Enzyme/pH-sensitive polyHPMA-DOX conjugate as a biocompatible and efficient anticancer agent.

Area of Science:

• Biomaterials Science
• Polymer Chemistry
• Cancer Therapeutics

Background:

• Doxorubicin (DOX) is a potent chemotherapy drug with significant side effects.
• Developing targeted drug delivery systems can improve therapeutic efficacy and reduce toxicity.
• Biodegradable polymers offer a promising platform for controlled drug release.

Purpose of the Study:

• To synthesize and characterize a biodegradable N-(2-hydroxypropyl) methacrylamide (HPMA) polymer-DOX conjugate.
• To investigate the drug release mechanism and cellular uptake of the conjugate.
• To evaluate the in vivo anticancer efficacy and biosafety of the HPMA-DOX conjugate.

Main Methods:

• Preparation of the HPMA-DOX conjugate using reversible addition fragmentation chain transfer (RAFT) polymerization and conjugation chemistry.
• Utilizing a pH-responsive hydrazone bond for covalent linkage of DOX to the polymer.
• In vitro studies on cellular uptake, apoptosis, and cytotoxicity; in vivo pharmacokinetic, biodistribution, and efficacy studies in 4T1 tumor models.

Main Results:

• The high molecular weight (94 kDa) HPMA-DOX conjugate degraded to lower MW products (45 kDa) in lysosomes.
• The conjugate exhibited pH-responsive drug release and was effectively taken up by 4T1 cancer cells, inducing apoptosis.
• In vivo studies showed a longer half-life, enhanced tumor accumulation, superior anticancer efficacy, and reduced side effects compared to free DOX.

Conclusions:

• The developed biodegradable HPMA-DOX conjugate is an effective and safer anticancer agent.
• The enzyme/pH-sensitive nature of the conjugate enables targeted drug delivery and release.
• This polymeric conjugate holds potential for improved cancer therapy with reduced systemic toxicity.