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Polymer–drug conjugates for novel molecular targets

    , ,
    Rut Lucas

    Polymer Therapeutics Laboratory, Medicinal Chemistry Department, Centro de Investigación Príncipe Felipe. Av. Autopista del Saler, 16. E-46012 Valencia, Spain

    &
    María J Vicent

    Polymer Therapeutics Laboratory, Medicinal Chemistry Department, Centro de Investigación Príncipe Felipe. Av. Autopista del Saler, 16. E-46012 Valencia, Spain

    Published Online:https://doi.org/10.2217/nnm.10.71

    Polymer therapeutics can be already considered as a promising field in the human healthcare context. The discovery of the enhanced permeability and retention effect by Maeda, together with the modular model for the polymer–drug conjugate proposed by Ringsdorf, directed the early steps of polymer therapeutics towards cancer therapy. Orthodox anticancer drugs were preferentially chosen in the development of the first conjugates. The fast evolution of polymer chemistry and bioconjugation techniques, and a deeper understanding of cell biology has opened up exciting new challenges and opportunities. Four main directions have to be considered to develop this ‘platform technology’ further: the control of the synthetic process, the exhaustive characterization of the conjugate architectures, the conquest of combination therapy and the disclosure of new therapeutic targets. We illustrate in this article the exciting approaches offered by polymer–drug conjugates beyond classical cancer therapy, focusing on new, more effective and selective targets in cancer and in their use as treatments for other major human diseases.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    Bibliography

    • Duncan R: The dawning era of polymer therapeutics. Nat. Rev. Drug Discov.2(5),347–360 (2003).▪▪ Landmark paper defining the polymer therapeutics field.
    • Haag R, Kratz F: Polymer therapeutics: Concepts and applications. Angew. Chem. Int. Ed.45(8),1198–1215 (2006).
    • Duncan R: Polymer conjugates as anticancer nanomedicines. Nat. Rev. Cancer6(9),688–701 (2006).
    • Li C, Wallace S: Polymer–drug conjugates: recent development in clinical oncology. Adv. Drug Deliv. Rev.60(8),886–898 (2008).
    • Vicent MJ, Duncan R: Polymer therapeutics: clinical applications and challenges for development. Adv. Drug Deliv. Rev.61(13),1117–1232 (2009).
    • Ringsdorf H: Structure and properties of pharmacologically active polymers. J. Polym. Sci. C-Polym. Symp.51,135–153 (1975).
    • Meerum Terwogt JM, Ten Bokkel Huinink WW, Schellens JH et al.: Phase I clinical and pharmacokinetic study of PNU166945, a novel water-soluble polymer-conjugated prodrug of paclitaxel. Anticancer Drugs12(4),315–323 (2001).
    • 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.5(1),83–94 (1999).▪▪ First paper describing a polymer–drug conjugate that reached the clinical trials.
    • Yurkovetskiy AV, Fram RJ: XMT-1001, a novel polymeric camptothecin pro-drug in clinical development for patients with advanced cancer. Adv. Drug Deliv. Rev.61(13),1193–1202 (2009).
    • 10  Brocchini S, Duncan R: Polymer–drug conjugates: drug release from pendent linkers. In: Encyclopaedia of controlled release. Mathiowitz E (Ed.). Wiley, NY, USA 786–816 (1999).
    • 11  Duncan R, Cable HC, Lloyd JB, Rejmanova P, Kopecek J: Polymers containing enzymatically degradable bonds .7. Design of oligopeptide side-chains in poly[N-(2-hydroxypropyl)methacrylamide] co-polymers to promote efficient degradation by lysosomal-enzymes. Makromol. Chem.Macromol. Chem. Phys.184(10),1997–2008 (1983).
    • 12  Allen TM: Ligand-targeted therapeutics in anticancer therapy. Nat. Rev. Cancer2(10),750–763 (2002).
    • 13  Brumlik MJ, Daniel BJ, Waehler R, Curiel DT, Giles FJ, Curiel TJ: Trends in immunoconjugate and ligand–receptor based targeting development for cancer therapy. Expert Opin. Drug Deliv.5(1),87–103 (2008).
