PDLLA length on anti-breast cancer efficacy of acid-responsive self-assembling mPEG-PDLLA-docetaxel conjugates

Engineering small-molecule drugs into nanoparticulate formulations provides an unprecedented oppor-tunity to improve the performance of traditional chemo drugs,but suffers from poor compatibility between drugs and nanocarriers.Stimuli-responsiive mPEG-PDLLA-drug conjugate-based nanomedicines can facilitate the exploitation of beneficial properties of the carrier and enable the practical fabrica-tion of highly efficacious self-assembled nanomedicines.However,the influence of hydrophobic length on the performance of this type of nanomedicine is little known.Here we synthesized two acid-sensitive ketal-linked mPEG-PDLLA-docetaxel prodrugs with different lengths of PDLLA,and engineered them into self-assembled sub-20 nm micellar nanomedicines for breast cancer chemotherapy.We found that the nanomedicine consisting of a mPEG-PDLLA-docetaxel prodrug with the shorter length of PDLLA stood out due to its potent cytotoxicity,deep penetration into multicellular spheroids,and improved in vivo anticancer performance.Additionally,our prodrug-based nanomedicines outperformed the generic for-mulation of commercial Nanoxel in terms of safety profile,tolerated doses,and tumor suppression.Our findings indicate that the hydrophobic content of a polymeric prodrug nanomedicine plays an impor-tant role in the performance of the nanomedicine,and should be instructive for developing polymeric prodrug-based nanomedicines with clinical translational potential.