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pH-sensitive poly (histidine)-PEG/DSPE-PEG co-polymer micelles for cytosolic drug delivery
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To introduce pH sensitivity into the DSPE-PEG-based micellar system and achieve the quick intracellular drug release in response to the acidity in endosomes, a mixed polymeric micelle was developed based on three grafted copolymers, including 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000(DSPE-PEG(2000)), antinucleosome antibody (mAb 2C5)-modified DSPE-PEG(3400) (DSPE-PEG(3400)-2C5), and poly(ethylene glycol)-coupled poly(L-histidine) (PHIS-PEG(2000)). The structure of PHIS-PEG(2000) was confirmed by (1)H NMR spectroscopy. The mixed micelles with the diameter ranging from 110 to 135 nm were prepared using a dialysis method against pH 7.6 PBS. Paclitaxel (PCT) was used as a model drug, the encapsulation efficiency and loading content of PCT were 88% and 5%, respectively. The mixed micelles composed with 50 wt% of PHIS-PEG(2000) showed the desired pH-dependent drug release property with much faster drug release than micelles without PHIS-PEG(2000). At pH around 5.5, about 75-95% of the loaded drug was released within 2 h. The MTT assay showed PCT-loaded mixed micelles had higher cytotoxicity at pH 5.8 than that at pH 7.4. Further modification of the mixed micelles with anti-cancer nucleosome-specific monoclonal antibody 2C5 significantly increased their cellular uptake efficiency and cytotoxicity. Thus, the low pH in endosomes could trigger the PCT release from the pH-sensitive mixed micelles after 2C5-mediated endocytosis. The results of this study suggest that the mixed micelles (DSPE-PEG(2000)/DSPE-PEG(3400)-2C5/PHIS-PEG(2000)) could enhance the tumor cell-specific internalization and trigger the quick drug release, resulting in the improved anti-cancer efficacy.
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“Several pH-sensitive polymers have been employed in polymeric micelle formulations including polycations such as poly(histidine) [131], poly(4-vinylpyridine) [132], poly(N,N-dimethylaminoethylmethacrylate) [133], poly(β-amino ester) (PBAE) [134], and polyanions, such as poly(acrylic acid) [135], poly(methacrylic acid) (PMAA) [136], and poly(sulfonamides) [137].”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [131]
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“Therefore, poly(histidine) can be used as a core-forming block in the polymeric micelles that is hydrophobic at the extracellular pH but becomes positively charged and soluble upon acidification, which can result in the local release of an incorporated drug [131].”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [131]
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“On the other hand, the imidazole groups in poly(histidine) are uncharged at the physiologic pH 7.4 and become protonated at acidic pH.”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [131]
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Metadata
- Authors
- Wu, H., Zhu, L., & Torchilin, V. P.
- Affiliations
- Northeastern University (US)
- Corresponding author
- Torchilin, Vladimir P.
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 34
- Issue
- 4
- Pages
- 1213-1222
- ISSN
- 0142-9612 (ISSN-L)
- PMC
- PMC3587181
- OpenAlex
- W1979335059
- Cited by
- 355
- References
- 40
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 11 · 2023: 13 · 2022: 27 · 2021: 25 · 2020: 26 · 2019: 33 · 2018: 30 · 2017: 45 · 2016: 37 · 2015: 40 · 2014: 31 · 2013: 12
- FWCI
- 10.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (1R01CA121838)
- National Natural Science Foundation of China (30970788)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- pH-responsive micelles, DSPE-PEG, mixed micelles, paclitaxel, cellular uptake, tumor cell internalization, cytosolic drug delivery, anticancer drug delivery
- MeSH terms
- Animals, Antineoplastic Agents, Phytogenic, Breast Neoplasms, Cytosol, Diffusion, Hydrogen-Ion Concentration, Micelles, Phosphatidylethanolamines, Polyethylene Glycols, Proteins, Paclitaxel, Cell Line, Tumor, Mice, Nanocapsules
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