    • 14  Seymour LW, Ferry DR, Anderson D et al.: Hepatic drug targeting: Phase I evaluation of polymer-bound doxorubicin. J. Clin. Oncol.20(6),1668–1676 (2002).
    • 15  Matsumura Y, Maeda H: A new concept for macromolecular therapeutics in cancer-chemotherapy – mechanism of tumoritropic accumulation of proteins and the antitumor agent SMANCS. Cancer Res.46(12),6387–6392 (1986).
    • 16  Iyer AK, Khaled G, Fang J, Maeda H: Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov. Today11(17–18),812–818 (2006).
    • 17  Vicent MJ, Duncan R: Polymer conjugates: nanosized medicines for treating cancer. Trends Biotechnol.24(1),39–47 (2006).
    • 18  Vicent MJ, Ringsdorf H, Duncan R: Polymer therapeutics: clinical applications and challenges for development. Adv. Drug Deliv. Rev.61(13),1117–1120 (2009).
    • 19  Chipman SD, Oldham FB, Pezzoni G, Singer JW: Biological and clinical characterization of paclitaxel poliglumex (PPX, CT-2103), a macromolecular polymer–drug conjugate. Int. J. Nanomed.1(4),375–383 (2006).
    • 20  Seymour LW, Ferry DR, Kerr DJ et al.: Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer. Int. J. Oncol.34(6),1629–1636 (2009).
    • 21  Danhauserriedl S, Hausmann E, Schick HD et al.: Phase-I clinical and pharmacokinetic trial of dextran conjugated doxorubicin (AD-70, DOX-OXD). Invest. New Drugs11(2–3),187–195 (1993).
    • 22  Springett GM, Takimoto C, McNamara M et al.: Phase I study of CT-2106 (polyglutamate camptothecin) in patients with advanced malignancies. J. Clin. Oncol.22(14),3127 (2004).
    • 23  Schluep T, Hwang J, Cheng JJ et al.: Preclinical efficacy of the camptothecin–polymer conjugate IT-101 in multiple cancer models. Clin. Cancer Res.12(5),1606–1614 (2006).
    • 24  Bissett D, Cassidy J, de Bono JS et al.: Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT). Brit. J. Cancer91(1),50–55 (2004).
    • 25  Soepenberg O, de Jonge MJA, Sparreboom A et al.: Phase I and pharmacokinetic study of DE-310 in patients with advanced solid tumors. Clin. Cancer Res.11(2),703–711 (2005).
    • 26  Davis ME: Design and development of IT-101, a cyclodextrin-containing polymer conjugate of camptothecin. Adv. Drug Deliv. Rev.61(13),1189–1192 (2009).
    • 27  Li C, Yu DF, Newman RA et al.: Complete regression of well-established tumors using a novel water-soluble poly(L-glutamic acid) paclitaxel conjugate. Cancer Res.58(11),2404–2409 (1998).
    • 28  Singer JW, Shaffer S, Baker B et al.: Paclitaxel poliglumex (XYOTAX; CT-2103): an intracellularly targeted taxane. Anticancer Drugs16(3),243–254 (2005).
    • 29  Shaffer SA, Baker Lee C, Kumar A, Singer JW: Proteolysis of XYOTAX by lysosomal cathepsin B; metabolic profiling in tumor cells using LC-MS. Eur. J. Cancer38,428 (2002).
    • 30  Rademaker-Lakhai JM, Terret C, Howell SB et al.: A Phase I and pharmacological study of the platinum polymer AP5280 given as an intravenous infusion once every 3 weeks in patients with solid tumors. Clin. Cancer Res.10(10),3386–3395 (2004).
    • 31  Nowotnik DP, Cvitkovic E: ProLindac™ (AP5346): a review of the development of an HPMA DACH platinum polymer therapeutic. Adv. Drug Deliv. Rev.61(13),1214–1219 (2009).
    • 32  Greco F, Vicent MJ: Polymer–drug conjugates: current status and future trends. Frontiers Biosci.13,2744–2756 (2008).
    • 33  Vicent MJ, Dieudonne L, Carbajo RJ, Pineda-Lucena A: Polymer conjugates as therapeutics: future trends, challenges and opportunities. Expert Opin. Drug Deliv.5(5),593–614 (2008).
