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. 2007 Jun 15;9(2):E200–E207. doi: 10.1208/aapsj0902022

Polymer-drug conjugates as modulators of cellular apoptosis

Maria J Vicent 1,✉
PMCID: PMC2751409  PMID: 17907762

Abstract

The successful clinical application of polymer-protein conjugates (PE Gylated enzymes and cytokines) and the promising results arising from clinical trials with polymerbound chemotherapy (eg, doxorubicin or paclitaxel) have established their potential to reduce toxicity and improve activity in chemotherapy-refractory patients. Furthermore, and more important, they have also provided a firm foundation for more sophisticated second-generation constructs that deliver the newly energing target-directed bioactive agents (eg, modulators of apoptosis, cell cycle, anti-angiogenic drugs) in addition to polymer-based drug combinations (eg, endocrine therapy and chemotherapy). This review will focus on polymer-drug conjugate modulators of cellular apoptosis to be used as single pro-poptotic (eg, cancer) or anti-apoptotic (eg, ischemia) agents or as a combination therapy.

Keywords: Polymer-drug conjugates, apoptosis modulators, targeted delivery

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References

  • 1.Duncan R. Polymer-drug conjugates. In: Budman D, Calvert H, Rowinsky E, editors. Handbook of Anticancer Drug Development. Baltimore, MD: Lippincott Williams & Wilkins; 2003. pp. 239–260. [Google Scholar]
  • 2.Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor or agent smanes. Cancer Res. 1986;46:6387–6392. [PubMed] [Google Scholar]
  • 3.Duncan R. Polymer conjugates as anticancer nanomedicines. Nat Rev Cancer. 2006;6:688–701. doi: 10.1038/nrc1958. [DOI] [PubMed] [Google Scholar]
  • 4.Satchi-Fainaro R, Duncan R, Bames CM. Polymer therapeutics for cancer: current status and future challenges. Adv Polym Sci. 2006;193:1–65. doi: 10.1007/12_024. [DOI] [Google Scholar]
  • 5.Vicent MJ, Duncan R. Polymer conjugates: nanosized medicines for treating cancer. Trends Biotechnol. 2006;24:39–47. doi: 10.1016/j.tibtech.2005.11.006. [DOI] [PubMed] [Google Scholar]
  • 6.Khandare J, Minko T. Polymer-drug conjugates: progress in polymeric prodrugs. Prog Polym Sci. 2006;31:359–397. doi: 10.1016/j.progpolymsci.2005.09.004. [DOI] [Google Scholar]
  • 7.Alam JJ. Apoptosis: target for novel drugs. Trends Biotechnol. 2003;21:479–483. doi: 10.1016/j.tibtech.2003.08.006. [DOI] [PubMed] [Google Scholar]
  • 8.Sausville EA, Elsayed Y, Monga M, Kim G. Signal transduction: directed cancer treatments. Annu Rev Pharmacol Toxicol. 2003;43:199–231. doi: 10.1146/annurev.pharmtox.43.100901.135813. [DOI] [PubMed] [Google Scholar]
  • 9.Vicent MJ, Greco F, Nicholson RI, Paul A, Griffiths PC, Duncan R. Polymer therapeutics designed for a combination therapy of hormone-dependent cancer. Angew Chem Int Ed Engl. 2005;44:4061–4066. doi: 10.1002/anie.200462960. [DOI] [PubMed] [Google Scholar]
  • 10.Reed RC. Apoptosis-based therapies. Nat Rev Drug Discov. 2002;1:111–121. doi: 10.1038/nrd726. [DOI] [PubMed] [Google Scholar]
