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Drug solubility and permeability are two major challenges affecting oral delivery, the most popular route of drug administration. Polymeric micelles is an emerging technology for overcoming the current oral drug delivery hurdles. Previous study primarily focused on developing new polymers or new micellar systems and a systematic investigation of the impact of the polymer block length on solubility and permeability enhancement; and their subsequent effect on oral bioavailability is lacking. Herein, by using paclitaxel, a poorly soluble P-glycoproteins (P-gp) substrate, as a model, we aim to assess and compare the drug-loaded micelles prepared with two different molecular weight of poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL), with the ultimate goal of establishing a strong scientific rationale for proper design of formulations for oral drug delivery. PEG-b-PCL (750:570) (PEG 17 -b-PCL 5 ) and PEG-b-PCL (5k:10k) (PEG 114 -b-PCL 88 ) effectively enhanced the solubility of paclitaxel compared to the free drug. PEG-b-PCL (750:570) increased both P-gp and non P-gp substrate cellular uptake and increased the apparent permeability coefficient of a P-gp substrate. In vivo animal study showed that PEG-b-PCL micelles efficiently enhanced the oral bioavailability of paclitaxel. In addition to solubility enhancement, polymer choice also plays a pivotal role in determining the oral bioavailability improvement, probably via permeation enhancement. In conclusion, the knowledge gained in this study enables rational design of polymeric micelles to overcome the current challenges of oral drug delivery and it also provides a basis for future clinical translation of the technology., (Copyright © 2019 Elsevier B.V. All rights reserved.)