2026/07/07 by Marianne Ferrere, Lorenzo Tomasini, Grégoire Gessain +2 · 1 voice
Materials Science · Pharmacology, Toxicology and Pharmaceutics · #Advanced Drug Delivery Systems #Advancements in Transdermal Drug Delivery #Nanoparticle-Based Drug Delivery
paper · doi:10.26434/chemrxiv.15005770/v1
openalex publication_date 2026/07/07 · openalex created_date 2026/07/08 · openalex updated_date 2026/07/14
Subcutaneous (SC) administration is attracting increasing interest as an alternative to intravenous (IV) delivery due to its numerous clinical and practical advantages. However, the SC administration of vesicant and irritant anticancer drugs remains precluded by their severe local toxicity. To overcome this limitation, the concept of water-soluble polymer prodrugs has recently emerged as a promising strategy. Herein, to fully exploit this potential and make a significant step forward clinical translation, we investigated water-soluble polymer prodrugs based on paclitaxel and a library of clinically relevant hydrophilic polymers, including: polyacrylamide (PAAm), poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA300 and POEGMA950), poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) and poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC). Through a comprehensive preclinical evaluation encompassing physicochemical characterization, in vitro studies, in vivo efficacy and safety assessments, and ex vivo toxicological evaluation in living human skin biopsies, we established detailed structure–property relationships governing SC performance. Varying the polymer backbone enabled broad modulation of key parameters, including injectable doses (100–700 mg.kg-1 in Ptx), plasma drug release kinetics (3–35% released after 24 h), cytotoxicity (IC50 = 10–105 nM in MCF-7 cells), and pharmacokinetic behavior (bioavailability = 10–79%). Importantly, polymer prodrugs based on PAAm, POEGMA300, POEGMA950, and PHPMA achieved antitumor efficacy in mice comparable to Taxol administered IV at 15 mg.kg-1 and outperformed the commercial formulation at 60 mg.kg-1 owing to their three-fold higher maximum tolerated doses. Remarkably, all polymer prodrugs exhibited excellent local tolerability in both murine and human skin models. Overall, this study provides, to our knowledge, the first comprehensive framework linking polymer structure to biological performance for the SC delivery of irritant and vesicant anticancer agents, as well as the first assessment in human skin, thereby offering valuable design guidelines and paving the way toward clinical translation.