Optimal Liposomal Formulation Research Articles

Folate receptor-targeted liposomes as vectors for therapeutic agents

The folate receptor is a cell surface protein that has recently been identified as a tumor marker, due to its differential overexpression in several malignancies. Current research indicates that folate can be covalently attached to the surface of liposomes to mediate their selective internalization by tumor cells through the folate receptor-mediated endocytic pathway. Optimized liposome formulations, characterized by improvements in drug loading, extended residence times in the circulation and improved drug release, have been developed to improve the biodistribution of therapeutic molecules. Theoretically, folate receptor-targeting can be combined with liposome encapsulation to synergistically affect disease outcome by enhancing the delivery of chemotherapeutic agents to neoplastic cells, while reducing systemic toxicities to normal tissues. The purpose of this chapter is to characterize the components of folate receptor-targeted liposomes, and summarize their applications in gene and drug delivery.

Modulation of human ovarian tumor cell sensitivity to N-(phosphonacetyl)-L-aspartate (PALA) by liposome drug carriers.

Carrier-based formulations of cytotoxic agents may be highly efficacious for intracavitary therapy of malignancies which reside in or metastasize to the peritoneal cavity. N-(Phosphonacetyl)-L-aspartic acid (PALA) is a transition-state inhibitor of aspartate transcarbamylase which has shown enhanced activity against several cell lines upon encapsulation in liposomes. We have examined the growth inhibitory effects of PALA-containing liposome formulations against four human ovarian cancer cell lines (Ovcar-3, Hey-1b, A90, and A121a) that have significantly different growth characteristics. With the optimal liposome formulation defined in the present studies, the potency of encapsulated PALA was 22- to 570-fold greater than that of free PALA, depending on the cell line. Control liposomes containing buffer, rather than PALA, did not inhibit cell growth. Fluorescence studies of liposome-cell interaction suggest that high liposome negative surface charge density and high phase transition temperature increase both cellular association and retention of liposome contents. Briefer exposure of tumor cells to treatment accentuates the advantage of liposome formulations; on Hey-1b cells, the cytostatic effect of 1-hr exposure to PALA-liposomes is 900-fold greater than is the equivalent exposure to free PALA. The considerable increase in in vitro potency of PALA-liposome formulations, coupled with potential pharmacokinetic advantages in vivo (i.e., intraperitoneal retention of liposome-associated drug versus rapid clearance of free PALA), suggests the possibility of enhanced antitumor activity of liposome-encapsulated PALA for both single-agent and combination chemotherapy.