Recent paclitaxel formulation strategies: expanding the therapeutic index by addressing biopharmaceutical and toxicity limitations

Paclitaxel (PTX) is a standard-of-care antineoplastic agent that stabilizes microtubules. However, its clinical utility is limited by dose limiting toxicities (e.g., myelosuppression and neuropathy), influencing decades of formulation development. Therefore, this review aims to analyze formulation strategies developed to address the three primary limitations. First, solvent-free formulations (e.g., albumin-bound PTX) mitigated the solvent-related toxicity and nonlinear pharmacokinetics of Cremophor EL-based PTX, improving the safety profile by eliminating hypersensitivity reactions. Second, intravenous formulations using liposomes or polymeric micelles for mitigating dose limiting toxicities via prolonged circulation and enhanced tumor retention demonstrated inconsistent clinical translation. Recently, active targeting platforms aimed to keep PTX largely inactive systemically while promoting mechanism-triggered delivery or tumoral uptake are under preclinical evaluation to expand the therapeutic index. Third, poor oral bioavailability, attributed to P-glycoprotein (P-gp)-mediated efflux and first-pass metabolism, was addressed via two strategies: gut-specific P-gp inhibition and lipid-based bypass formulations; however, interpatient absorption variability remains limited. In this review, decades of formulation research, tracing the evolution of PTX from a challenging molecule to a versatile therapeutic platform, were synthesized, highlighting the effect of addressing key biopharmaceutical and toxicity limitations in expanding its therapeutic index. Additionally, we examined the factors contributing to the frequent failure of passive targeting strategies to separate tumor exposure from systemic toxicity in human solid tumors. In conclusion, understanding PTX formulation strategies may facilitate future therapies to adopt flexible administration routes, incorporate biomarker-guided decision-making, and achieve controlled systemic exposure to reduce intrinsic dose-limiting toxicities.