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Synthesis and evaluation of a backbone biodegradable multiblock HPMA copolymer nanocarrier for the systemic delivery of paclitaxel.

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.
AuthorsRui Zhang, Kui Luo, Jiyuan Yang, Monika Sima, Yongen Sun, Margit M Janát-Amsbury, Jindřich Kopeček
JournalJournal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 166 Issue 1 Pg. 66-74 (Feb 28 2013) ISSN: 1873-4995 [Electronic] Netherlands
PMID23262201 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2012 Elsevier B.V. All rights reserved.
Chemical References
  • Acrylamides
  • Acrylic Resins
  • Antineoplastic Agents, Phytogenic
  • Biocompatible Materials
  • Drug Carriers
  • N-(2-hydroxypropyl)methacrylamide copolymer-paclitaxel conjugate
  • N-(2-hydroxypropyl)methacrylamide
  • Paclitaxel
Topics
  • Acrylamides (chemical synthesis, chemistry)
  • Acrylic Resins (chemical synthesis, chemistry, pharmacokinetics, therapeutic use)
  • Animals
  • Antineoplastic Agents, Phytogenic (administration & dosage, pharmacokinetics, therapeutic use)
  • Biocompatible Materials (chemical synthesis, chemistry)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Drug Carriers (chemical synthesis, chemistry)
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Molecular Weight
  • Nanoparticles (chemistry)
  • Ovarian Neoplasms (drug therapy, pathology)
  • Paclitaxel (administration & dosage, analogs & derivatives, chemical synthesis, chemistry, pharmacokinetics, therapeutic use)
  • Tissue Distribution
  • Xenograft Model Antitumor Assays

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