pH/Reduction Dual‐Triggered Degradable Poly(doxorubicin) Prodrug Nanoparticles for Leakage‐Free Tumor‐Specific Self‐Delivery

Abstract

Poly(doxorubicin) (PDOX) is synthesized with Mn of 1.66 × 10 and DOX content of 78% as prodrug for tumor-specific triggered release, via a facile condensation polymerization of DOX-SS-DOX and adipic dihydrazide. The PDOX nanoparticles (PDOX-NPs) could completely release DOX-SH within 1.5 days at the simulated tumor microenvironment, but no measurable leakage in the physiological media. The in vitro controlled release results show that the releasing rate is influenced by the dosage and independent of the particle size, while the solubility of the degraded products should be the main determining factor for the drug release from the PDOX-NPs. The PDOX-NPs are expected to be promising prodrug nanopharmaceutics for the on-demand self-delivery of DOX with enhanced anticancer efficacy in future tumor treatment.

Synthesis of Acid-Labile Poly(Doxazolidine) as a Polyprodrug with an Ultra-High Drug Content for Self-Delivery of High-Performance Chemotherapeutics

“…The retention time in its GPC trace was 19.367 min (Figure S1), demonstrating the successful synthesis of the P­(Doxaz) polyprodrug with an M n of 2.1 × 10 4 g/mol. Besides, the smaller shoulder peak with a retention time of about 13 min might originate from the assemblies of the P­(Doxaz) because of the high content of the anthracycline chemotherapy drug as structural units, due to the π–π stacking interaction as reported previously …”

“…11 In our previous work, the pH/reduction dual-responsive poly-(doxorubicin) (PDOX) prodrug was synthesized for the tumor-specific drug delivery via a facile condensation polymerization of DOX-SS-DOX and adipic dihydrazide. 18 Despite the high drug content of 78% and complete degradation with 1.5 days, it showed a similar antitumor efficacy as the free DOX, also due to the lower antitumor efficacy of the DOX-SH. Doxazolidine (Doxaz) has been recognized as a proposed active DOX metabolite to cross-link DNA, 19 and its dimer, DoxF, has been recognized for overcoming the MDR.…”

“…The polyprodrugs showed a lower in vitro antitumor efficacy than the free DOX, due to the fact that the doxorubicin derivative (DOX-SH) was released during the degradation of the polyprodrugs, which possessed a lower antitumor efficacy than the free DOX . In our previous work, the pH/reduction dual-responsive poly­(doxorubicin) (PDOX) prodrug was synthesized for the tumor-specific drug delivery via a facile condensation polymerization of DOX-SS-DOX and adipic dihydrazide . Despite the high drug content of 78% and complete degradation with 1.5 days, it showed a similar antitumor efficacy as the free DOX, also due to the lower antitumor efficacy of the DOX-SH.…”

Self‐Assembly of Drug–Drug Conjugates as Drug Self‐Delivery System for Tumor‐Specific pH‐Triggered Release

“…To overcome these problems, drug self‐delivery systems (DSDSs) have been developed most recently, exhibiting nanoscale characteristic to endow intracellular delivery by themselves without any nanocarriers, as drug–drug conjugates, polymer prodrugs, or molecular hydrogels . Such nano‐DSDSs could release therapeutics or their derivatives by cleaving the conjugating linkages, responding to the acidic media or high reductant level in tumor microenvironment.…”

“…PEGylation has been recognized to improve the pharmacokinetic and pharmacodynamic outcomes of therapeutics . Among the nano‐DSDSs, the prolonged blood circulation time was desired for those with higher drug content but without PEGylated, while the PEGylation led a lower drug content in the others . Furthermore, lower tumor‐inhibition efficacy was achieved than the free chemotherapeutics in some cases, because the drug was released as its derivative …”