    • 34  Gaspar R, Duncan R: Polymeric carriers: preclinical safety and the regulatory implications for design and development of polymer therapeutics. Adv. Drug Deliv. Rev.61(13),1220–1232 (2009).
    • 35  Lammers T: Improving the efficacy of combined modality anticancer therapy using HPMA copolymer-based nanomedicine formulations. Adv. Drug Deliv. Rev.62(2),203–230 (2010).
    • 36  Greco F, Vicent MJ: Combination therapy: Opportunities and challenges for polymer-drug conjugates as anticancer nanomedicines. Adv. Drug Deliv. Rev.61(13),1203–1213 (2009).
    • 37  Satchi-Fainaro R, Duncan R, Barnes CM: Polymer therapeutics for cancer: current status and future challenges. Polymer Therapeutics II193,1–65 (2006).
    • 38  Khandare J, Minko T: Polymer–drug conjugates: progress in polymeric prodrugs. Progr. Polym. Sci.31(4),359–397 (2006).
    • 39  Lammers T, Ulbrich K: HPMA copolymers: 30 years of advances. Adv. Drug Deliv. Rev.62(2),119–121 (2009).
    • 40  Hanahan D, Weinberg RA: The hallmarks of cancer. Cell100(1),57–70 (2000).
    • 41  Gerber HP, McMurtrey A, Kowalski J et al.: Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3´-kinase Akt signal transduction pathway – requirement for Flk-1/KDR activation. J. Biol. Chem.273(46),30336–30343 (1998).
    • 42  Arcaro A, Wymann MP: Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor – the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem. J.296,297–301 (1993).
    • 43  Vlahos CJ, Matter WF, Hui KY, Brown RF: A specific inhibitor of phosphatidylnositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4h-1-benzopyran-4-one (Ly294002). J. Biol. Chem.269(7),5241–5248 (1994).
    • 44  Varticovski L, Lu ZR, Mitchell K, de Aos I, Kopecek J: Water-soluble HPMA copolymer-wortmannin conjugate retains phosphoinositide 3-kinase inhibitory activity in vitro and in vivo. J. Control. Rel.74(1–3),275–281 (2001).
    • 45  Bae Y, Diezi TA, Zhao A, Kwon GS: Mixed polymeric micelles for combination cancer chemotherapy through the concurrent delivery of multiple chemotherapeutic agents. J. Control. Rel.122,324–330 (2007).
    • 46  Takabe K, Paugh SW, Milstien S, Spiegel S: ‘Inside-out’ signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol. Rev.60(2),181–195 (2008).
    • 47  Avery K, Avery S, Shepherd J, Heath PR, Moore H: Sphingosine-1-phosphate mediates transcriptional regulation of key targets associated with survival, proliferation, and pluripotency in human embryonic stem cells. Stem Cells Dev.17(6),1195–1205 (2008).
    • 48  Huwiler A, Pfeischifter J: New players on the center stage: sphingosine 1-phosphate and its receptors as drug targets. Biochem. Pharmacol.75(10),1893–1900 (2008).
    • 49  Ghosh SC, Auzenne E, Khodadadian M, Farquhar D, Klostergaard J: N,N-dimethylsphingosine conjugates of poly-L-glutamic acid: synthesis, characterization, and initial biological evaluation. Bioorg. Med. Chem. Lett.19(3),1012–1017 (2009).
    • 50  Richter K, Buchner J: HSP90: chaperoning signal transduction. J. Cell. Physiol.188(3),281–290 (2001).
    • 51  Blagosklonny MV: HSP-90-associated oncoproteins: multiple targets of geldanamycin and its analogs. Leukemia16(4),455–462 (2002).
    • 52  Borgman MP, Ray A, Kolhatkar RB, Sausville EA, Burger AM, Ghandehari H: Targetable HPMA copolymer-aminohexylgeldanamycin conjugates for prostate cancer therapy. Pharm. Res.26(6),1407–1418 (2009).▪ Geldanamycin, an HSP-90 inhibitor, was conjugated designing a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer–AHGDM-RDGfK. The conjugate showed greater activity and reduced toxicity than the free drug for treatment of prostate cancer.
