Modified-Release Formulations for Cancer Therapy

Abstract

Cancer is one of the most virulent diseases in modern times that is ranked as the secondleading cause of death worldwide. The conventional and modern treatment protocols (e.g. chemotherapy and immunotherapy) for cancer still have some drawbacks that range from mild adverse effects to limited efficacy and the risk of tumor recurrence. Long-acting depots can mitigate these drawbacks and lend the current therapeutic protocols with improved efficacy and safety through their numerous advantages such as localizing the drug administration, prolonging the drug exposure, protecting the drug against degradation, conferring targeting functionality, and reducing side effects. Therefore, the utilization of long-acting depots for cancer therapy was investigated in this thesis. The first chapter describes the long-acting depots concerning their definition, historical development, advantages, and the major classes that are prevalent in the pharmaceutical market. The second and third chapters present the utilization of long-acting depots for cancer immunotherapy. The second chapter discusses the development of multivesicular liposomes (MVLs) for the localized depot delivery of ingenol-3-angelate (I3A), a protein kinase C agonist. The in vitro release study, in vitro cytotoxicity assay, and the in vivo pharmacokinetics demonstrated the potential MVLs to overcome I3A’s poor solubility, sustain drug release, and prevent the rapid clearance from the injection site. The third chapter describes the use of the ethyl oleate (EO) oil vehicle for prolonging the release of two developed kifunensine (KIF), named JDW-II-002 and JDW-II-008. These analogues act as potent inhibitors of type I mannosidase and potential agents for cancer immunotherapy. The therapeutic efficiency of the developed formulation was examined using an immunocompetent mice model of colon cancer which showed a delay in the tumor growth with JDW-II-008 treatments. The immunohistochemistry analysis demonstrated overexpression of high mannose N-glycans with all KIF treatments and an indication2 of a possible antitumor immune response. While chapter four discusses a photodynamic therapy (PDT) approach for the treatment of head and neck squamous cell carcinoma (HNSCC). In that chapter, we relied on an alternative approach to long-acting depots, in which we developed hyaluronan nanoconjugates to enhance the specific tumor cells’ uptake and retention of the photosensitizer, pyropheophorbide-a (PPa). The results demonstrated improvement in the water solubility of PPa, increase in its accumulation in HNSCC, and preservation of its photoactivity. The in vivo efficacy and survival time of the developed formulation were statistically better than conventional PDT therapy. Accordingly, we believe in the long-acting depots’ potential to substantially contribute to the pursuit of next-generation cancer therapeutics.