin is converted into amorphous form inside lipid-chitosan hybrid nanoparticles system. Thermal studies using differential scanning calorimetry and thermogravimetric analysis confirmed the excellent stability of prepared hybrid nanoparticles. The in vitro release showed that controlled release of drug over prolong period of time. Kinetic modeling showed that the release pattern follows super case II transport mechanism. The physicochemical evaluation confirmed the excellent stability and controlled release profile. The therapeutic efficacy of cisplatin loaded lipid-chitosan hybrid nanoparticles was evaluated by using A2780 ovarian cell lines. The results confirmed the enhanced cytotoxicity of cisplatin loaded lipid-chitosan hybrid nanoparticles as compared to cisplatin solution. Cellular interaction and cell uptake showed 8 times greater uptake as compared to control. Further in vivo pharmacokinetic studies confirmed enhanced mean residence time of LPHNPS inside the biological system. Toxicology studies confirmed the safety profile of lipid-chitosan hybrid nanoparticles. The folic acid was conjugated with chitosan for folate targeting to achieve maximum therapeutic benefits at the tumor site. The TLC analysis confirmed the purity of conjugate and absence of free folic acid while nuclear magnetic resonance spectroscopy confirmed the successful conjugation of folic acid with chitosan. The folate-chitosan conjugate was then used to prepare nanoparticle by ionic gelation method with anionic lipids. The prepared nanoparticles have particle size in range of 200nm and low polydispersity index and surface charge of greater than +20. The folate LPHNPs showed greater than 75% encapsulation with excellent drug loading. The prepared nanoparticles are spherical in shape with lipoplex like structure having folate on the outer side of nanoparticles. In vitro release profile shows sustained release of cisplatin over a period of 48 hours. The therapeutic efficacy of folate lipid-chitosan hybrid nanoparticles was evaluated on ovarian and breast cell lines. The A2780 and SKOV3 were used as ovarian cell lines and treated with folate targeted LPHNPs and untargeted LPHNPs and cisplatin solution. The results confirmed the enhanced cytotoxic effect of folate LPHNPs as compared to untargeted LPHNPs and cisplatin solution. Similar enhanced cytotoxic effect of folate LPHNPs was observed on MCF-7 breast cancer cell lines. The cell uptake studies showed two times more uptake of folate LPHNPs are compared to untargeted LPHNPs that is due to folate receptor mediated endocytosis and leads to enhanced therapeutic efficacy. The therapeutic efficacy of folate LPHNPs was further evaluated on 3D spheroids in vivo model to check the response of nanoparticles in in vivo environment. The cell viability studies on 3D spheroids confirmed the enhanced cytotoxic effect of folate LPHNPs as compared to untargeted and much more significant cytotoxic effect as compared to cisplatin solution. The fluorescence microscopy images, and flow cytometry analysis confirmed the enhanced cellular uptake of folate LPHNPs in 3D spheroids that leads to enhanced therapeutic efficacy. In conclusion, lipid-chitosan hybrid nanoparticles are suitable platform for controlled delivery of chemotherapeutic agents. Folate targeted LPHNPs with added advantage of lipid coating is suitable for active targeting with enhanced therapeutic efficacy and minimum side effects.
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