    • 53  Bae Y, Buresh RA, Williamson TP, Chen TH, Furgeson DY: Intelligent biosynthetic nanobiomaterials for hyperthermic combination chemotherapy and thermal drug targeting of HSP90 inhibitor geldanamycin. J. Control. Rel.122(1),16–23 (2007).
    • 54  Alam JJ: Apoptosis: target for novel drugs. Trends Biotechnol.21(11),479–483 (2003).
    • 55  Reed JC: Apoptosis-based therapies. Nat. Rev. Drug Discov.1(2),111–121 (2002).
    • 56  Green DR: Apoptotic pathways: ten minutes to dead. Cell121(5),671–674 (2005).
    • 57  Vicent MJ: Polymer–drug conjugates as modulators of cellular apoptosis. AAPS J.9(2),E200–207 (2007).
    • 58  Sharma RA, Gescher AJ, Steward WP: Curcumin: the story so far. Eur. J. Cancer41(13),1955–1968 (2005).
    • 59  Li J, Wang Y, Yang C et al.: PEGylated curcumin conjugate inhibits pancreatic cancer cell growth through inactivation of Jab1. Mol. Pharmacol.76(1),81–90 (2009).▪ Curcumin, a Jab1 inhibitor with poor solubility, was PEGylated showing antiproliferative activity higher than the free drug.
    • 60  Juin P, Geneste O, Raimbaud E, Hickman JA: Shooting at survivors: Bcl-2 family members as drug targets for cancer. Biochim. Biophys. Acta1644(2–3),251–260 (2004).
    • 61  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. Gen. Ther. Mol. Biol.10A,113–122 (2006).
    • 62  Greco F, Vicent MJ, Penning NA, Nicholson RI, Duncan R: HPMA copolymer-aminoglutethimide conjugates inhibit aromatase in MCF-7 cell lines. J. Drug Target.13(8–9),459–470 (2005).
    • 63  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.44(26),4061–4066 (2005).▪▪ HPMA–doxorubicin–aminoglutethimide conjugate represents the first polymer-based combination therapy in this case as treatment for hormone-dependent breast cancer.
    • 64  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. Rel.117(1),28–39 (2007).
    • 65  Lammers T, Subr V, Ulbrich K et al.: Simultaneous delivery of doxorubicin and gemcitabine to tumors in vivo using prototypic polymeric drug carriers. Biomaterials30(20),3466–3475 (2009).
    • 66  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.20(2),765–776 (2006).
    • 67  Santucci L, Mencarelli A, Renga B et al.: Cardiac safety and antiturnoral activity of a new nitric oxide derivative of PEGylated epirubicin in mice. Anti-Cancer Drugs18(9),1081–1091 (2007).
    • 68  Folkman J: Tumor angiogenesis: therapeutic implications. N. Engl. J. Med.285,1182–1186 (1971).
    • 69  Segal E, Satchi-Fainaro R: Design and development of polymer conjugates as anti-angiogenic agents. Adv. Drug Deliv. Rev.61(13),1159–1176 (2009).
    • 70  Kragh M, Spang-Thomsen M, Kristjansen PE: Time until initiation of tumor growth is an effective measure of the anti-angiogenic effect of TNP-470 on human glioblastoma in nude mice. Oncol. Rep.6(4),759–762 (1999).
    • 71  Satchi-Fainaro R, Puder M, Davies JW et al.: Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Nat. Med.10(3),255–261 (2004).▪▪ Key paper describing the first polymer antiangiogenic conjugate.
    • 72  Satchi-Fainaro R, Mamluk R, Wang L et al.: Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin. Cancer Cell7(3),251–261 (2005).
    • 73  Chesler L, Goldenberg DD, Seales IT et al.: Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma. Cancer Res.67,9435–9442 (2007).
    • 74  Benny O, Fainaru O, Adini A et al.: An orally delivered small-molecule formulation with antiangiogenic and anticancer activity. Nat. Biotechnol.26(7),799–807 (2008).
    • 75  Segal E, Pan H, Ofek P et al.: Targeting angiogenesis-dependent calcified neoplasms using combined polymer therapeutics. PLoS One4(4),e5233 (2009).
    • 76  Browder T, Butterfield CE, Kraling BM et al.: Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer. Res.60,1878–1886 (2000).
