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Mitochondrial Protein Sorting01:39

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Mitochondria are double-membrane organelles of the eukaryotes involved in cellular metabolism, signaling, ATP synthesis, and programmed cell death.  Each of these processes requires specific proteins and enzymes that must be correctly sorted to the right mitochondrial subcompartment for the proper functioning of the organelle.
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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
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Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70  chaperones are targetted to TOM20-TOM22 receptor complexes.
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Author Spotlight: Advancing Techniques and Discoveries in Protein Synthesis and Assembly Through Innovative Mitochondrial Research
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A pH-responsive sequential-disassembly nanohybrid for mitochondrial targeting.

Lijia Li1, Wei Sun, Lian Li

  • 1Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China. huangyuan0@163.com.

Nanoscale
|December 3, 2016
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Summary

Researchers developed a pH-responsive nanohybrid drug delivery system for enhanced cancer therapy. This system targets mitochondria, improving drug efficacy and reducing side effects by utilizing stepwise charge and pH responsiveness.

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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.