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Synthesis and evaluation of a backbone biodegradable multiblock HPMA copolymer nanocarrier for the systemic delivery of paclitaxel.
- Source :
-
Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2013 Feb 28; Vol. 166 (1), pp. 66-74. Date of Electronic Publication: 2012 Dec 20. - Publication Year :
- 2013
-
Abstract
- The performance and safety of current antineoplastic agents, particularly water-insoluble drugs, are still far from satisfactory. For example, the currently widely used Cremophor EL®-based paclitaxel (PTX) formulation exhibits pharmacokinetic concerns and severe side effects. Thus, the concept of a biodegradable polymeric drug-delivery system, which can significantly improve therapeutic efficacy and reduce side effects is advocated. The present work aims to develop a new-generation of long-circulating, biodegradable carriers for effective delivery of PTX. First, a multiblock backbone biodegradable N-(2-hydroxypropyl)methacrylamide(HPMA) copolymer-PTX conjugate (mP-PTX) with molecular weight (Mw) of 335 kDa was synthesized by RAFT (reversible addition-fragmentation chain transfer) copolymerization, followed by chain extension. In vitro studies on human ovarian carcinoma A2780 cells were carried out to investigate the cytotoxicity of free PTX, HPMA copolymer-PTX conjugate with Mw of 48 kDa (P-PTX), and mP-PTX. The experiments demonstrated that mP-PTX has a similar cytotoxic effect against A2780 cells as free PTX and P-PTX. To further compare the behavior of this new biodegradable conjugate (mP-PTX) with free PTX and P-PTX in vivo evaluation was performed using female nu/nu mice bearing orthotopic A2780 ovarian tumors. Pharmacokinetics study showed that high Mw mP-PTX was cleared more slowly from the blood than commercial PTX formulation and low Mw P-PTX. SPECT/CT imaging and biodistribution studies demonstrated biodegradability as well as elimination of mP-PTX from the body. The tumors in the mP-PTX treated group grew more slowly than those treated with saline, free PTX, and P-PTX (single dose at 20 mg PTX/kg equivalent). Moreover, mice treated with mP-PTX had no obvious ascites and body-weight loss. Histological analysis indicated that mP-PTX had no toxicity in liver and spleen, but induced massive cell death in the tumor. In summary, this biodegradable drug delivery system has a great potential to improve performance and safety of current antineoplastic agents.<br /> (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Subjects :
- Acrylamides chemistry
Acrylic Resins chemistry
Acrylic Resins pharmacokinetics
Acrylic Resins therapeutic use
Animals
Antineoplastic Agents, Phytogenic pharmacokinetics
Antineoplastic Agents, Phytogenic therapeutic use
Biocompatible Materials chemistry
Cell Line, Tumor
Cell Survival drug effects
Drug Carriers chemistry
Female
Humans
Mice
Mice, Nude
Molecular Weight
Ovarian Neoplasms drug therapy
Ovarian Neoplasms pathology
Paclitaxel chemical synthesis
Paclitaxel chemistry
Paclitaxel pharmacokinetics
Paclitaxel therapeutic use
Tissue Distribution
Xenograft Model Antitumor Assays
Acrylamides chemical synthesis
Acrylic Resins chemical synthesis
Antineoplastic Agents, Phytogenic administration & dosage
Biocompatible Materials chemical synthesis
Drug Carriers chemical synthesis
Nanoparticles chemistry
Paclitaxel administration & dosage
Paclitaxel analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4995
- Volume :
- 166
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of controlled release : official journal of the Controlled Release Society
- Publication Type :
- Academic Journal
- Accession number :
- 23262201
- Full Text :
- https://doi.org/10.1016/j.jconrel.2012.12.009