Interlayer‐Crosslinked Micelle with Partially Hydrated Core Showing Reduction and pH Dual Sensitivity for Pinpointed Intracellular Drug Release

Dai, Jian; Lin, Shudong; Cheng, Du; Zou, Seyin; Shuai, Xintao

doi:10.1002/anie.201103806

Cited by 371 publications

(239 citation statements)

References 32 publications

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“…15 Thus, the development of new polymer scaffolds that can undergo cleavage by pH variation at the cancer tissue level (in the range of 6.5 to 5.0) and enzymes (like esterase or glutathione transferase) in intracellular compartments could give potential dual stimuli vectors for efficient drug administration. 16 Avidin responsive dendrimer based assemblies, 17 trypsin and hepsin cleavable peptide nanoparticles, 18 sugar and pH responsive mesoporous silica, 19 glucose oxidase, myoglobin and pH responsive crosslinked polymersomes, 20 carbohydrate coated graphene nanocarriers 21 and glutathione and pH responsive micelles 22 are some important example materials for the achieving the above target. Gu and coworkers 23 recently reviewed the roles of various enzyme-responsive nanomaterials for controlled drug delivery.…”

Section: Introductionmentioning

confidence: 99%

Dual stimuli polysaccharide nanovesicles for conjugated and physically loaded doxorubicin delivery in breast cancer cells

2015

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The present work reports the development of pH and enzyme dual responsive polysaccharide vesicular nano-scaffolds for the administration of doxorubicin via physical loading and polymer-drug conjugation to breast cancer cells. Dextran was suitably modified with a renewable resource 3-pentadecyl phenol unit through imine and aliphatic ester chemical linkages that acted as pH and esterase enzyme stimuli, respectively. These dual responsive polysaccharide derivatives self-organized into 200 ± 10 nm diameter nano-vesicles in water. The water soluble anticancer drug doxorubicin (DOX·HCl) was encapsulated in the hydrophilic pocket to produce core-loaded polysaccharide vesicles whereas chemical conjugation produced DOX anchored at the hydrophobic layer of the dextran nano-vesicles. In vitro studies revealed that about 70-80% of the drug was retained under circulatory conditions at pH = 7.4 and 37 °C. At a low pH of 6.0 to 5.0 and in the presence of esterase; both imine and ester linkages were cleaved instantaneously to release 100% of the loaded drugs. Cytotoxicity assays on Wild Type Mouse Embryonic Fibroblasts (WTMEFs) confirmed the non-toxicity of the newly developed dextran derivatives at up to 500 μg mL(-1) in PBS. MTT assays on fibroblast cells revealed that DOX·HCl loaded nano-vesicles exhibited better killing abilities than DOX conjugated polymer nano-vesicles. Both DOX loaded and DOX conjugated nano-vesicles were found to show significant killing in breast cancer cells (MCF 7). Confocal microscopy images confirmed the uptake of DOX loaded (or conjugated) nano-vesicles by cells compared to free DOX. Thus, the newly developed pH and enzyme dual responsive polysaccharide vesicular assemblies are potential drug vectors for the administration of DOX in both loaded and chemically conjugated forms for the efficient killing of breast cancer cells.

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Section: Introductionmentioning

confidence: 99%

Dual stimuli polysaccharide nanovesicles for conjugated and physically loaded doxorubicin delivery in breast cancer cells

2015

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“…However, no pH-triggered release of drugs can be achieved inside tumor cells, which is very important for the chemotherapy of cancers. [34][35][36] In the present study, degradable polyaspartamide amphiphilic derivatives phe/DEAE-g-PHPA-g-mPEGs containing pendant SCHEME 1 Synthesis and structure of the polymers phe/DEAEg-PHPA (x 5 0; 0 < y, z < 1) and phe/DEAE-g-PHPA-g-mPEG (0 < x, y, z < 1).…”

Section: Resultsmentioning

confidence: 99%

Temperature and pH dual‐sensitive polyaspartamide derivatives for antitumor drug delivery

