Advancements in anticancer strategies spotlight proteolysis targeting chimera (PROTAC) technology, yet it is hindered by poor water solubility and bioavailability. This study introduces a novel amphiphilic PROTAC, , synthesized through PEGylation of an optimized PROTAC molecule, , to enhance its properties. is engineered to self-organize into micelles in water and releases its active form in response to the tumor-specific high GSH environment. Comparative pharmacokinetic analysis revealed 's superior bioavailability at 84.8%, outperforming the unmodified PROTAC molecule . When tested in a H3122 xenograft mouse model, significantly regressed tumors, underscoring its potential as a formidable candidate in targeted cancer therapy. Our findings offer a promising direction for overcoming bioavailability limitations in PROTAC drug design.
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