  • 11.Green DR, Kroemer G. Pharmacological manipulation of cell death: clinical applications in sight? J Clin Invest. 2005;115:2610–2617. doi: 10.1172/JCI26321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Green DR. Apoptotic pathways: ten minutes to dead. Cell. 2005;121:671–674. doi: 10.1016/j.cell.2005.05.019. [DOI] [PubMed] [Google Scholar]
  • 13.Spierings D, McStay G, Saleh M, et al. Connected to death: the (unexpurgated) mitochondrial pathway of apoptosis. Science. 2005;310:66–67. doi: 10.1126/science.1117105. [DOI] [PubMed] [Google Scholar]
  • 14.Strasser A, O'Connor L, Dixit VM. Apoptosis signaling. Annu Rev Biochem. 2000;69:217–245. doi: 10.1146/annurev.biochem.69.1.217. [DOI] [PubMed] [Google Scholar]
  • 15.Zou H, Li YC, Lin HS, Wang XD. An APAF-1 center dot cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem. 1999;274:11549–11556. doi: 10.1074/jbc.274.17.11549. [DOI] [PubMed] [Google Scholar]
  • 16.Chai JJ, Du CY, Wu JW, Kyin S, Wang XD, Shi YG. Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature. 2000;406:855–862. doi: 10.1038/35022514. [DOI] [PubMed] [Google Scholar]
  • 17.Hao ZY, Duncan GS, Chang CC, et al. Specific ablation of the apoptotic functions of cytochrome c reveals a differential requirement for cytochrome c and apaf-1 in apoptosis. Cell. 2005;121:579–591. doi: 10.1016/j.cell.2005.03.016. [DOI] [PubMed] [Google Scholar]
  • 18.Riedl SJ, Li WY, Chao Y, Schwarzenbacher R, Shi YG. Structure of the apoptotic protease-activating factor 1 bound to ADP. Nature. 2005;434:926–933. doi: 10.1038/nature03465. [DOI] [PubMed] [Google Scholar]
  • 19.Chereau D, Zou H, Spada AP, Wu JC. A nucleotide binding site in caspase-9 regulates apoptosome activation. Biochemistry. 2005;44:4971–4976. doi: 10.1021/bi047360+. [DOI] [PubMed] [Google Scholar]
  • 20.Kaufimann SH, Earnshaw WC. Induction of apoptosis by cancer chemotherapy. Exp Cell Res. 2000;256:42–49. doi: 10.1006/excr.2000.4838. [DOI] [PubMed] [Google Scholar]
  • 21.Vasey PA, Kaye SB, Morrison R, et al. Phase I clinical and pharmacokinetic study of PK1 N-(2-hydroxypropyl)methacrylamide copolymer doxorubicin: first member of a new class of chemotherapeutic agents—drug-polymer conjugates. Clin Cancer Res. 1999;5:83–94. [PubMed] [Google Scholar]
  • 22.Minko T, Kopeckova P, Kopecek J. Mechanisms of anticancer action of HPMA copolymer-bound doxorubicin. Macromol Symp. 2001;172:35–48. doi: 10.1002/1521-3900(200107)172:1<35::AID-MASY35>3.0.CO;2-N. [DOI] [Google Scholar]
  • 23.Kovar M, Mrkvan T, Strohalm J, et al. HPMA copolymer-bound doxorubicin targeted to tumor-specific antigen of BCL1 mouse B cell leukemia. J Control Release. 2003;92:315–330. doi: 10.1016/S0168-3659(03)00340-7. [DOI] [PubMed] [Google Scholar]
  • 24.Rihova B, Strohalm J, Kubackova K, et al. Acquired and specific immunological mechanism co-responsible for efficacy of polymer-bound drugs. J Control Release. 2002;78:97–114. doi: 10.1016/S0168-3659(01)00489-8. [DOI] [PubMed] [Google Scholar]
  • 25.Rihova B, Strohalm J, Prausova J, et al. Cytostatic and immunomobilizing activities of polymer-bound drugs: experimental and first clinical data. J Control Release. 2003;91:1–16. doi: 10.1016/S0168-3659(03)00235-9. [DOI] [PubMed] [Google Scholar]
