Development of paclitaxel-loaded liposomal nanocarrier stabilized by triglyceride incorporation

Abstract

Studies have highlighted the challenge of developing injectable liposomes as a paclitaxel (PTX) carrier, a challenge attributable to the limitations in liposomal stability caused by PTX loading. Poor stability of PTX-loaded liposomes is caused by PTX-triggered aggregation or fusion of liposomal membranes and is exacerbated in the presence of PEGylated lipid. In the present study, the effect of triglyceride incorporation on the stability of PTX-loaded/PEGylated liposomes was explored. Incorporation of a medium chain triglyceride Captex 300 into saturated phosphatidylcholine (PC)-based liposomes (1,2-dimyristoyl- sn -glycero-3-phosphocholine [DMPC]:cholesterol [CHOL]:N-(Carbonyl-methoxypolyethyleneglycol 2000)-1, 2-distearoyl- sn -glycero-3-phospho-ethanolamine [PE-PEG]), produced a fine, homogeneous, and membrane-filterable PTX-loaded liposomes fulfilling the requirement of an injectable lipid formulation. Triglyceride incorporation also greatly inhibited the time-dependent leakage of PTX from saturated PC-based liposomes, which appears to be mediated by the inhibition of liposome fusion. In contrast, triglyceride incorporation induced the destabilization and PTX leakage of unsaturated PC-based liposomes, indicating the opposite effect of triglyceride depending on the fluidity status of PC constituting the liposomal membrane. PTX release profile and the in vitro and in vivo anticancer efficacy of triglyceride-incorporated DMPC:CHOL:PE-PEG liposomes were similar to Taxol ® while the toxicity of liposomal PTX was significantly lower than that of Taxol. Taken together, triglyceride incorporation provided an injectable PTX formulation by functioning as a formulation stabilizer of PEGylated/saturated PC-based liposomes.

Distinct solubility and cytotoxicity regimes of paclitaxel-loaded cationic liposomes at low and high drug content revealed by kinetic phase behavior and cancer cell viability studies

“…Figure 1h shows a low-magnification polarized optical micrograph displaying such crystals in an unsonicated CL PTXL sample 5 days after hydration. While previous studies have largely relied on multi-step HPLC experiments to monitor drug loading and retention over time [30,31,43], we set out to establish a DIC microscopy-based experimental protocol that would allow us to determine the PTXL stability in novel lipid formulations with higher throughput.…”

“…Various studies indicate that liposome–PTXL formulations exhibit lower toxicity compared to Taxol®, may increase the maximum tolerated drug dose, and may improve biodistribution [30,35–38]. One liposomal formulation of PTXL is approved in China (Lipusu®) [39,40], while others are in clinical trials.…”

“…Other types of PTXL-containing liposomes (e.g. PEGylated, antibody-targeted) have shown some promising early results, but have not progressed to clinical trials [30,35,42–45]. …”

Distinct Solubility and Cytotoxicity Regimes of Paclitaxel-Loaded Cationic Liposomes at Low and High Drug Content Revealed by Kinetic Phase Behavior and Cancer Cell Viability Studies

“…1b,c). These drugs, which include PTXL, are quickly expelled from membranes consisting of saturated lipid tails or those that have a high concentration of cholesterol [26][27][28][29][30][31]. This observation indicates that the maximum loading and residence time of hydrophobic drugs within liposomes are particularly sensitive to the liposome composition.…”

“…Various studies indicate that liposome-PTXL formulations exhibit lower toxicity compared to Taxol®, may increase the maximum tolerated drug dose, and may improve biodistribution [28,[33][34][35][36]. One liposomal formulation of PTXL is approved in China (Lipusu®) [37,38], while others are in clinical trials.…”