With countless preclinical studies on block copolymer micelles (BCMs) successfully demonstrating the superiority of these advanced drug delivery formulations over conventional formulations, it remains somehow discouraging that only a few have reached clinical evaluation and practice. With a critical eye, this review aims to compare and summarize the preclinical and clinical data available on several BCM formulations and to identify their primary role in drug delivery as "carrier" or "solubilizer". This review focuses on polymeric micelles that have reached clinical evaluation and/or are being pursued commercially. Where available, we aim to compare the pharmacokinetics, toxicity, and efficacy data obtained in preclinical studies to identify the factors that likely played a key role in a decision to move these formulations forward from the bench to a first-in-human trial. Finally, we summarize clinical data obtained to date, where available, and conclude with the impact that each formulation has had on patients in terms of safety and efficacy.

The efficient penetration of drug nanocarriers into tumors is an important prerequisite for therapeutic and diagnostic success.

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Clinical studies examining the combination of paclitaxel (PTX) and everolimus (EVER), an mTOR inhibitor, have failed to result in significant improvements in efficacy and toxicity in patients with breast cancer (BC), relative to treatment with PTX alone. These disappointing clinical trial results have been attributed to poorly designed preclinical studies using the combination of PTX and EVER as well as the significantly different pharmacokinetic profiles of the two drugs. In the current work, the potential synergy between PTX and EVER was examined in a panel of six BC cell lines that differ in terms of their molecular subtype and drug sensitivity. Polymeric nanoparticles (NPs) were used to encapsulate PTX and EVER at an optimal synergistic ratio to achieve specific, colocalized delivery of the combination therapy in BC cell lines. Combinations of PTX and EVER (especially at relatively high doses of EVER) resulted in pronounced synergy in all BC cell lines evaluated. The optimal molar ratio of PTX:EVER was determined to be 1:0.5. The combination was delivered to BC cells at the synergistic ratio via encapsulation within polymeric NPs formed from the poly(ethylene glycol)- b-poly(lactide- co-glycolide) (PEG- b-PLGA) copolymer. The NPs had an average diameter of less than 100 nm and were capable of in vitro retention of the encapsulated PTX and EVER at the optimal synergistic molar ratio for over 7 days. Cytotoxicity data demonstrated that PTX+EVER-loaded NPs were significantly less cytotoxic than the free drug combination in MCF-7 and SKBR3 BC cell lines following 72 h, suggesting that PTX+EVER-loaded NPs remain stable and retain the drug combination loaded within the core after 72 h. The uptake of FITC-labeled NPs in SKBR3 cells was evaluated by flow cytometry, with approximately 41% of cells demonstrating detectable fluorescence after 24 h of exposure. The thorough and systematic approach used in this study to determine and evaluate a synergistic PTX:EVER ratio in conjunction with a potentially promising delivery vector for the drug combination could offer a future clinical benefit for patients with BC.