Liposome based radiosensitizer cancer therapy: Potential of enzymesensitive liposomes

Liposome-encapsulated chemotherapeutics have been used in the treatment of a variety of cancers and are feasible for use as mono-therapeutics as well as for combination therapy in conjunction with other modalities. Despite widespread use of liposomal drugs in cancer patient care, insufficient drug bioavailability following accumulation in solid tumors remains one of the major obstacles limiting their clinical efficacy.
Long-circulating stimuli-responsive liposomes offer apart from increased tumor accumulation, control over the level of drug exposure from an ability to trigger the release of entrapped biomolecules. By modulating the liposomal membrane, liposomes can become sensitive towards enzymatically-driven destabilization and/or functionalization, thereby allowing control of the release of encapsulated
therapeutics within the diseased tissue upon intrinsic stimulation from tumor-associated enzymes. And may thereby improve therapeutic outcome. Two types of enzymes commonly overexpressed in solid cancers and exploited for liposomal drug delivery purposes, are secretory phospholipase A₂ (sPLA₂) and matrix metalloproteinases (MMPs).Furthermore, as platinum-based chemotherapeutic compounds are renowned for their radiosensitizing capacity, tumor-associated enzyme-sensitive liposomal platinum drugs can enhance the effect of radiotherapy (RT) specifically in the tumor tissue.In this thesis, we investigate the utility of enzyme-sensitive liposomal oxaliplatin (L-OHP) to improve inhibition of tumor growth and increase survival in tumor-bearing mice.The safety and efficacy of sPLA₂-sensitive liposomal L-OHP was assessed in sPLA₂-deficient FaDu hypopharyngeal squamous cell carcinoma and sPLA₂-expressing Colo205 colorectal adenocarcinoma. Also, the feasibility of multimodal cancer therapy employing L-OHP encapsulated in MMP-sensitive liposomes with fractionated RT was evaluated in MMP-proficient FaDu cancer xenografts.