    • 77  Miller K, Erez R, Segal E, Shabat D, Satchi-Fainaro R: Targeting bone metastases with a bispecific anticancer and antiangiogenic polymer-alendronate-taxane conjugate. Angew. Chem. Int. Ed.48(16),2949–2954 (2009).
    • 78  Zhu G, Cao X, Chang JY, Milas L, Wallace S, Li C: Polymeric retinoid prodrug PG-4HPR enhances the radiation response of lung cancer. Oncol. Rep.18(3),645–651 (2007).
    • 79  Cuchelkar V, Kopeckova P, Kopecek J: Synthesis and biological evaluation of disulfide-linked HPMA copolymer-mesochlorin e6 conjugates. Macromol. Biosci.8(5),375–383 (2008).
    • 80  Lammers T, Peschke P, Kuhnlein R et al.: Effect of radiotherapy and hyperthermia on the tumor accumulation of HPMA copolymer-based drug delivery systems. J. Control. Rel.117(3),333–341 (2007).
    • 81  Lammers T, Subr V, Peschke P et al.: Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy. Br. J. Cancer99(6),900–910 (2008).
    • 82  Bettio F, Canevari M, Marzano C et al.: Synthesis and biological in vitro evaluation of novel PEG-psoralen conjugates. Biomacromol.7(12),3534–3541 (2006).
    • 83  Tsujihara K, Hongu M, Saito K et al.: Na+-glucose cotransporter inhibitors as antidiabetics. 1. Synthesis and pharmacological properties of 4´-dehydroxyphlorizin derivatives based on a new concept. Chem. Pharm. Bull.44(6),1174–1180 (1996).
    • 84  Ikumi Y, Kida T, Sakuma S, Yamashita S, Akashi M: Polymer-phloridzin conjugates as an anti-diabetic drug that inhibits glucose absorption through the Na+/glucose cotransporter (SGLT1) in the small intestine. J. Control. Rel.125(1),42–49 (2008).▪ Poly-L-glutamic acid–phloridzin conjugate is a novel oral antidiabetic drug. The conjugate inhibits the increase in the blood glucose level (after oral administration of glucose in rats), comparing to the free drug.
    • 85  Sakuma S, Sagawa T, Masaoka Y et al.: Stabilization of enzyme-susceptible glucoside bonds of phloridzin through conjugation with poly(γ-glutamic acid). J. Control. Rel.133(2),125–131 (2009).
    • 86  Miyamoto Y, Akaike T, Yoshida M, Goto S, Horie H, Maeda H: Potentiation of nitric oxide-mediated vasorelaxation by xanthine oxidase inhibitors. Proc. Soc. Exp. Biol. Med.211(4),366–373 (1996).
    • 87  Fang J, Iyer AK, Seki T, Nakamura H, Greish K, Maeda H: SMA-copolymer conjugate of AHPP: a polymeric inhibitor of xanthine oxidase with potential antihypertensive effect. J. Control. Rel.135(3),211–217 (2009).▪ Conjugation of 4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine to copoly(styrene-maleic acid) showed significantly antihypertensive effect with sustained in vivo activity, increasing amount of nitric oxide in vascular endothelial system, by inhibition of O2-.
    • 88  Flexner C: HIV-protease inhibitors. N. Engl. J. Med.338(18),1281–1292 (1998).
    • 89  Gunaseelan S, Debrah O, Wan L et al.: Synthesis of poly(ethylene glycol)-based saquinavir prodrug conjugates and assessment of release and anti-HIV-1 bioactivity using a novel protease inhibition assay. Bioconjug. Chem.15(6),1322–1333 (2004).
    • 90  Wan L, Zhang X, Gunaseelan S et al.: Novel multi-component nanopharmaceuticals derived from poly(ethylene) glycol, retro-inverso-Tat nonapeptide and saquinavir demonstrate combined anti-HIV effects. AIDS Res. Ther.3,12 (2006).
    • 91  Gao Y, Katsuraya K, Kaneko Y, Mimura T, Nakashima H, Uryu T: Synthesis of Azidothymidine-bound sulfated alkyl oligosaccharides and their inhibitory effects on AIDS virus infection in vitro. Polym. J.30,243–248 (1998).
