The anticancer efficacy of
chemotherapy is greatly limited by short blood circulation and poor
tumor selectivity. Thus, anticancer
prodrugs with prolonged systemic circulation,
tumor-specific distribution and bioactivation, could significantly strengthen the
chemotherapy efficacy. Herein, we design two novel
tumor cell reduction/oxidation-responsive
docetaxel (DTX)
prodrugs, DTX-
maleimide conjugates with
disulfide bond (DSSM) or
thioether bond (DSM) linkages, to evaluate the roles of different sensitive linkages in drug release, pharmacokinetics and therapeutic efficacy. An
ester bond-linkage
prodrug (DM) is utilized as a non-sensitive control. DSSM and DSM show reduction- or oxidation-sensitive release behavior, respectively, and exhibit hyperselective bioactivation and cytotoxicities between cancerous and normal cells. They could instantly hitchhike blood circulating
albumin after i.v. administration with
albumin-binding half-lives as short as 1 min, resulting in prolonged systemic circulation, increased
tumor accumulation. In response to the upregulated reduction/oxidation environment within
tumor cells, DSSM and DSM exhibit selectively release capacity in
tumor tissues, their TAITumor/Liver values are over 30-fold greater than DM. Combining the above delivery advantages into one, DSSM and DSM achieve enhanced antitumor efficacy of DTX. Such a uniquely developed strategy, integrating high
albumin-binding capability and reduction/oxidation-sensitive
drug superselective release in
tumors, has great potential to be applied in clinical
cancer therapy.