  • 26.Duncan R. N-(2-hydroxypropyl)methacrylamide copolymer conjugates. In: Kwon GS, editor. Polymeric Drug Delivery Systems. New York, NY: Marcel Dekker, Inc; 2005. pp. 1–92. [Google Scholar]
  • 27.Li C, Yu DF, Newman R, et al. Complete regression of well-established tumors using novel water-soluable poly(L-glutamic acid)-paclitaxel conjugate. Cancer Res. 1998;58:2404–2409. [PubMed] [Google Scholar]
  • 28.Singer JW. Paclitaxel poliglumex (XYOTAX™, CT-2103): a macromolecular taxane. J Control Release. 2005;109:120–126. doi: 10.1016/j.jconrel.2005.09.033. [DOI] [PubMed] [Google Scholar]
  • 29.Ross H, Bonomi P, Langer C. Effect of gender on outcome in two randomized phase III trials of paclitaxel poliglumex (PPX) in chemonaive patients with advanced NSCLC and poor performance status (PS2) [abstract].Clin Oncol. 2006;97:
  • 30.O'Brien M, Bonomi P, Langer C. Analysis of prognostic factors in chemo-naive patients with advanced NSCLC and poor performance status (PS): Cox regression analysis of two phase III trials [abstract].Clin Oncol. 2006;97.
  • 31.Oldham EA, Li C, Ke S, Wallace S, Huang P. Comparison of action of paclitaxel and poly(L-glutamic acid)paclitaxel conjugate in human breast cancer cells. Int J Oncol. 2000;16:125–132. [PubMed] [Google Scholar]
  • 32.Bhatt R, de Vries P, Tulinsky J, et al. Synthesis and in vivo antitumor activity of poly(L-glutamic acid) conjugates of 20(S)-camptothecin. J Med Chem. 2003;46:190–193. doi: 10.1021/jm020022r. [DOI] [PubMed] [Google Scholar]
  • 33.Hertzberg RP, Caranfa MJ, Hecht SM. On the mechanism of topoisomerase-I inhibition by camptothecin—evidence for binding to an enzyme DNA complex. Biochemistry. 1989;28:4629–4638. doi: 10.1021/bi00437a018. [DOI] [PubMed] [Google Scholar]
  • 34.Posey JA, Saif MW, Carlisle R, et al. Phase 1 study of weekly polyethylene glycol-camptothecin in patients with advanced solid tumors and lymphomas. Clin Cancer Res. 2005;11:7866–7871. doi: 10.1158/1078-0432.CCR-05-0783. [DOI] [PubMed] [Google Scholar]
  • 35.Schluep T, Hwang J, Cheng JJ, et al. Preclinical efficacy of the camptothecin-polymer conjugate IT-101 in multiple cancer models. Clin Cancer Res. 2006;12:1606–1614. doi: 10.1158/1078-0432.CCR-05-1566. [DOI] [PubMed] [Google Scholar]
  • 36.Zamboni WC, Goel S, Iqbal T, et al. Clinical and pharmacokinetic study evaluating the effect of food on the disposition of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite in patients with solid tumors. Cancer Chem Pharmacol. 2006;57:631–639. doi: 10.1007/s00280-005-0084-6. [DOI] [PubMed] [Google Scholar]
  • 37.Schluep T, Cheng JJ, Khin KT, Davis ME. Pharmacokinetics and biodistribution of the camptothecin-polymer conjugate IT-101 in rats and tumor-bearing mice. Cancer Chem Pharmacol. 2006;57:654–662. doi: 10.1007/s00280-005-0091-7. [DOI] [PubMed] [Google Scholar]
  • 38.Minko T, Paranjpe PV, Qiu B, et al. Enhancing the anticancer efficacy of camptothecin using biotinylated poly(ethyleneglycol) conjugates in sensitive and multidrug-resistant human ovarian carcinoma cells. Cancer Chem Pharmacol. 2002;50:143–150. doi: 10.1007/s00280-002-0463-1. [DOI] [PubMed] [Google Scholar]