    • 92  Vlieghe P, Clerc T, Pannecouque C et al.: Synthesis of new covalently bound κ-carrageenan-AZT conjugates. J. Med. Chem.45,1275–1283 (2002).
    • 93  Wannachaiyasit S, Chanvorachote P, Nimmannit U: A novel anti-HIV dextrin-zidovudine conjugate improving the pharmacokinetics of zidovudine in rats. AAPS Pharm. Sci. Tech.9(3),840–850 (2008).
    • 94  Giammona G, Cavallaro G, Pitarresi G: Studies of macromolecular prodrugs of zidovudine. Adv. Drug Deliv. Rev.39,153–164 (1999).
    • 95  Chimalakonda KC, Agarwal HK, Kumar A, Parang K, Mehvar R: Synthesis, analysis, in vitro characterization, and in vivo disposition of a lamivudine-dextran conjugate for selective antiviral delivery to the liver. Bioconjug. Chem.18(6),2097–2108 (2007).
    • 96  Heidemann HT, Gerkens JF, Jackson EK, Branch RA: Effect of aminophylline on renal vasoconstriction produced by amphotericin B in the rat. Naunyn Schmi. Arch. Pharmacol.324(2),148–152 (1983).
    • 97  Cereghetti DM, Carreira EM: Amphotericin B: 50 years of chemistry and biochemistry. Synthesis-Stuttgart (6),914–942 (2006).
    • 98  Trejo WH, Bennett RE: Streptomyces nodosus sp. n., the amphotericin-producing organism. J. Bacteriol.85,436–439 (1963).
    • 99  Sedlak M, Buchta V, Kubicova L, Simunek P, Holcapek M, Kasparova P: Synthesis and characterisation of a new amphotericin B-methoxypoly(ethylene glycol) conjugate. Bioorg. Med. Chem. Lett.11(21),2833–2835 (2001).
    • 100  Sedlak M, Pravda M, Staud F, Kubicova L, Tycova K, Ventura K: Synthesis of pH-sensitive amphotericin B-poly(ethylene glycol) conjugates and study of their controlled release in vitro. Bioorg. Med. Chem.15(12),4069–4076 (2007).
    • 101  Sedlak M, Drabina P, Bilkova E, Simunek P, Buchta V: New targeting system for antimycotic drugs: β-glucosidase sensitive amphotericin B-star poly(ethylene glycol) conjugate. Bioorg. Med. Chem. Lett.18(9),2952–2956 (2008).
    • 102  Chappuis F, Sundar S, Hailu A et al.: Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? Nat. Rev. Microbiol.5(11),873–882 (2007).
    • 103  Mueller Y, Nguimfack A, Cavailler P et al.: Safety and effectiveness of amphotericin B deoxycholate for the treatment of visceral leishmaniasis in Uganda. Ann. Trop. Med. Parasitol.102(1),11–19 (2008).
    • 104  Golenser J, Frankerburg S, Erhenfreund T, Domb AJ: Efficacious treatment of experimental leishmaniasis with amphotericin B- arabinogalactan water-soluble derivatives Antimicrob. Agent Chemother.43 (9),2209–2214 (1999).
    • 105  Nicoletti S, Seifert K, Gilbert IH: N-(2-hydroxypropyl)methacrylamide-amphotericin B (HPMA-AmB) copolymer conjugates as antileishmanial agents. Int. J. Antimicrob. Agents33(5),441–448 (2009).
    • 106  Chaudhuri G, Mukhopadhyay A, Basu SK: Selective delivery of drugs to macrophages through a highly specific receptor. An efficient chemotherapeutic approach against leishmaniasis. Biochem. Pharmacol.38,2995–3002 (1989).
    • 107  Nan A, Nanayakkara NP, Walker LA, Yardley V, Croft SL, Ghandehari H: N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers for targeted delivery of 8-aminoquinoline antileishmanial drugs. J. Control. Rel.94,115–127 (2001).
    • 108  Nan A, Croft SL, Yardley V, Ghandehari H: Targetable water-soluble polymer–drug conjugates for the treatment of visceral leishmaniasis. J. Control. Rel.94,115–127 (2004).
    • 109  Minino AM, Heron MP, Murphy SL, Kochanek KD: Deaths: final data for 2004. Natl Vital. Stat. Rep.55(19),1–119 (2007).
