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Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates.

ABSTRACT: For rapid and effective clinical translation, polymer-based anticancer therapeutics need long circulating conjugates that produce a sustained concentration gradient between the vasculature and solid tumor. To this end, we designed second-generation backbone-degradable diblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers and evaluated sequential combination therapy of HPMA copolymer-paclitaxel and HPMA copolymer-gemcitabine conjugates against A2780 human ovarian carcinoma xenografts. First, extensive in vitro assessment of administration sequence impact on cell cycle, viability, apoptosis, migration, and invasion revealed that treatment with paclitaxel conjugate followed by gemcitabine conjugate was the most effective scheduling strategy. Second, in an in vivo comparison with first-generation (nondegradable, molecular weight below the renal threshold) conjugates and free drugs, the second-generation degradable high-molecular weight conjugates showed distinct advantages, such as favorable pharmacokinetics (three- to five-times half-life compared with the first generation), dramatically enhanced inhibition of tumor growth (complete tumor regression) by paclitaxel and gemcitabine conjugate combination, and absence of adverse effects. In addition, multimodality imaging studies of dual-labeled model conjugates confirmed the efficacy of second-generation conjugates by visualizing more than five-times enhanced tumor accumulation, rapid conjugate internalization, and effective intracellular release of payload. Taken together, the results indicate that the second-generation degradable HPMA copolymer carrier can provide an ideal platform for the delivery of a range of antitumor compounds, which makes it one of the most attractive candidates for potential clinical application.

SUBMITTER: Zhang R

PROVIDER: S-EPMC4143033 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates.

Zhang Rui R Yang Jiyuan J Sima Monika M Zhou Yan Y Kopeček Jindřich J

Proceedings of the National Academy of Sciences of the United States of America 20140804 33

For rapid and effective clinical translation, polymer-based anticancer therapeutics need long circulating conjugates that produce a sustained concentration gradient between the vasculature and solid tumor. To this end, we designed second-generation backbone-degradable diblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers and evaluated sequential combination therapy of HPMA copolymer-paclitaxel and HPMA copolymer-gemcitabine conjugates against A2780 human ovarian carcinoma xenograft ...[more]

PMID: 25092316

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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.

Project description:The design, synthesis, and physicochemical characterization of conjugates are arduous and tedious processes. Several synthetic pathways for polymeric conjugation have been reported; however, conjugation through monomers with suitable reaction conditions can be a simple and robust approach. In the present study, three different conjugates of hydrophilic N-2-hydroxypropyl methacrylamide (HPMA) and hydrophobic polycaprolactone (PCL) were synthesized. The followed synthetic pathway not only was simple and robust but also reduced the overall synthetic steps as well as harsh reaction conditions significantly. In a nutshell, three conjugates, i.e., N-2-hydroxypropyl methacrylamide and polycaprolactone (HP-PCL), n-butanol-polycaprolactone-N-2-hydroxypropyl methacrylamide (nBu-PCL-HP), and isoamyl alcohol-polycaprolactone-N-2-hydroxypropyl methacrylamide (ISAL-PCL-HP), were synthesized through this simple synthetic strategy following the monomer conjugation approach along with exhaustive spectroscopic and rheological characterization. The conjugates HP-PCL, nBu-PCL-HP, and ISAL-PCL-HP were characterized by Fourier transform infrared (FT-IR) and NMR (13C and 1H) spectroscopies. The size and ζ potential of conjugates were determined through the dynamic light scattering (DLS) method. The nBu-PCL-HP conjugate displayed a hexagonal-like shape, as evidenced by scanning electron microscopy (SEM) with an obtained size of 237.9 ± 0.21 nm. X-ray diffraction (XRD) analysis proved the crystalline nature of nBu-PCL-HP conjugates. The results of smartly synthesized conjugates intrigued us to study their flow properties in detail. Rheological evaluation resulted in their non-Newtonian type of flow with the best-fit behavior for all of the conjugates followed as per the Herschel-Bulkley and power-law models applied herein. Conclusively, the synthesized HPMA and PCL conjugates may have applications in the preparation of blends, fibers, etc. in the future. The study portrayed that the explored synthetic scheme using monomers and initiators could be a suitable approach for the synthesis of HPMA and PCL conjugates.

Dataset Information

Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates.

Publications

Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates.

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