  • 39.Dharap SS, Qiu B, Williams GC, Sinko P, Stein S, Minko T. Molecular targeting of drug delivery systems to ovarian cancer by BH3 and LHRH peptides. J Control Release. 2003;91:61–73. doi: 10.1016/S0168-3659(03)00209-8. [DOI] [PubMed] [Google Scholar]
  • 40.Dharap SS, Wang Y, Chandna P, et al. Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide. Proc Natl Acad Sci USA. 2005;102:12962–12967. doi: 10.1073/pnas.0504274102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Kabanov AV. Polymer genomics: an insight into pharmacology and toxicology of nanomedicines. Adv Drug Deliv Rev. 2006;58:1597–1621. doi: 10.1016/j.addr.2006.09.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Fiebig HH, Burger AM. Target-directed in vitro and in vivo testing procedures for the discovery of anticancer agents. Clin Cancer Res. 1999;5:S3870–S3870. [Google Scholar]
  • 43.Eskens F, Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer. 2006;42:3127–3139. doi: 10.1016/j.ejca.2006.09.015. [DOI] [PubMed] [Google Scholar]
  • 44.Lippert JW. Vascular disrupting agents. Bioorg Med Chem. 2007;15:605–615. doi: 10.1016/j.bmc.2006.10.020. [DOI] [PubMed] [Google Scholar]
  • 45.Dayam R, Grande F, Al-Mawsawi LQ, Neamati N. Recent advances in the design and discovery of small-molecule therapeutics targeting HER2/neu. Expert Opin Ther Pat. 2007;17:83–102. doi: 10.1517/13543776.17.1.83. [DOI] [Google Scholar]
  • 46.Satchi-Fainaro R, Puder M, Davies JW, et al. Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Nat Med. 2004;10:255–261. doi: 10.1038/nm1002. [DOI] [PubMed] [Google Scholar]
  • 47.Huang JZ, Frischer JS, New T, et al. TNP-470 promotes initial vascular sprouting in xenograft tumors. Mol Cancer Ther. 2004;3:335–343. [PubMed] [Google Scholar]
  • 48.Inoue K, Chikazawa M, Fukata S, Yoshikawa C, Shuin T. Docetaxel enhances the therapeutic effect of the angiogenesis inhibitor TNP-470 (AGM-1470) in metastatic human transitional cell carcinoma. Clin Cancer Res. 2003;9:886–899. [PubMed] [Google Scholar]
  • 49.Bhujwalla ZM, Artemov D, Natarajan K, Solaiyappan M, Kollars P, Kristjansen PEG. Reduction of vascular and permeable regions in solid tumors detected by macromolecular contrast magnetic resonance imaging after treatment with antiangiogenic agent TNP-470. Clin Cancer Res. 2003;9:355–362. [PubMed] [Google Scholar]
  • 50.Mitra A, Nan A, Papadimitriou JC, Ghandehari H, Line BR. Polymer-peptide conjugates for angiogenesis targeted tumor radiotherapy. Nucl Med Biol. 2006;33:43–52. doi: 10.1016/j.nucmedbio.2005.09.005. [DOI] [PubMed] [Google Scholar]
  • 51.Chen X, Hou Y, Tohme M, et al. Pegylated Arg-Gly-Asp peptide: Cu-64 labeling and PET imaging of brain tumor alpha(v)beta(3)-integrin expression. J Nucl Med. 2004;45:1776–1783. [PubMed] [Google Scholar]
  • 52.Chen X, Park R, Hou Y, et al. MicroPET and autoradiographic imaging of GRP receptor expression with Cu-64-DOTA-Lys(3) bombesin in human prostate adenocarcinoma xenografts. J Nucl Med. 2004;45:1390–1397. [PubMed] [Google Scholar]
  • 53.Juin P, Geneste O, Raimbaud E, Hickman JA. Shooting at survivors: Bcl-2 family members as drug targets for cancer. Biochim Biophys Acta. 2004;1644:251–260. doi: 10.1016/j.bbamcr.2003.10.010. [DOI] [PubMed] [Google Scholar]
