Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In cancer treatment, surface modification by penetrating peptides and size control have been exploited as the two main strategies to tackle the problems of deep tumor penetration and cell internalization for nanocarriers. Polymeric nanocarriers with small size are beneficial for deep tumor penetration; however, they always undergo rapid clearance during body circulation and have low tumor accumulation efficiency. To solve this dilemma, a tumor-targeted size-switchable CPT/IR780@H30-PCL-PPI(L-)/PEI(-COOH/FA) nanoassembly with a "pomegranate" construction was designed in this study. Initially, it possessed a large size and negative charge to meet the long blood circulation time but rapidly disassembled into small-sized guanidinium and helical chain-modified unimolecular micelle-based nanocarriers, CPT/IR780@H30-PCL-PPI(L-/ + ), at tumor sites due to the tumor microenvironment-induced charge reversal. The CPT/IR780@H30-PCL-PPI(L-/+) assembly could efficiently expand the penetration depth and accelerate cell internalization due to the guanidinium group-modified helical chains, which exhibited a similar structure to that of the cell penetrating peptides. In addition, the nanoassembly exhibited strong photothermal conversion and acoustic generation efficiency. Moreover, the generated heat significantly improved the drug release, thus realizing functional cooperativity and adaptability. This proof of concept can be supposed to be a significant progress in the design and preparation of tumor microenvironment-responsive drug delivery systems and their use for photoacoustic imaging-assisted chemo-photothermal synergistic therapy.
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PMID:Positively charged helical chain-modified stimuli-responsive nanoassembly capable of targeted drug delivery and photoacoustic imaging-guided chemo-photothermal synergistic therapy. 3084 57

The drug resistance in cancer treatment with DOX is mainly related to the overexpression of drug efflux proteins, residing in the plasma and nuclear membranes. Delivering DOX into the mitochondria, lacking drug efflux proteins, is an interesting method to overcome DOX resistance. To solve the problem of positively charged triphenylphosphonium (TPP) for mitochondrial targeting in vivo, a charge reversal strategy was developed. Methods: An acidity triggered cleavable polyanion PEI-DMMA (PD) was coated on the surface of positively charged lipid-polymer hybrid nanoparticle (DOX-PLGA/CPT) to form DOX-PLGA/CPT/PD via electrostatic interaction. The mitochondrial localization and anticancer efficacy of DOX-PLGA/CPT/PD was evaluated both in vitro and in vivo. Results: The surface negative charge of DOX-PLGA/CPT/PD prevents from rapid clearance in the blood and improved the accumulation in tumor tissue through the enhanced permeability and retention (EPR) effect. The hydrolysis of amide bonds in PD in weakly acidic tumor tissue leads to the conversion of DOX-PLGA/CPT/PD to DOX-PLGA/CPT. The positive charge of DOX-PLGA/CPT enhances the interaction with tumor cells, promotes the uptake and improves DOX contents in tumor cells. Once endocytosed by tumor cells, the exposed TPP in nanomedicine results in effective mitochondrial localization of DOX-PLGA/CPT. Afterward, DOX can release from the nanomedicine in the mitochondria, target mtDNA, induce tumor cells apoptosis and overcome DOX resistance of MCF-7/ADR breast cancer. Conclusion: Tumor acidity triggered charge reversal of TPP-containing nanomedicine and activation of mitochondrial targeting is a simple and effective strategy for the delivery of DOX into the mitochondria of cancer cells and overcoming DOX resistance of MCF-7/ADR tumor both in vitro and in vivo, providing new insight in the design of nanomedicines for cancer chemotherapy.
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PMID:Tumor acidity activated triphenylphosphonium-based mitochondrial targeting nanocarriers for overcoming drug resistance of cancer therapy. 3166 85