Bioreducible Amphiphilic Hyperbranched Polymer-Drug Conjugate for Intracellular Drug Delivery

Area of Science:

• Polymer Chemistry
• Materials Science
• Nanotechnology
• Drug Delivery

Background:

• Development of advanced drug delivery systems is crucial for improving therapeutic efficacy and reducing side effects of potent drugs like camptothecin (CPT).
• Hyperbranched polymers offer unique advantages in drug delivery due to their globular structure, high solubility, and numerous functionalization sites.
• Bioreducible polymers are desirable for targeted drug release in response to intracellular stimuli, such as elevated glutathione (GSH) levels in cancer cells.

Purpose of the Study:

• To synthesize a novel bioreducible hyperbranched (HB) polymer using a straightforward A2+B3 approach.
• To functionalize the HB polymer with camptothecin (CPT) to create an amphiphilic conjugate for targeted cancer therapy.
• To investigate the self-assembly, drug release kinetics, cellular uptake, and anticancer efficacy of the developed CPT-loaded nanoparticles.

Main Methods:

• Synthesis of HB polymer via thiol-activated disulfide exchange reaction between dithiothreitol (DTT) and a trifunctional pyridyl-disulfide monomer.
• Postpolymerization modification to conjugate CPT and introduce oligo-oxyethylene-thiol for amphiphilicity.
• Characterization of polymer properties (molecular weight, dispersity), nanoparticle formation, drug loading, in vitro drug release (GSH-triggered), cellular uptake (confocal microscopy), and cytotoxicity (MTT assay).

Main Results:

• A well-defined HB polydisulfide with high drug loading (∼40%) was successfully synthesized and functionalized with CPT.
• The conjugate self-assembled into nanoparticles (∼135 nm) in water, exhibiting efficient GSH-triggered release of active CPT via a cascade-degradation mechanism.
• The HB-CPT nanoparticles demonstrated excellent cellular uptake in HeLa cells, predominantly via endocytosis, leading to highly potent and efficient cancer cell killing (IC50 ∼ 0.6 μg/mL), outperforming linear conjugates.

Conclusions:

• The developed bioreducible hyperbranched polymer serves as an effective platform for formulating CPT-loaded nanoparticles with enhanced anticancer activity.
• The GSH-triggered cascade-degradation mechanism facilitates efficient intracellular drug release, contributing to superior therapeutic outcomes compared to linear polymer conjugates.
• This HB polymer-based drug delivery system holds significant promise for advanced cancer therapy.