The liposomal delivery of
cancer therapeutics, including gene therapy vectors, is an area of intense study. Poor penetration of
liposomes into interstitial
tumor spaces remains a problem, however. In this work, the penetration of different liposomal formulations into prostate
carcinoma spheroids was examined. Spheroid penetration was assessed by confocal microscopy of fluorescently labeled
liposomes. The impact of liposomal surface charge, mean diameter,
lipid bilayer fluidity and fusogenicity on spheroid penetration was examined. A variety of different
liposome systems relevant to clinical or preclinical protocols have been studied, including classical zwitterionic (
DMPC:chol) and sterically stabilized
liposomes (
DMPC:chol:DOPE-
PEG2000), both used clinically, and cationic
liposomes (
DMPC:DOPE:
DC-chol and
DOTAP), forming the basis of the vast majority of nonviral gene transfer vectors tested in various
cancer trials. Surface interactions between strongly cationic vesicles and the
tumor cells led to an electrostatically derived binding-site barrier effect, inhibiting further association of the delivery systems with the
tumor spheroids (
DMPC:
DC-chol). However, inclusion of the fusogenic
lipid DOPE and use of a cationic
lipid of lower surface charge density (
DOTAP instead of
DC-chol) led to improvements in the observed intratumoral distribution characteristics. Sterically stabilized
liposomes did not interact with the
tumor spheroids, whereas small unilamellar classical
liposomes exhibit extensive distribution deeper into the
tumor volume. Engineering liposomal delivery systems with a relatively low charge molar ratio and enhanced fusogenicity, or electrostatically neutral
liposomes with fluid bilayers, offered enhanced intratumoral penetration. This study shows that a delicate balance exists between the strong affinity of delivery systems for the
tumor cells and the efficient penetration and distribution within the
tumor mass, similar to previous work studying targeted delivery by
ligand-receptor interactions of
monoclonal antibodies. Structure-function relationships from the interaction of different
liposome systems with 3-dimensional
tumor spheroids can lead to construction of delivery systems able to target efficiently and penetrate deeper within the
tumor interstitium and act as a screening tool for a variety of
therapeutics against
cancer.