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Synthesis of long-circulating, backbone degradable HPMA copolymer-doxorubicin conjugates and evaluation of molecular-weight-dependent antitumor efficacy.

ABSTRACT: Backbone degradable, linear, multiblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (DOX) conjugates are synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization followed by chain extension via thiol-ene click reaction. The examination of molecular-weight-dependent antitumor activity toward human ovarian A2780/AD carcinoma in nude mice reveals enhanced activity of multiblock, second-generation, higher molecular weight conjugates when compared with traditional HPMA copolymer-DOX conjugates. The examination of body weight changes during treatment indicates the absence of non-specific adverse effects.

SUBMITTER: Pan H

PROVIDER: S-EPMC4595041 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Synthesis of long-circulating, backbone degradable HPMA copolymer-doxorubicin conjugates and evaluation of molecular-weight-dependent antitumor efficacy.

Pan Huaizhong H Sima Monika M Yang Jiyuan J Kopeček Jindřich J

Macromolecular bioscience 20130122 2

Backbone degradable, linear, multiblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (DOX) conjugates are synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization followed by chain extension via thiol-ene click reaction. The examination of molecular-weight-dependent antitumor activity toward human ovarian A2780/AD carcinoma in nude mice reveals enhanced activity of multiblock, second-generation, higher molecular weight conjugates when compared with ...[more]

PMID: 23339052

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Project description:Degradable diblock and multiblock (tetrablock and hexablock) N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-gemcitabine (GEM) and -paclitaxel (PTX) conjugates were synthesized by reversible addition-fragmentation chain-transter (RAFT) copolymerization followed by click reaction for preclinical investigation. The aim was to validate the hypothesis that long-circulating conjugates are needed to generate a sustained concentration gradient between vasculature and a solid tumor and result in significant anticancer effect. To evaluate the impact of molecular weight of the conjugates on treatment efficacy, diblock, tetrablock, and hexablock GEM and PTX conjugates were administered intravenously to nude mice bearing A2780 human ovarian xenografts. For GEM conjugates, triple doses with dosage 5 mg/kg were given on days 0, 7, and 14 (q7dx3), whereas a single dose regime with 20 mg/kg was applied on day 0 for PTX conjugates treatment. The most effective conjugates for each monotherapy were the diblock ones, 2P-GEM and 2P-PTX (Mw ≈ 100 kDa). Increasing the Mw to 200 or 300 kDa resulted in decrease of activity most probably due to changes in the conformation of the macromolecule because of interaction of hydrophobic residues at side chain termini and formation of "unimer micelles". In addition to monotherapy, a sequential combination treatment of diblock PTX conjugate followed by GEM conjugate (2P-PTX/2P-GEM) was also performed, which showed the best tumor growth inhibition due to synergistic effect: complete remission was achieved after the first treatment cycle. However, because of low dose applied, tumor recurrence was observed 2 weeks after cease of treatment. To assess optimal route of administration, intraperitoneal (i.p.) application of 2P-GEM, 2P-PTX, and their combination was examined. The fact that the highest anticancer efficiency was achieved with diblock conjugates that can be synthesized in one scalable step bodes well for the translation into clinics.

Dataset Information

Synthesis of long-circulating, backbone degradable HPMA copolymer-doxorubicin conjugates and evaluation of molecular-weight-dependent antitumor efficacy.

Publications

Synthesis of long-circulating, backbone degradable HPMA copolymer-doxorubicin conjugates and evaluation of molecular-weight-dependent antitumor efficacy.

Similar Datasets

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