    • 110  Heine H, Rietschel ET, Ulmer AJ: The biology of endotoxin. Mol. Biotechnol.19(3),279–296 (2001).
    • 111  Vincent JL: Drotrecogin α (activated): the treatment for severe sepsis? Expert Opin. Biol. Ther.7(11),1763–1777 (2007).
    • 112  Cruz DN, Perazella MA, Bellomo R et al.: Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review. Crit. Care11(2),R47 (2007).
    • 113  Shoji H: Extracorporeal endotoxin removal for the treatment of sepsis: endotoxin adsorption cartridge (Toraymyxin). Ther. Apher. Dial.7(1),108–114 (2003).
    • 114  Vicent MJ, Cascales L, Carbajo RJ, Cortés N, Messeguer A, Pérez-Payá E: Nanoconjugates as intracorporeal neutralizers of bacterial endotoxins. J. Control. Rel.142,277–285 (2010).
    • 115  Pasut G, Veronese FM: PEG conjugates in clinical development or use as anticancer agents: an overview. Adv. Drug Deliv. Rev.61(13),1176–1188 (2009).
    • 116  Rodriguez M, Antunez JA, Taboada C, Seijo B, Torres D: Colon-specific delivery of budesonide from microencapsulated cellulosic cores: evaluation of the efficacy against colonic inflammation in rats. J. Pharm. Pharmacol.53(9),1207–1215 (2001).
    • 117  Varshosaz J, Emami J, Tavakoli N et al.: Synthesis and evaluation of dextran-budesonide conjugates as colon specific prodrugs for treatment of ulcerative colitis. Int. J. Pharm.365(1–2),69–76 (2009).
    • 118  Keely S, Ryan SM, Haddleton DM et al.: Dexamethasone-pDMAEMA polymeric conjugates reduce inflammatory biomarkers in human intestinal epithelial monolayers. J. Control. Rel.135(1),35–43 (2009).▪ pDMAEMA–dexamethasone was found to offer advantages in mucosal delivery over free dexamethasone being a useful tool for the localized delivery of the hydrophobic compound across the epithelium.
    • 119  Henson PM: Dampening inflammation. Nat. Immunol.6,1179–1181 (2005).
    • 120  Liu X-M, Miller SC, Wang D: Beyond oncology-Application of HPMA copolymers in non-cancerous diseases. Adv. Drug Deliv. Rev.62,258–271 (2010).
    • 121  Wang D, Miller SC, Liu XM, Anderson B, Wang XS, Goldring SR: Novel dexamethasone-HPMA copolymer conjugate and its potential application in treatment of rheumatoid arthritis. Arthritis Res. Ther.9(1),R2 (2007).
    • 122  Hwang J, Rodgers K, Oliver JC, Schluep T: α-methylprednisolone conjugated cyclodextrin polymer-based nanoparticles for rheumatoid arthritis therapy. Int. J. Nanomed.3(3),359–371 (2008).
    • 123  Kurtoglu YE, Navath RS, Wang B, Kannan S, Romero R, Kannan RM: Poly(amidoamine) dendrimer-drug conjugates with disulfide linkages for intracellular drug delivery. Biomaterials30(11),2112–2121 (2009).
    • 124  Hardwicke J, Ferguson EL, Moseley R, Stephens P, Thomas DW, Duncan R: Dextrin-rhEGF conjugates as bioresponsive nanomedicines for wound repair. J. Control. Rel.130(3),275–283 (2008).
    • 125  Vicent MJ, Perez-Paya E: Poly-L-glutamic acid (PGA) aided inhibitors of apoptotic protease activating factor 1 (Apaf-1): an antiapoptotic polymeric nanomedicine. J. Med. Chem.49(13),3763–3765 (2006).▪▪ Key paper describing the first polymer antiapoptotic conjugate.
    • 126  Shaunak S, Thomas S, Gianasi E et al.: Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation. Nat. Biotechnol.22(8),977–984 (2004).
    • 127  Fisher M: The ischemic penumbra: identification, evolution and treatment conecpts. Cerebrovasc. Dis.17(Suppl. 1),1–6 (2004).
