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Concurrent Drug Unplugging and Permeabilization of Polyprodrug‐Gated Crosslinked Vesicles for Cancer Combination Chemotherapy

Combination chemotherapy with both hydrophobic and hydrophilic therapeutic drugs is clinically vital toward the treatment of persistent cancers. Though conventional liposomes and polymeric vesicles possessing hydrophobic bilayers and aqueous interiors can serve as codelivery nanocarriers, it remains... Full description

Journal Title: Advanced Materials May 2018, Vol.30(21), pp.n/a-n/a
Main Author: Hu, Xianglong
Other Authors: Zhai, Shaodong , Liu, Guhuan , Xing, Da , Liang, Haojun , Liu, Shiyong
Format: Electronic Article Electronic Article
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ID: ISSN: 0935-9648 ; E-ISSN: 1521-4095 ; DOI: 10.1002/adma.201706307
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recordid: wj10.1002/adma.201706307
title: Concurrent Drug Unplugging and Permeabilization of Polyprodrug‐Gated Crosslinked Vesicles for Cancer Combination Chemotherapy
format: Article
creator:
  • Hu, Xianglong
  • Zhai, Shaodong
  • Liu, Guhuan
  • Xing, Da
  • Liang, Haojun
  • Liu, Shiyong
subjects:
  • Combination Chemotherapy
  • Gated Crosslinked Vesicles
  • Permeabilization
  • Polyprodrug Amphiphiles
  • Therapeutic Activation
ispartof: Advanced Materials, May 2018, Vol.30(21), pp.n/a-n/a
description: Combination chemotherapy with both hydrophobic and hydrophilic therapeutic drugs is clinically vital toward the treatment of persistent cancers. Though conventional liposomes and polymeric vesicles possessing hydrophobic bilayers and aqueous interiors can serve as codelivery nanocarriers, it remains a considerable challenge to achieve synchronized release of both types of drugs due to distinct encapsulation mechanisms; premature release of water‐soluble cargos from unstable liposomes and ruptured vesicles is also a major concern. Herein, the fabrication of physiologically stable polyprodrug‐gated crosslinked vesicles (GCVs) via the self‐assembly of camptothecin (CPT) polyprodrug amphiphiles and in situ bilayer crosslinking through traceless sol–gel reaction is reported. Polyprodrug‐GCVs possess high CPT loading (>30 wt%) and minimized leakage of encapsulated hydrophilic doxorubicin (DOX) hydrochloride due to the suppressed permeability of crosslinked membrane, exhibiting extended blood circulation ( > 13 h) with caged cytotoxicity in physiological circulation. Upon cellular uptake by cancer cells, cytosolic reductive milieu‐triggered CPT unplugging from vesicle bilayers is demonstrated to generate hydrophilic mesh channels and make the membrane highly permeable. Concurrently, it will promote DOX corelease from hydrophilic lumen (≈36‐fold increase). The reduction‐activated combination chemotherapeutic potency based on polyprodrug‐GCVs is confirmed by both in vitro and in vivo explorations. (GCVs) are activated by cytosolic glutathione (GSH) for cancer combination chemotherapy. The GCVs exhibit high camptothecin (CPT) loading content, minimized leakage of encapsulated hydrophilic doxorubicin (DOX), caged cytotoxicity, and extended blood circulation. In cancer cells, cytosolic GSH triggers CPT unplugging and concurrent formation of hydrophilic channels to promote DOX corelease.
language:
source:
identifier: ISSN: 0935-9648 ; E-ISSN: 1521-4095 ; DOI: 10.1002/adma.201706307
fulltext: fulltext
issn:
  • 0935-9648
  • 09359648
  • 1521-4095
  • 15214095
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titleConcurrent Drug Unplugging and Permeabilization of Polyprodrug‐Gated Crosslinked Vesicles for Cancer Combination Chemotherapy
creatorHu, Xianglong ; Zhai, Shaodong ; Liu, Guhuan ; Xing, Da ; Liang, Haojun ; Liu, Shiyong
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subjectCombination Chemotherapy ; Gated Crosslinked Vesicles ; Permeabilization ; Polyprodrug Amphiphiles ; Therapeutic Activation
descriptionCombination chemotherapy with both hydrophobic and hydrophilic therapeutic drugs is clinically vital toward the treatment of persistent cancers. Though conventional liposomes and polymeric vesicles possessing hydrophobic bilayers and aqueous interiors can serve as codelivery nanocarriers, it remains a considerable challenge to achieve synchronized release of both types of drugs due to distinct encapsulation mechanisms; premature release of water‐soluble cargos from unstable liposomes and ruptured vesicles is also a major concern. Herein, the fabrication of physiologically stable polyprodrug‐gated crosslinked vesicles (GCVs) via the self‐assembly of camptothecin (CPT) polyprodrug amphiphiles and in situ bilayer crosslinking through traceless sol–gel reaction is reported. Polyprodrug‐GCVs possess high CPT loading (>30 wt%) and minimized leakage of encapsulated hydrophilic doxorubicin (DOX) hydrochloride due to the suppressed permeability of crosslinked membrane, exhibiting extended blood circulation ( > 13 h) with caged cytotoxicity in physiological circulation. Upon cellular uptake by cancer cells, cytosolic reductive milieu‐triggered CPT unplugging from vesicle bilayers is demonstrated to generate hydrophilic mesh channels and make the membrane highly permeable. Concurrently, it will promote DOX corelease from hydrophilic lumen (≈36‐fold increase). The reduction‐activated combination chemotherapeutic potency based on polyprodrug‐GCVs is confirmed by both in vitro and in vivo explorations. (GCVs) are activated by cytosolic glutathione (GSH) for cancer combination chemotherapy. The GCVs exhibit high camptothecin (CPT) loading content, minimized leakage of encapsulated hydrophilic doxorubicin (DOX), caged cytotoxicity, and extended blood circulation. In cancer cells, cytosolic GSH triggers CPT unplugging and concurrent formation of hydrophilic channels to promote DOX corelease.
