A pH-responsive sequential-disassembly nanohybrid for mitochondrial targeting

Area of Science:

• Biomaterials Science
• Nanotechnology
• Drug Delivery

Background:

• Cationic materials show potential for mitochondrial targeting but suffer from rapid in vivo clearance.
• Developing safe and effective in vivo delivery systems for mitochondria-targeted therapies remains a challenge.

Purpose of the Study:

• To fabricate a pH-responsive nanohybrid system for enhanced mitochondrial targeting and cancer therapy.
• To overcome the limitations of cationic materials in vivo by incorporating a charge-releasing shield.
• To investigate the 'assembly-disassembly' strategy for improved drug delivery and therapeutic outcomes.

Main Methods:

• Fabrication of a nanohybrid using pH-responsive N-(2-hydroxypropyl)methacrylamide (HPMA) co-polymer shells and mesoporous silica nanoparticle (MSN) cores.
• Encapsulation of docetaxel (DTX) within the MSN cores (MSN-DTX) and subsequent shielding with HPMA co-polymers to form R-P@MSN-DTX.
• Evaluation of the nanohybrid's stepwise pH-responsive behavior, charge reversion, cell internalization, endo/lysosome escape, and mitochondrial targeting.
• Assessment of in vivo tumor inhibition efficacy in nude mice.

Main Results:

• The R-P@MSN-DTX nanohybrid exhibited prolonged blood circulation and enhanced EPR effect due to the R-P shield.
• Stepwise charge reversion occurred at tumor and endo/lysosomal pH, facilitating cell internalization and endo/lysosome escape.
• The nanohybrid successfully targeted mitochondria, leveraging intracellular acidity for drug release.
• Achieved a significant tumor inhibition rate of 72.6% in nude mice.

Conclusions:

• The developed nanohybrid system effectively addresses the in vivo limitations of cationic materials for mitochondrial targeting.
• The 'assembly-disassembly' strategy combined with stepwise pH-responsiveness offers a promising approach for enhanced systemic drug delivery.
• This work provides a valuable reference for designing advanced nanocarriers for targeted cancer therapy.