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Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery.
J Control Release 2005; 103(2):341-53JC

Abstract

The preparation, release and in vitro cytotoxicity of a novel polymeric micellar formulation of paclitaxel (PTX) were investigated. The micelles consisted of an AB block copolymer of poly(N-(2-hydroxypropyl) methacrylamide lactate) and poly(ethylene glycol) (pHPMAmDL-b-PEG). Taking advantage of the thermosensitivity of pHPMAmDL-b-PEG, the loading was done by simply mixing of a small volume of a concentrated PTX solution in ethanol and an aqueous polymer solution and subsequent heating of the resulting solution above the critical micelle temperature of the polymer. PTX could be almost quantitatively loaded in the micelles up to 2 mg/mL. By dynamic light scattering and cryo-transmission electron microscopy, it was shown that PTX-loaded micelles have a mean size around 60 nm with narrow size distribution. At pH 8.8 and 37 degrees C, PTX-loaded micelles destabilized within 10 h due to the hydrolysis of the lactic acid side group of the pHPMAmDL. Because the hydrolysis of the lactic acid side groups is first order in hydroxyl ion concentration, the micelles were stable for about 200 h at physiological conditions. The presence of serum proteins did not have an adverse effect on the stability of the micelles during at least 15 h. Interestingly, the dissolution kinetics of pHPMAmDL-b-PEG micelles was retarded by incorporation of PTX, indicating a strong interaction between PTX and the pHPMAmDL block. The PTX-loaded micelles showed a release of the incorporated 70% of PTX during 20 h at 37 degrees C and at pH 7.4. PTX-loaded pHPMAmDL-b-PEG micelles showed comparable in vitro cytotoxicity against B16F10 cells compared to the Taxol standard formulation containing Cremophor EL, while pHPMAmDL-b-PEG micelles without PTX were far less toxic than the Cremophor EL vehicle. Confocal laser-scanning microscopy (CLSM) and fluorescence activated cell sorting (FACS) analysis of fluorescently labelled micelles showed that pHPMAmDL-b-PEG micelles were internalized by the B16F10 cells. The present results suggest that pHPMAmDL-b-PEG block copolymer micelles are a promising delivery system for the parenteral administration of PTX.

Authors+Show Affiliations

Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Pharmaceutical Sciences, Utrecht University, P.O. Box 80.082, 3508 TB Utrecht, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo 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

15763618

Citation

Soga, Osamu, et al. "Thermosensitive and Biodegradable Polymeric Micelles for Paclitaxel Delivery." Journal of Controlled Release : Official Journal of the Controlled Release Society, vol. 103, no. 2, 2005, pp. 341-53.
Soga O, van Nostrum CF, Fens M, et al. Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery. J Control Release. 2005;103(2):341-53.
Soga, O., van Nostrum, C. F., Fens, M., Rijcken, C. J., Schiffelers, R. M., Storm, G., & Hennink, W. E. (2005). Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery. Journal of Controlled Release : Official Journal of the Controlled Release Society, 103(2), pp. 341-53.
Soga O, et al. Thermosensitive and Biodegradable Polymeric Micelles for Paclitaxel Delivery. J Control Release. 2005 Mar 21;103(2):341-53. PubMed PMID: 15763618.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery. AU - Soga,Osamu, AU - van Nostrum,Cornelus F, AU - Fens,Marcel, AU - Rijcken,Cristianne J F, AU - Schiffelers,Raymond M, AU - Storm,Gert, AU - Hennink,Wim E, PY - 2004/08/27/received PY - 2004/11/29/revised PY - 2004/12/02/accepted PY - 2005/3/15/pubmed PY - 2005/9/1/medline PY - 2005/3/15/entrez SP - 341 EP - 53 JF - Journal of controlled release : official journal of the Controlled Release Society JO - J Control Release VL - 103 IS - 2 N2 - The preparation, release and in vitro cytotoxicity of a novel polymeric micellar formulation of paclitaxel (PTX) were investigated. The micelles consisted of an AB block copolymer of poly(N-(2-hydroxypropyl) methacrylamide lactate) and poly(ethylene glycol) (pHPMAmDL-b-PEG). Taking advantage of the thermosensitivity of pHPMAmDL-b-PEG, the loading was done by simply mixing of a small volume of a concentrated PTX solution in ethanol and an aqueous polymer solution and subsequent heating of the resulting solution above the critical micelle temperature of the polymer. PTX could be almost quantitatively loaded in the micelles up to 2 mg/mL. By dynamic light scattering and cryo-transmission electron microscopy, it was shown that PTX-loaded micelles have a mean size around 60 nm with narrow size distribution. At pH 8.8 and 37 degrees C, PTX-loaded micelles destabilized within 10 h due to the hydrolysis of the lactic acid side group of the pHPMAmDL. Because the hydrolysis of the lactic acid side groups is first order in hydroxyl ion concentration, the micelles were stable for about 200 h at physiological conditions. The presence of serum proteins did not have an adverse effect on the stability of the micelles during at least 15 h. Interestingly, the dissolution kinetics of pHPMAmDL-b-PEG micelles was retarded by incorporation of PTX, indicating a strong interaction between PTX and the pHPMAmDL block. The PTX-loaded micelles showed a release of the incorporated 70% of PTX during 20 h at 37 degrees C and at pH 7.4. PTX-loaded pHPMAmDL-b-PEG micelles showed comparable in vitro cytotoxicity against B16F10 cells compared to the Taxol standard formulation containing Cremophor EL, while pHPMAmDL-b-PEG micelles without PTX were far less toxic than the Cremophor EL vehicle. Confocal laser-scanning microscopy (CLSM) and fluorescence activated cell sorting (FACS) analysis of fluorescently labelled micelles showed that pHPMAmDL-b-PEG micelles were internalized by the B16F10 cells. The present results suggest that pHPMAmDL-b-PEG block copolymer micelles are a promising delivery system for the parenteral administration of PTX. SN - 0168-3659 UR - https://www.unboundmedicine.com/medline/citation/15763618/Thermosensitive_and_biodegradable_polymeric_micelles_for_paclitaxel_delivery_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-3659(04)00597-8 DB - PRIME DP - Unbound Medicine ER -