Design and biological activity of novel stealth polymeric lipid nanoparticles for enhanced delivery of hydrophobic photodynamic therapy drugs

Advances in in vivo stability and preferential tumor uptake of cancer nanomedicine are warranted for effective chemotherapy. Here, we describe a novel nanoformulation using an unconventional polymeric tubule-forming phospholipid, DC_8,9PC. We report that DC_8,9PC transitions to stable vesicles (LNPs) in the presence of PEGylated lipid (DSPE-PEG2000); the resulting DC_8,9PC:DSPE-PEG2000 LNPs efficiently included a hydrophobic PDT drug, HPPH. Remarkably, these LNPs incorporated unusually high DSPE-PEG2000 concentrations; LNP₁₀-HPPH and LNP₂₀-HPPH (10 & 20 mol% PEGylated lipid, respectively) exhibited >90% serum stability at 37 °C. Increased PEGylation in the LNPs correlated with enhanced tumor accumulation in intravenously injected HT29 tumor mouse xenographs. Colon-26 bearing BALB/c mice, intravenously injected with LNP₂₀-HPPH showed superior PDT efficacy and animal survival (no tumor recurrence up to 100 days) as compared to a formulation currently used in clinical trials. Taken together, we present a simple stealth binary lipid nanosystem with enhanced efficiency of tumor accumulation and superior therapeutic efficacy.