Cationic Amphiphiles for delivering drugs to cancer cells and genetic materials to antigen presenting cells

Rahaman, Wahida (2024) Cationic Amphiphiles for delivering drugs to cancer cells and genetic materials to antigen presenting cells. PhD thesis, Indian Institute of Science Education & Research Kolkata.

Text (PhD thesis of Wahida Rahaman (17RS020)) 17RS020.pdf - Submitted Version Restricted to Repository staff only Download (15MB)

Abstract

Cancer is the second leading cause of death globally. Currently used highly cytotoxic anti-cancer drugs, in addition to killing cancer cells, often kill non-cancerous healthy cells causing adverse side effects. Efforts are now being directed on developing tumor-selective chemotherapy. Furthermore, in the still emerging field of genetic immunization for fighting both cancer and infectious diseases, plasmid DNA or mRNA encoded distinguishing tumor antigens or infectious disease-causing pathogenic antigens (genetic vaccines) are being selectively targeted to antigen presenting cells (APCs). Mannose receptor (over expressed on APCs) mediated DNA vaccine delivery to APCs has been reported in the past. However, integrin receptor (expressed on APCs) mediated DNA vaccine delivery has not yet been reported. After providing a lucid introduction of the field in Chapter I, Chapter II reports on the first-time use of integrin receptor mediated pDNA delivery to mouse macrophage cells (a widely used model APC) for use in APC-transfection based cancer immunotherapy. Chapter III embodies development of new self-assembled lipid nano-particles (LNPS) based systems for selectively delivering mRNA vaccines to APCs. Despite many prior uses of the liposomes of RGDK- & CGKRK-lipopeptides for tumor-selective delivery of anti-cancer drugs/genes, studies aimed at examining their relative biomembrane fusogenicities have not been undertaken. Chapter IV delineates this unaddressed issue. Chapter V describes first time use of 17-AAG (a commercially available potent anti-cancer drug) solubilised in self-assembled LNP formulations of pegylated RGDK- and CGKRK-lipopeptides in killing highly drug-resistant triple negative breast cancer cells (TNBCs). Understanding the structural parameters and cationic liposome-gene interactions at the molecular level remain incompletely understood in non-viral gene therapy. Chapter VI describes use of density functional theory (DFT) analysis toward deciphering the regulatory elements involved behind the priorly reported dramatic influence of linker orientation in liposomal gene delivery.

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