Block copolymer micelles with acid-labile ortho ester side-chains: synthesis, characterization, and enhanced drug delivery to human glioma cells
Open accessAbstract
A new type of block copolymer micelles for pH-triggered delivery of poorly water-soluble anticancer drugs has been synthesized and characterized. The micelles were formed by the self-assembly of an amphiphilic diblock copolymer consisting of a hydrophilic poly(ethylene glycol) (PEG) block and a hydrophobic polymethacrylate block (PEYM) bearing acid-labile ortho ester side-chains. The diblock copolymer was synthesized by atom transfer radical polymerization (ATRP) from a PEG macro-initiator to obtain well-defined polymer chain-length. The PEG-b-PEYM micelles assumed a stable core-shell structure in aqueous buffer at physiological pH with a low critical micelle concentration as determined by proton NMR and pyrene fluorescence spectroscopy. The hydrolysis of the ortho ester side-chain at physiological pH was minimal yet much accelerated at mildly acidic pHs. Doxorubicin (Dox) was successfully loaded into the micelles at pH 7.4 and was released at a much higher rate in response to slight acidification to pH 5. Interestingly, the release of Dox at pH 5 followed apparently a biphasic profile, consisting of an initial fast phase of several hours followed by a sustained release period of several days. Dox loaded in the micelles was rapidly taken up by human glioma (T98G) cells in vitro, accumulating in the endolysosome and subsequently in the nucleus in a few hours, in contrast to the very low uptake of free drug at the same dose. The dose-dependent cytotoxicity of the Dox-loaded micelles was determined by the MTT assay and compared with that of the free Dox. While the empty micelles themselves were not toxic, the IC(50) values of the Dox-loaded micelles were approximately ten-times (by 24h) and three-times (by 48h) lower than the free drug. The much enhanced potency in killing the multi-drug-resistant human glioma cells by Dox loaded in the micelles could be attributed to high intracellular drug concentration and the subsequent pH-triggered drug release. These results establish the PEG-b-PEYM block copolymer with acid-labile ortho ester side-chains as a novel and effective pH-responsive nano-carrier for enhancing the delivery of drugs to cancer cells.
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San Miguel et al. analyzed the effects of the length of the hydrophilic block of three block copolymers on drug incorporation and release.
“For example, a study was conducted by San Miguel et al. [125] to analyze the effects of the length of the hydrophilic block of three block copolymers on drug incorporation and release.”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [125]
The Results (3.1; page unavailable) identify three copolymers, but say their hydrophobic PEYM blocks—not their hydrophilic PEG blocks—differed in length. The Methods (2.5; page unavailable) state that the subsequent micelle characterization focused on PEG-b-PEYM45. The cited paper therefore does not describe the attributed comparison of hydrophilic-block length across three copolymers. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredThe release profiles of chlorambucil from PDMAEMA-b-PCL micelles differed depending on the length of PDMAEMA blocks (polymerization degree 20, 25, or 30) and helped to figure out the mechanisms involved, i.e., a combination of degradation and diffusion.
“The release profiles, that differed depending on the length of PDMAEMA blocks (polymerization degree: 20, 25 or 30) (Fig. 5A), helped to figure out the mechanisms involved in the release, i. e. a combination of degradation and diffusion (See Fig. 4).”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [125]
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- Authors
- Tang, R., Ji, W., Panus, D., Palumbo, R. N., & Wang, C.
- Affiliations
- Jiangnan University (CN)
- University of Minnesota (US)
- Corresponding author
- Wang, Chun
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 151
- Issue
- 1
- Pages
- 18-27
- ISSN
- 0168-3659 (ISSN-L)
- PMC
- PMC3081958
- OpenAlex
- W2052979358
- Cited by
- 202
- References
- 59
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 7 · 2022: 6 · 2021: 10 · 2020: 13 · 2019: 13 · 2018: 15 · 2017: 24 · 2016: 16 · 2015: 18 · 2014: 22 · 2013: 26 · 2012: 13
- FWCI
- 5.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA129189)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Chemistry › Organic Chemistry › Advanced Polymer Synthesis and Characterization
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- block copolymer micelles, pH-responsive drug delivery, atom transfer radical polymerization, doxorubicin, glioma cells, T98G cells, core-shell micelles, multidrug resistance, nanoparticle drug carriers
- MeSH terms
- Antibiotics, Antineoplastic, Cell Survival, Delayed-Action Preparations, Doxorubicin, Glioma, Humans, Hydrogen-Ion Concentration, Micelles, Polyethylene Glycols, Polymethacrylic Acids, Cell Line, Tumor
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