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Solubilization and controlled release of a hydrophobic drug using novel micelle-forming ABC triblock copolymers.
Biomacromolecules 2003 Nov-Dec; 4(6):1636-45B

Abstract

Amphiphilic ABC triblock copolymers composed of monomethoxy-capped poly(ethylene glycol) (MPEG), poly(2-(dimethylamino)ethyl methacrylate) (DMA), and poly(2-(diethylamino)ethyl methacrylate) (DEA) have been synthesized by atom transfer radical polymerization (ATRP). These copolymers dissolve molecularly in acidic aqueous media at room temperature due to protonation of the tertiary amine groups on the DMA and DEA residues. On adjusting the pH with base, micellization occurred at pH 8, with the water-insoluble, deprotonated DEA block forming the hydrophobic cores and the MPEG and DMA blocks forming the hydrophilic micellar coronas and inner shells, respectively. This pH-induced micellization has been exploited to develop a solvent-free protocol for drug loading. A model hydrophobic drug, dipyridamole (DIP), which dissolves in acid but is insoluble above pH 5.8, was incorporated into the micelles by increasing the pH of an aqueous drug/copolymer mixture to 9. Both the empty and the drug-loaded micelles were characterized by dynamic light scattering and fluorescence studies. The interaction of both pyrene and DIP with the MPEG-DMA-DEA micelles was studied by fluorescence; both compounds had relatively high partition coefficients into the micelles, 4.5 x 10(5) and 1.5 x 10(4), respectively. Intensity-average micelle diameters ranged from 20 to 90 nm, depending on the polymer composition and concentration. Shorter MPEG blocks (Mn = 2000) produced larger micelles than longer MPEG blocks (Mn = 5000) due to the shift in the hydrophilic-hydrophobic balance of the copolymer. Transmission electron microscopy studies of the drug-loaded micelles indicated spherical morphologies and reasonably uniform particle size distributions, which is in marked contrast to the needlelike morphology observed for pure DIP in the absence of the copolymer. Experiments on controlled release demonstrated that DIP-loaded MPEG-DMA-DEA micelles act as a drug carrier, giving slow release to the surrounding solution over a period of days. Rapid release can be triggered by reducing the pH to reverse the micellization.

Authors+Show Affiliations

Department of Chemistry, University of Sussex, Falmer, Brighton BN1 9QJ, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14606890

Citation

Tang, Yiqing, et al. "Solubilization and Controlled Release of a Hydrophobic Drug Using Novel Micelle-forming ABC Triblock Copolymers." Biomacromolecules, vol. 4, no. 6, 2003, pp. 1636-45.
Tang Y, Liu SY, Armes SP, et al. Solubilization and controlled release of a hydrophobic drug using novel micelle-forming ABC triblock copolymers. Biomacromolecules. 2003;4(6):1636-45.
Tang, Y., Liu, S. Y., Armes, S. P., & Billingham, N. C. (2003). Solubilization and controlled release of a hydrophobic drug using novel micelle-forming ABC triblock copolymers. Biomacromolecules, 4(6), pp. 1636-45.
Tang Y, et al. Solubilization and Controlled Release of a Hydrophobic Drug Using Novel Micelle-forming ABC Triblock Copolymers. Biomacromolecules. 2003;4(6):1636-45. PubMed PMID: 14606890.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Solubilization and controlled release of a hydrophobic drug using novel micelle-forming ABC triblock copolymers. AU - Tang,Yiqing, AU - Liu,Shiyong Y, AU - Armes,Steven P, AU - Billingham,Norman C, PY - 2003/11/11/pubmed PY - 2004/7/28/medline PY - 2003/11/11/entrez SP - 1636 EP - 45 JF - Biomacromolecules JO - Biomacromolecules VL - 4 IS - 6 N2 - Amphiphilic ABC triblock copolymers composed of monomethoxy-capped poly(ethylene glycol) (MPEG), poly(2-(dimethylamino)ethyl methacrylate) (DMA), and poly(2-(diethylamino)ethyl methacrylate) (DEA) have been synthesized by atom transfer radical polymerization (ATRP). These copolymers dissolve molecularly in acidic aqueous media at room temperature due to protonation of the tertiary amine groups on the DMA and DEA residues. On adjusting the pH with base, micellization occurred at pH 8, with the water-insoluble, deprotonated DEA block forming the hydrophobic cores and the MPEG and DMA blocks forming the hydrophilic micellar coronas and inner shells, respectively. This pH-induced micellization has been exploited to develop a solvent-free protocol for drug loading. A model hydrophobic drug, dipyridamole (DIP), which dissolves in acid but is insoluble above pH 5.8, was incorporated into the micelles by increasing the pH of an aqueous drug/copolymer mixture to 9. Both the empty and the drug-loaded micelles were characterized by dynamic light scattering and fluorescence studies. The interaction of both pyrene and DIP with the MPEG-DMA-DEA micelles was studied by fluorescence; both compounds had relatively high partition coefficients into the micelles, 4.5 x 10(5) and 1.5 x 10(4), respectively. Intensity-average micelle diameters ranged from 20 to 90 nm, depending on the polymer composition and concentration. Shorter MPEG blocks (Mn = 2000) produced larger micelles than longer MPEG blocks (Mn = 5000) due to the shift in the hydrophilic-hydrophobic balance of the copolymer. Transmission electron microscopy studies of the drug-loaded micelles indicated spherical morphologies and reasonably uniform particle size distributions, which is in marked contrast to the needlelike morphology observed for pure DIP in the absence of the copolymer. Experiments on controlled release demonstrated that DIP-loaded MPEG-DMA-DEA micelles act as a drug carrier, giving slow release to the surrounding solution over a period of days. Rapid release can be triggered by reducing the pH to reverse the micellization. SN - 1525-7797 UR - https://www.unboundmedicine.com/medline/citation/14606890/Solubilization_and_controlled_release_of_a_hydrophobic_drug_using_novel_micelle_forming_ABC_triblock_copolymers_ L2 - https://dx.doi.org/10.1021/bm030026t DB - PRIME DP - Unbound Medicine ER -