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titleConcurrent Drug Unplugging and Permeabilization of Polyprodrug‐Gated Crosslinked Vesicles for Cancer Combination Chemotherapy
descriptionCombination chemotherapy with both hydrophobic and hydrophilic therapeutic drugs is clinically vital toward the treatment of persistent cancers. Though conventional liposomes and polymeric vesicles possessing hydrophobic bilayers and aqueous interiors can serve as codelivery nanocarriers, it remains a considerable challenge to achieve synchronized release of both types of drugs due to distinct encapsulation mechanisms; premature release of water‐soluble cargos from unstable liposomes and ruptured vesicles is also a major concern. Herein, the fabrication of physiologically stable polyprodrug‐gated crosslinked vesicles (GCVs) via the self‐assembly of camptothecin (CPT) polyprodrug amphiphiles and in situ bilayer crosslinking through traceless sol–gel reaction is reported. Polyprodrug‐GCVs possess high CPT loading (>30 wt%) and minimized leakage of encapsulated hydrophilic doxorubicin (DOX) hydrochloride due to the suppressed permeability of crosslinked membrane, exhibiting extended blood circulation ( > 13 h) with caged cytotoxicity in physiological circulation. Upon cellular uptake by cancer cells, cytosolic reductive milieu‐triggered CPT unplugging from vesicle bilayers is demonstrated to generate hydrophilic mesh channels and make the membrane highly permeable. Concurrently, it will promote DOX corelease from hydrophilic lumen (≈36‐fold increase). The reduction‐activated combination chemotherapeutic potency based on polyprodrug‐GCVs is confirmed by both in vitro and in vivo explorations. (GCVs) are activated by cytosolic glutathione (GSH) for cancer combination chemotherapy. The GCVs exhibit high camptothecin (CPT) loading content, minimized leakage of encapsulated hydrophilic doxorubicin (DOX), caged cytotoxicity, and extended blood circulation. In cancer cells, cytosolic GSH triggers CPT unplugging and concurrent formation of hydrophilic channels to promote DOX corelease.
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abstractCombination chemotherapy with both hydrophobic and hydrophilic therapeutic drugs is clinically vital toward the treatment of persistent cancers. Though conventional liposomes and polymeric vesicles possessing hydrophobic bilayers and aqueous interiors can serve as codelivery nanocarriers, it remains a considerable challenge to achieve synchronized release of both types of drugs due to distinct encapsulation mechanisms; premature release of water‐soluble cargos from unstable liposomes and ruptured vesicles is also a major concern. Herein, the fabrication of physiologically stable polyprodrug‐gated crosslinked vesicles (GCVs) via the self‐assembly of camptothecin (CPT) polyprodrug amphiphiles and in situ bilayer crosslinking through traceless sol–gel reaction is reported. Polyprodrug‐GCVs possess high CPT loading (>30 wt%) and minimized leakage of encapsulated hydrophilic doxorubicin (DOX) hydrochloride due to the suppressed permeability of crosslinked membrane, exhibiting extended blood circulation ( > 13 h) with caged cytotoxicity in physiological circulation. Upon cellular uptake by cancer cells, cytosolic reductive milieu‐triggered CPT unplugging from vesicle bilayers is demonstrated to generate hydrophilic mesh channels and make the membrane highly permeable. Concurrently, it will promote DOX corelease from hydrophilic lumen (≈36‐fold increase). The reduction‐activated combination chemotherapeutic potency based on polyprodrug‐GCVs is confirmed by both in vitro and in vivo explorations. (GCVs) are activated by cytosolic glutathione (GSH) for cancer combination chemotherapy. The GCVs exhibit high camptothecin (CPT) loading content, minimized leakage of encapsulated hydrophilic doxorubicin (DOX), caged cytotoxicity, and extended blood circulation. In cancer cells, cytosolic GSH triggers CPT unplugging and concurrent formation of hydrophilic channels to promote DOX corelease.
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