Design and Evaluation of a Folate-Targeted PEG-MMAE Conjugate with Enzyme-Activated Drug Release for Enhanced Tumor Selectivity and Antitumor Efficacy

Polymer-drug conjugates hold significant promise for
drug delivery
applications. Water-soluble polymers prolong circulation, enhance
solubility, reduce immunogenicity, and promote tumor accumulation
via an enhanced permeability and retention effect. We first present
the design and evaluation of an enzyme-activatable folate-targeted
polyethylene glycol–monomethyl auristatin E conjugate. The
folate-targeted conjugate 4A-BFA-11 maintains affinity
for the folate receptor while achieving tumor enrichment through the
synergistic effects of PEG-mediated prolonged circulation and folate-driven
targeting. Subsequently, the conjugate undergoes enzymatic cleavage
at the tumor site to release the active payload, enabling precise
therapy. In vivo studies demonstrated that 4A-BFA-11, constructed using a folate-targeting strategy and
a multiarm PEG carrier, effectively prolongs circulation time, improves
tumor selectivity, and enhances antitumor efficacy. This strategy
offers a novel approach for the efficient delivery of potent cytotoxic
drugs through an enzyme-controlled activation mechanism, significantly
broadening the therapeutic window while reducing systemic toxicity.