  • 54.Duncan R. The dawning era of polymer therapeutics. Nat Rev Drug Discov. 2003;2:347–360. doi: 10.1038/nrd1088. [DOI] [PubMed] [Google Scholar]
  • 55.Oman M, Liu JH, Chen J, et al. Using N-(2-hydroxypropyl) methacrylamide copolymer drug bioconjugate as a novel approach to deliver a Bcl-2-targeting compound HA14-1 in vivo. Gene Ther Mol Biol. 2006;10A:113–122. [Google Scholar]
  • 56.Fang J, Sawa T, Akaike T, Maeda H. Tumor-targeted delivery of polyethylene glycol-conjugated D-amino acid oxidase for antitumor therapy via enzymatic generation of hydrogen peroxide. Cancer Res. 2002;62:3138–3143. [PubMed] [Google Scholar]
  • 57.Fang J, Sawa T, Maeda H. Factors and Mechanism of “EPR” Effect and the Enhanced Antitumor Effects of Macromolecular Drugs Including SMANCS Book Series Advances in Experimental Medicine and Biology. In: Maeda H, Kabanov A, Kataoka K, Okano T, editors. Polymer Drugs in the Clinical Stage. Dordrecht, The Netherlands: SpringerLink Netherlands; 2004. pp. 29–49. [DOI] [PubMed] [Google Scholar]
  • 58.Fang J, Akaike T, Maeda H. Antiapoptotic role of heme oxygenase (HO) and the potential of HO as a target in anticancer treatment. Apoptosis. 2004;9:27–35. doi: 10.1023/B:APPT.0000012119.83734.4e. [DOI] [PubMed] [Google Scholar]
  • 59.Fang J, Sawa T, Akaike T, Greish K, Maeda H. Enhancement of chemotherapeutic response of tumor cells by a heme oxygenase inhibitor, pegylated zinc protoporphyrin. Int J Cancer. 2004;109:1–8. doi: 10.1002/ijc.11644. [DOI] [PubMed] [Google Scholar]
  • 60.Sahoo SK, Sawa T, Fang J, et al. Pegylated zinc protoporphyrin: a water-soluble heme oxygenase inhibitor with tumor-targeting capacity. Bioconjugate Chem. 2002;13:1031–1038. doi: 10.1021/bc020010k. [DOI] [PubMed] [Google Scholar]
  • 61.Fang J, Sawa T, Akeike T, et al. In vivo antitumor activity of pegylated zinc protoporphyrin: targeted inhibition of heme oxygenase in solid tumor. Cancer Res. 2003;63:3567–3574. [PubMed] [Google Scholar]
  • 62.Herzog T, Barret RJ, Edwards R, Oldham FB. Phase II study of paclitaxel poliglumex (PPX)/carboplatin (C) for 1st line induction and maintenance therapy of stage III/IV ovarian or primary peritoneal carcinoma. J Clin Oncol. 2005;23:16S–16S. [Google Scholar]
  • 63.Greco F, Vicent MJ, Gee S, et al. Investigating the mechanism of enhanced cytotoxicity of HPMA copolymer-Dox-AGM in breast cancer cells. J Control Release. 2007;117:28–39. doi: 10.1016/j.jconrel.2006.10.012. [DOI] [PubMed] [Google Scholar]
  • 64.Santucci L, Mencarelli A, Renga B, et al. Nitric oxide modulates proapoptotic and antiapoptotic properties of chemotherapy agents: the case of NO-pegylated epirubicin. FASEB J. 2006;20:765–775. doi: 10.1096/fj.05-4452fje. [DOI] [PubMed] [Google Scholar]
  • 65.Khandare JJ, Chandna P, Wang Y, Pozharov VP, Minko T. Novel polymeric prodrug with multivalent components for cancer therapy. J Pharmacol Exp Ther. 2006;317:929–937. doi: 10.1124/jpet.105.098855. [DOI] [PubMed] [Google Scholar]
  • 66.Pasut G, Mero A, Bertuglia S, Veronese FM. Novel PEG conjugates releasing nitric oxide: preparation and activity against oxidative stress in ischemia reperfusion injury. Paper presented at: 33rd Annual Meeting & Expo of the Controlled Release Society; June 21–26, 2006; Vienna, Austria.
