Clinical Translation of PEGylated Liposomal Drug Delivery Systems in Oncology

Progress, Barriers, and Future Prospects

Abstract

The development of PEGylated liposome drug delivery systems as a method to deliver nanomedicine in oncology, is a means to improve the pharmacokinetic and therapeutic properties of cytotoxic agents. Liposomes are flexible phospholipid bilayers capable of encapsulating hydrophilic and/or hydrophobic drugs; thereby providing protection to unstable drugs and control over how drugs distribute within the body. Once the surface of liposomes is modified using poly (ethylene glycol) (peg), ‘stealth’ liposomes are formed that demonstrate steric stabilization and inhibit the opsonization of the liposome. As a result of being less susceptible to removal from the circulation by the reticuloendothelial system (RES) due to sterically stabilized surfaces, stealth liposomes will remain in circulation longer than traditional liposomes. Additionally, stealth liposomes will increase the duration in which they remain in proximity to solid tumors through enhanced permeation and retention (EPR) effects. Pegylated liposomal doxorubicin (doxorubicin HCl liposome) and nanoliposomal irinotecan have been the first two liposomal formulations to receive FDA approval. Each formulation provided improvements to the therapeutic index and reduced dose-limiting toxicities relative to their non-pegylated counterparts. However, many obstacles exist that must be addressed prior to widespread adoption of pegylated liposomes. These obstacles include uniform delivery of the liposomes to tumors, ability of liposomes to penetrate into tumor tissue, the “peg dilemma”, and the possibility of eliciting an immune response leading to accelerated blood clearance (ABC) or anti-peg antibodies. Researchers continue to develop novel stealth polymers, PEG-based architectures that respond to stimulus, theragnostic liposomes, and combine liposomes with immunotherapy as methods to achieve more reliable delivery of liposomes and better clinical outcomes for patients. Although pegylated liposomes represent one of the most efficient platforms available for the delivery of chemotherapeutic agents, it is critical to take into consideration both the design of the liposome and the individual characteristics of each patient to obtain optimal results in treating cancers. This revised synthesis explicitly reframes EPR-based deposition as one component of a broader, heterogeneous tumor-transport process; highlights the quantitative limitation that generally less than 2% of the injected nanoparticle dose reaches tumors; incorporates anti-PEG antibody prevalence and patient-stratification considerations; adds manufacturing or CMC reproducibility barriers; and proposes testable translational hypotheses for imaging-guided patient selection and rational immunotherapy combinations.