Zhang

et al. 2015

J. Polym. Sci. Part A: Polym. Chem.

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The pH-sensitive tertiary amino groups were introduced to synthesize temperature and pH dual-sensitive degradable polyaspartamide derivatives (phe/DEAE-g-PHPA) containing pendant aromatic structures and ionizable tertiary amino groups. The thermo/pH-responsive behavior of phe/ DEAE-g-PHPA polymer can be tuned by adjusting the graft copolymer composition. Due to the pH sensitivity of the phe/ DEAE-g-PHPA-g-mPEG polymer with hydrophilic long PEG chain, the micelles and the anticancer drug-loaded micelles were prepared by a quick pH-changing method without using toxic organic solvent. The obtained polymeric micelles, paclitaxel-loaded micelles and doxorubicin-loaded micelles were stable under physiological conditions. Both the drugloaded micelles showed much faster release at pH 5 than at pH 7.4. The doxorubicin-loaded micelles showed obvious and better anticancer activity against both HepG2 and HeLa cells than free doxorubicin. Thus these nontoxic, dual thermo-and pHsensitive phe/DEAE-g-PHPA-g-mPEG micelles may be a promising anticancer drug delivery system.

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“…In micelles, PEG forms an outer corona stabilizing the micelles to avoid uptake of reticuloendothelial system [27], [28]. P(Asp-DIP) is a pH-sensitive interlayer that undergoes hydrophobic-hydrophilic transition in the acidic lysosomes of cells [29]. Cholic acid (Ca) forms the micelle core to encapsulate hydrophobic drugs and also contribute to rapid drug release [18], [30].…”

Section: Discussionmentioning

confidence: 99%

pH-Sensitive Nanomicelles for Controlled and Efficient Drug Delivery to Human Colorectal Carcinoma LoVo Cells

Feng

Luo

et al. 2014

PLoS ONE

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BackgroundThe triblock copolymers PEG-P(Asp-DIP)-P(Lys-Ca) (PEALCa) of polyethylene glycol (PEG), poly(N-(N’,N’-diisopropylaminoethyl) aspartamide) (P(Asp-DIP)), and poly (lysine-cholic acid) (P(Lys-Ca)) were synthesized as a pH-sensitive drug delivery system. In neutral aqueous environment such as physiological environment, PEALCa can self-assemble into stable vesicles with a size around 50-60 nm, avoid uptake by the reticuloendothelial system (RES), and encase the drug in the core. However, the PEALCa micelles disassemble and release drug rapidly in acidic environment that resembles lysosomal compartments.Methodology/Principal FindingsThe anticancer drug Paclitaxel (PTX) and hydrophilic superparamagnetic iron oxide (SPIO) were encapsulated inside the core of the PEALCa micelles and used for potential cancer therapy. Drug release study revealed that PTX in the micelles was released faster at pH 5.0 than at pH 7.4. Cell culture studies showed that the PTX-SPIO-PEALCa micelle was effectively internalized by human colon carcinoma cell line (LoVo cells), and PTX could be embedded inside lysosomal compartments. Moreover, the human colorectal carcinoma (CRC) LoVo cells delivery effect was verified in vivo by magnetic resonance imaging (MRI) and histology analysis. Consequently effective suppression of CRC LoVo cell growth was evaluated.Conclusions/SignificanceThese results indicated that the PTX-SPION-loaded pH-sensitive micelles were a promising MRI-visible drug release system for colorectal cancer therapy.

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Interlayer‐Crosslinked Micelle with Partially Hydrated Core Showing Reduction and pH Dual Sensitivity for Pinpointed Intracellular Drug Release

Cited by 371 publications

References 32 publications

Dual stimuli polysaccharide nanovesicles for conjugated and physically loaded doxorubicin delivery in breast cancer cells

Dual stimuli polysaccharide nanovesicles for conjugated and physically loaded doxorubicin delivery in breast cancer cells

Temperature and pH dual‐sensitive polyaspartamide derivatives for antitumor drug delivery

pH-Sensitive Nanomicelles for Controlled and Efficient Drug Delivery to Human Colorectal Carcinoma LoVo Cells

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