Development of lipid based nanoparticles for melanoma treatment
Type of Degreedissertation
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Melanoma is the most malignant skin cancer with high mortality. Currently, it can be treated multiple ways, such as chemotherapy, immunotherapy and targeted therapy. However, patients under these therapies usually have low response rates due to inefficient drug delivery and multidrug resistance. Nanoparticles are a promising technology for delivering one or two agents to the cellular level. Among these, lipid based nanoparticles attract more attention due to its easy preparation and modification, biocompatibility, enhanced permeability and retention (EPR) effects and reduced toxicity. This dissertation focuses on the lipid based nanoparticles delivery system for leukemia and melanoma treatment. We prepared micelles with an oxidized phospholipid, 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PazPC), via both electrostatic and hydrophobic interaction for delivery of Doxorubicin (DOX) and Idarubicin (IDA). In vitro uptake and cytotoxicity were evaluated on leukemia P388 and its resistant subline P388/ADR. The drug-loaded PazPC micelles enhanced drug uptake and exhibited higher cytotoxicity in both leukemia P388 and its resistance subline P388/ADR in comparison to free drugs. Both zolendronic acid and Polyinosinic acid-polycytidylic acid [poly (I:C)] showed potent anticancer activity in melanoma treatment. However, high preferential accumulation of zolendronic acid within bone and poor intracellular delivery of poly (I:C) limited their uses in chemo-immunotherapy. Cationic lipid-coated calcium phosphate nanoparticles (LCP) were developed to enable intracellular co-delivery of zoledronic acid and poly (I: C). The co-delivery system demonstrated significantly enhanced and synergistic activity both in vitro in melanoma cell line B16BL6 and in vivo in melanoma-bearing mice. Genistein, a soy flavone, is a well-known anti-oxidant and has been reported to be effective in preventing UV induced skin damage and melanoma. However, intradermal delivery of genistein is inefficient due to its low permeability as well as its low solubility. We reported microemulsions for enhanced transdermal delivery of genistein, in vitro. The optimized formulation consisted of 2% (w/w) genistein, 18% (w/w) oleic acid, 60% (w/w) cremophor EL/ethanol (5:11), and 20% (w/w) water and it exhibited small particle size and highest skin permeation rate based on various formulation factors optimization. Finally, to achieve co-delivery of Doxorubicin (DOX) and ceramide using a liposomal system in B16BL6 melanoma cell lines for synergistic cytotoxic effects, different types of ceramides (C6-ceramide, C8-ceramide and C8-glucosylceramide) and lipids (DOTAP, DPPC, DSPE and DSPC) were screened to optimize the formulation. The optimum liposome formulation provided a mean diameter 150 nm with a narrow size distribution (poly-dispersity index, 0.09) and a positive zeta potential (+34mv) with 92% DOX recovery. DOX and C8-Ceramide loaded DOTAP liposomes exhibited a significantly higher anti-tumor activity in melanoma cell line B16BL6 in comparison with liposomes made with other lipids such as DSPC, and a combination of DSPC and DSPE (P < 0.05). Co-delivery of DOX and C8-ceramide with DOTAP lipids based liposome demonstrated 9 folds higher cytotoxicity in the B16BL6 melanoma cell line as compared to DOX alone.