"Clickable" polymer-caged nanobins as a modular drug delivery platform

Area of Science:

• Biomaterials Science
• Nanotechnology
• Cancer Therapeutics

Background:

• Developing targeted drug delivery systems is crucial for improving cancer treatment efficacy and reducing side effects.
• Polymer-based nanocarriers offer versatile platforms for drug encapsulation and controlled release.
• Folate receptor (FR) is overexpressed in various cancer cells, making it an attractive target for specific drug delivery.

Purpose of the Study:

• To synthesize and characterize modularly clickable polymer-caged nanobins (PCNs) for targeted drug delivery.
• To investigate the pH-responsive drug release capabilities of the PCNs.
• To evaluate the efficacy of folate-conjugated PCNs loaded with doxorubicin (DXR) against cancer cells with varying FR expression levels.

Main Methods:

• PCNs were fabricated using liposome templates and cross-linked with an alkyne-functionalized linker.
• Azide-modified targeting ligands, specifically folate, were conjugated to PCNs via click ligation.
• Doxorubicin (DXR) was encapsulated within the PCNs.
• The pH-responsive drug release was assessed under acidic conditions.
• The cytotoxicity and potency of folate-conjugated, DXR-loaded PCNs (f-PCN(DXR)) were evaluated in FR-positive (KB, OvCa432) and FR-negative (MCF7) cancer cell lines.

Main Results:

• The successful synthesis of modularly clickable PCNs was confirmed.
• PCNs exhibited pH-responsive release of DXR payload under mild acidic conditions.
• f-PCN(DXR) demonstrated significantly enhanced potency against FR-positive cancer cells compared to FR-negative cells.
• The potency of f-PCN(DXR) correlated with the level of FR expression on tumor cells.
• f-PCN(DXR) showed up to a fifty-fold increase in potency against cancer cells overexpressing FR compared to untargeted agents.

Conclusions:

• Modularly clickable PCNs can be effectively prepared using liposome templates and click chemistry.
• The developed PCNs possess pH-sensitive drug release properties, enabling triggered payload release in acidic tumor microenvironments.
• Folate conjugation enhances the targeted delivery and therapeutic efficacy of DXR-loaded PCNs against FR-positive cancer cells.
• These findings highlight the potential of f-PCN(DXR) as a targeted cancer therapeutic agent with improved potency and specificity.