  • 67.Acehan D, Jiang XJ, Morgan DG, Heuser JE, Wang XD, Akey CW. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell. 2002;9:423–432. doi: 10.1016/S1097-2765(02)00442-2. [DOI] [PubMed] [Google Scholar]
  • 68.Lademann U, Cain K, Gyrd-Hansen M, Brown D, Peters D, Jaattela M. Diarylurea compounds inhibit caspase activation by preventing the formation of the active 700-kilodalton apoptosome complex. Mol Cell Biol. 2003;23:7829–7837. doi: 10.1128/MCB.23.21.7829-7837.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Malet G, Martin AG, Orzáez M, et al. Small molecule inhibitors of Apaf-1-related caspase-3/-9 activation that control mitochondrial-dependent apoptosis. Cell Death Differ. 2006;13:1523–1532. doi: 10.1038/sj.cdd.4401828. [DOI] [PubMed] [Google Scholar]
  • 70.Vicent MJ, Pérez-Payá E. Poly-L-glutamic acid (PGA) aided inhibitors of apoptotic protease activating factor 1 (Apaf-1): an antiapoptotic polymeric nanomedicine. J Med Chem. 2006;49:3763–3765. doi: 10.1021/jm060458x. [DOI] [PubMed] [Google Scholar]
  • 71.Broxterman HJ, Georgopapadakou NH. Anticancer therapeutics: “addictive” targets, multi-targeted drugs, new drug combinations. Drug Resist Updat. 2005;8:183–197. doi: 10.1016/j.drup.2005.07.002. [DOI] [PubMed] [Google Scholar]
  • 72.Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006;58:621–681. doi: 10.1124/pr.58.3.10. [DOI] [PubMed] [Google Scholar]
  • 73.Audran M. Drug combination strategies for osteoporosis. Joint Bone Spine. 2006;73:374–378. doi: 10.1016/j.jbspin.2006.02.004. [DOI] [PubMed] [Google Scholar]
  • 74.Balan V, Rosati MJ, Anderson MH, Rakela J. Successful treatment with novel triple drug combination consisting of interferon-gamma, interferon alfacon-1, and ribavirin in a nonresponder HCV patient to pegylated interferon therapy. Dig Dis Sci. 2006;51:956–959. doi: 10.1007/s10620-006-9349-0. [DOI] [PubMed] [Google Scholar]
  • 75.Blank-Porat D, Nudelman A, Berkovitch G, Malik Z, Rephaeli A. In vitro drug combination investigation could assist clinical study design. Clin Cancer Res. 2005;11:8988S–8988S. [Google Scholar]
  • 76.Gupta M, Robinson B, Felix C, Barrett J. Strategies for assessment of drug combination therapy: response surface modeling of MTT assays to assess target agent synergy via cell survival. J Clin Pharmacol. 2005;45:1093–1093. [Google Scholar]
  • 77.Haag R, Kratz F. Polymer therapeutics: concepts and applications. Angew Chem Int Ed Engl. 2006;45:1198–1215. doi: 10.1002/anie.200502113. [DOI] [PubMed] [Google Scholar]
  • 78.Vermeulen K, Van Bockstaele DR, Berneman ZN. Apoptosis: mechanisms and relevance in cancer. Ann Hematol. 2005;84:627–639. doi: 10.1007/s00277-005-1065-x. [DOI] [PubMed] [Google Scholar]

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