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Related Concept Videos

Site-Targeted Drug Delivery Systems: Polymeric Carriers01:24

Site-Targeted Drug Delivery Systems: Polymeric Carriers

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Polymeric carriers enhance targeted drug delivery by increasing efficacy while minimizing off-target effects. These carriers comprise a biodegradable polymeric backbone integrated with functional elements that enable targeting, improve physicochemical properties, and regulate drug release.Targeting MechanismsThe targeting ability of polymeric carriers is mediated by a homing device, which is a molecular recognition component designed to selectively bind to specific tissues or cells. Monoclonal...
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Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
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Mitochondrial Protein Sorting01:39

Mitochondrial Protein Sorting

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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.
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...
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Energy to Drive Translocation01:37

Energy to Drive Translocation

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Mitochondrial protein import is powered by two distinct energy sources: ATP hydrolysis and electrochemical potential across the inner membrane. Newly synthesized precursors are bound by cytosolic chaperones of the Hsp70 family, which guide them to the import receptors on the mitochondrial surface. Utilizing the energy of ATP hydrolysis, Hsp70 chaperones transfer these precursors to the TOM receptors on the mitochondrial outer membrane.
Generally, polypeptides are unfolded by two distinct...
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Mitochondrial Precursor Proteins01:39

Mitochondrial Precursor Proteins

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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.
Most of the mitochondrial...
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Modified-Release Drug Delivery Systems: Site-Targeted01:24

Modified-Release Drug Delivery Systems: Site-Targeted

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Site-targeted drug delivery systems enhance therapeutic efficacy while minimizing systemic toxicity and treatment costs. Unlike conventional methods, these systems ensure precise drug delivery, improving bioavailability and reducing side effects. Targeted drug delivery is classified into three levels. First-order targeting directs drugs to the capillary beds of specific organs or tissues. Second-order targets specific cell types, such as tumor cells, using receptor-mediated interactions.
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Related Experiment Video

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Methionine Functionalized Biocompatible Block Copolymers for Targeted Plasmid DNA Delivery
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Charge-Reversible Multifunctional HPMA Copolymers for Mitochondrial Targeting.

Fengling Wang1, Wei Sun1, Lian Li1

  • 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, China.

ACS Applied Materials & Interfaces
|August 2, 2017
PubMed
Summary

This study introduces a novel N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer nanocomplex that targets cancer drug delivery to mitochondria. This approach enhances drug accumulation, improving antitumor efficiency and achieving an 82.9% tumor inhibition rate in mice.

Keywords:
HPMA copolymerscharge reversibleguanidinemitochondrial targetingtumor extracellular acidity

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Area of Science:

  • Biomedical Engineering
  • Materials Science
  • Cancer Therapeutics

Background:

  • Mitochondrial drug delivery enhances anticancer efficacy but faces physiological barriers.
  • Developing targeted delivery systems is crucial for overcoming these challenges.

Purpose of the Study:

  • To design a multifunctional N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer nanocomplex (MPC) for enhanced mitochondrial drug delivery.
  • To improve drug accumulation in mitochondria and boost antitumor efficiency.

Main Methods:

  • Synthesized MPC using oppositely charged HPMA copolymers: guanidine-modified (positive charge) and 2,3-dimethylmaleic anhydride (DMA)-modified (charge-reversible).
  • Evaluated MPC's pH-responsive behavior, stability, cellular uptake, lysosomal escape, and mitochondrial targeting in vitro.
  • Assessed MPC's tumor accumulation and antitumor efficacy in B16F10 tumor-bearing mice.

Main Results:

  • MPC demonstrated stability at pH 7.4 and charge-reversal at tumor-relevant pH 6.5, facilitating endocytosis, lysosomal escape, and mitochondrial targeting.
  • In vitro studies showed a 4.3-fold increase in cellular uptake and a 23.8-fold increase in mitochondrial targeting for MPC at pH 6.5 compared to controls.
  • In vivo studies revealed significant tumor accumulation and an 82.9% peak tumor inhibition rate in mice.

Conclusions:

  • Multifunctional mitochondrial-targeting HPMA copolymers offer a versatile platform for advanced cancer therapy.
  • The designed MPC effectively overcomes delivery barriers, enhancing drug accumulation and antitumor activity.