One-Step Synthesis of Targeted Acid-Labile Polysaccharide Prodrug for Efficiently Intracellular Drug Delivery

Area of Science:

• Biomaterials Science
• Drug Delivery Systems
• Cancer Therapeutics

Background:

• Tumor cells overexpress αvβ3 integrin, a receptor for cyclo(Arg-Gly-Asp-d-Phe-Lys) peptide (c(RGDfK)).
• Acid-sensitive drug release mechanisms can improve targeted cancer therapy.
• Polysaccharide-based drug conjugates offer potential for controlled drug delivery.

Purpose of the Study:

• To investigate the therapeutic potential of an active targeting and acid-sensitive polysaccharide prodrug.
• To synthesize and characterize a cRGD-modified doxorubicin-conjugated hydroxyethyl starch (HES=DOX/cRGD).
• To evaluate the in vitro and in vivo antitumor efficacy and safety of the developed prodrug.

Main Methods:

• Synthesis of HES=DOX/cRGD via Schiff base reaction between oxidized HES, doxorubicin (DOX), and c(RGDfK).
• Characterization of self-assembled micelle structure and hydrodynamic diameter.
• In vitro evaluation of cell uptake and cytotoxicity using A375 melanoma cells.
• In vivo assessment of tumor accumulation, antitumor efficacy, and systemic toxicity.

Main Results:

• HES=DOX/cRGD self-assembled into micelles with a 77.1 nm diameter.
• In vitro studies showed enhanced cell uptake and cytotoxicity of HES=DOX/cRGD against A375 cells compared to HES=DOX and DOX.
• In vivo results demonstrated increased tumor accumulation, improved antitumor activity, and reduced systemic toxicity of the smart prodrug.

Conclusions:

• The cRGD-decorated, acid-sensitive polysaccharide prodrug exhibits effective active targeting and controlled drug release.
• HES=DOX/cRGD demonstrates superior antitumor efficacy and enhanced safety profile compared to conventional doxorubicin.
• This smart prodrug holds significant promise for clinical application in cancer therapy.