    • 128  Bertuglia S, Giusti A: Microvascular oxygenation, oxidative stress, NO suppression and superoxide dismutase during postischemic reperfusion. Am. J. Physiol. Heart Circ. Physiol.285(3),H1064–H1071 (2003).
    • 129  Mondragon L, Orzaez M, Sanclimens G et al.: Modulation of cellular apoptosis with apoptotic protease-activating factor 1 (Apaf-1) inhibitors. J. Med. Chem.51(3),521–529 (2008).
    • 130  Vicent MJ, Mondragón L, Orzáez M et al.: Polymer-drug conjugates as inhibitors of cellular apoptosis. AAPS J.35,230 (2008).
    • 131  Goicoechea I, Peri L, Vicent MJ et al.: Evaluation of apoptosis inhibition using Apaf-1 inhibitors (peptoid 1) in an ischaemia-reperfusion Wistar rat model. Eur. Urol.8(Suppl. 4),144 (2009).
    • 132  Koh KK: Effects of hormone replacement therapy on coagulation and fibrinolysis in postmenopausal women. Int. J. Hematol.76(Suppl. 2),44–46 (2002).
    • 133  Di Bitondo R, Hall AJ, Peake IR, Iacoviello L, Winship PR: Oestrogenic repression of human coagulation factor VII expression mediated through an oestrogen response element sequence motif in the promoter region. Hum. Mol. Genet.11(7),723–731 (2002).
    • 134  Rodriguez-Hernandez A, Rubio-Gayosso I, Ramirez I et al.: Intraluminal-restricted 17 β-estradiol exerts the same myocardial protection against ischemia/reperfusion injury in vivo as free 17 β-estradiol. Steroids73(5),528–538 (2008).
    • 135  Bertuglia S, Veronese FM, Pasut G: Polyethylene glycol and a novel developed polyethylene glycol-nitric oxide normalize arteriolar response and oxidative stress in ischemia–reperfusion. Am. J. Physiol. Heart Circ. Physiol.291(4),H1536–H1544 (2006).
    • 136  Wang D, Miller SC, Kopeckova P, Kopecek J: Bone-targeting macromolecular therapeutics. Adv. Drug Deliv. Rev.57(7),1049–1076 (2005).
    • 137  Lindsay R: Hormones and bone health in postmenopausal women. Endocrine24(3),223–230 (2004).
    • 138  Pan H, Liu J, Dong Y et al.: Release of prostaglandin E(1) from N-(2-hydroxypropyl)methacrylamide copolymer conjugates by bone cells. Macromol. Biosci.8(7),599–605 (2008).
    • 139  Pan H, Sima M, Kopeckova P et al.: Biodistribution and pharmacokinetic studies of bone-targeting N-(2-hydroxypropyl)methacrylamide copolymer-alendronate conjugates. Mol. Pharm.5(4),548–558 (2008).
    • 140  Wang D, Miller S, Sima M, Kopecková P, Kopecek J: Synthesis and evaluation of water-soluble polymeric bone-targeted drug delivery systems. Bioconjug. Chem.14,853–859 (2003).
    • 141  Greco F, Vicent MJ: Polymer conjugates based combinations for improved treatment of cancer. Adv. Drug Deliv. Rev.61(13),1203–1213 (2009).
    • 142  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. Cancer42(18),3127–3139 (2006).
    • 143  Rowinsky EK, Rizzo J, Ochoa L et al.: A Phase I and pharmacokinetic study of PEGylated camptothecin as a 1-hour infusion every 3 weeks in patients with advanced solid malignancies. J. Clin. Oncol.21(1),148–157 (2003).
    • 201  Cerulean Nanopharmaceuticals www.ceruleanrx.com/scienceNanopharmaceuticals.html
    • 202  Nektar: NXTR-102 www.nektar.com/product_pipeline/oncology_nktr-102.html
    • 203  CTI. Clinical development: OPAXIO™ www.celltherapeutics.com/opaxio
    • 204  Nektar: NXTR-105 www.nektar.com/product_pipeline/oncology_nktr-105.html
    • 205  SynDevRx™, Inc. Synergistic drug development www.syndevrx.com
    • 206  Nectar: Oral NKTR-118 and Oral NKTR-119 www.nektar.com/product_pipeline/cns_pain_oral_nktr-118and119.html