Investigating Design Parameters for Combination Chemotherapeutic Liposomes

Abstract

Small-molecule drugs for cancer therapy have been hindered by short circulation times and pronounced patient toxicity. Nanoparticle-based drug delivery systems have significantly improved the safety profile of these drugs but have had less success in prolonging survival rates. The approach of many preclinical nanoparticle formulations is to switch from the delivery of a single drug to a synergistic drug combination, which would increase the therapeutic window of the formulation. However, synergism between two drugs is often optimized on immortalized tumor cell lines, and often does not apply when translated to more heterogenous patient samples. This makes nanoparticles based on synergy very difficult to translate clinically, and only one formulation (Vyxeos, liposomal daunorubicin and cytarabine) has been successful to date. In my dissertation research, I explored other design parameters besides synergy to develop a dual-encapsulated liposome formulation. I examined the in vitro characteristics of chemotherapy combinations and used these studies to design carefully considered liposomal formulations that are highly clinically relevant. I accounted for immunological responses to the liposome formulations, a factor generally neglected due to the prioritization of the cytotoxic effects of chemotherapeutic agents. My approach identified that the combination of doxorubicin and gemcitabine co-encapsulated in liposomes can significantly increase survival over clinically representative doxorubicin liposomes, as well as increase the M1/M2 macrophage ratio in the tumor immune infiltrating cells. Finally, I explored the development of an immunologically active liposome for the delivery of doxorubicin and gemcitabine by incorporating monophosphoryl lipid A, a clinically approved immune adjuvant, into the lipid bilayer. I observed increased dendritic cell activation and complete tumor regression in a portion of the treated mice. However, a tumor rechallenge study with 4T1 cells on the opposite mammary fat pad showed little difference between the treatment groups, which indicates that more immune stimulation is needed to produce a long-lasting immune response. My collaborators and I believe future nanoparticle formulations can benefit from a broader perspective on combination design, and this can better inform future development of chemotherapy and immunotherapy combinations.