title: 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.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Kui
authors.initials: K
authors.lastname: Luo
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Yang
authors.forename: Monika
authors.initials: M
authors.lastname: Sima
authors.forename: Yongen
authors.initials: Y
authors.lastname: Sun
authors.forename: Margit M
authors.initials: MM
authors.lastname: Janát-Amsbury
authors.forename: Jindřich
authors.initials: J
authors.lastname: Kopeček
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis* / Q000737:chemistry; D000180:Acrylic Resins / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001672:Biocompatible Materials / Q000138:chemical synthesis* / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D053758:Nanoparticles / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D000180:Acrylic Resins; D000972:Antineoplastic Agents, Phytogenic; D001672:Biocompatible Materials; D004337:Drug Carriers; C582518:N-(2-hydroxypropyl)methacrylamide copolymer-paclitaxel conjugate; D017239:Paclitaxel; C032976:N-(2-hydroxypropyl)methacrylamide