Polymer drug conjugate


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Polymer drug conjugate

  1. 1. Content  Introduction  Advantages of Polymer-drug conjugates  Characteristics of Ideal drug for conjugation  Clinical status of polymer–drug conjugates  Designing the polymer drug conjugates  Polymers for drug conjugation  Recent studies  Conclusion  References 21/06/2012 2G.I.P.S.
  2. 2. Introduction  Polymer-drug conjugates are a novel class of nanocairrers for drug delivery, which can protect the drug from premature degradation, prevent drug from prematurely interaction with the biological environment and enhance the absorption of the drugs into tissues (by enhanced permeability and retention effect or active targeting).  Polymer-drug conjugates are often considered as new chemical entities (NCEs) owing to a distinct pharmacokinetic profile from that of the parent drug.  A conjugation of a drug with a polymer forms so-called ‘polymeric prodrug’. 21/06/2012 3G.I.P.S.
  3. 3.  Synthetic polymers may be conjugated covalently to a variety of natural or synthetic bio-molecules for many diverse uses.  In 1975, Helmut Ringsdorf published his famous cartoon suggesting the use of a synthetic polymer backbone as a carrier for drug molecules.  In 1977, Abuchowski et. al. published the first paper on the conjugation of poly(ethylene glycol) to protein drugs.  Polymeric conjugates of conventional drugs (polymeric prodrugs) have several advantages over their low molecular weight precursors. Introduction 21/06/2012 4G.I.P.S.
  4. 4.  In general, the conjugation of hydrophilic polymers deeply changes the behavior of the parent (free) compound both in vitro and in vivo.  This change happens with both proteins and low molecular weight agents. Introduction 21/06/2012 5G.I.P.S.
  5. 5. The main advantages include… 1. Increased water solubility; enhancement of drug bioavailability. 2. Protection of drug from deactivation and preservation of its activity during circulation, transport to targeted organ or tissue and intracellular trafficking. 3. An improvement in pharmacokinetics. 4. A reduction in antigenic activity of the drug leading to a less pronounced immunological body response. Advantages of Polymer-drug conjugates 21/06/2012 6G.I.P.S.
  6. 6. Advantages of Polymer-drug conjugates 5. The ability to provide passive or active targeting of the drug specifically to the site of its action. 6. In addition to drug and polymer carrier, may include several other active components that enhance the specific activity of the main drug. 7. Specific accumulation in organs, tissues or cells, by actively targeted polymers or exploiting the known ‘‘enhanced permeability and retention(EPR) effect’’. 21/06/2012 7G.I.P.S.
  7. 7. Characteristics of Ideal drug for conjugation The following properties of the drug molecules make it suitable as an ideal candidate to form the polymeric conjugate… a. lower aqueous solubility, b. instability at varied physiological pH, c. higher systemic toxicity, and d. reduced cellular entry. 21/06/2012 8G.I.P.S.
  8. 8. Conjugate Indication Year of market status Company A)High molecular drug SMANCS(ZINOSTIDIN,STIMILAMAN) PEG adenosine deamainase PEG-anti-TNF Fab (CDP870) Hepatocelluler carcinoma SCID syndrome RA, CROHN’S DISEASE 1993 1990 2008 Yamanochi pharmaceutical Enzon UCB B)Low molecular Wight drug HPMA co polymer- doxorubicin(PK1;FCE28068) PEG-paclitaxcel Breast cancer ,Lung cancer Solid cancer Phase II Phase I Pfizer Enzon Clinical status of polymer–drug conjugates 21/06/2012 9G.I.P.S.
  9. 9. Designing the polymer drug conjugates In a polymer-drug conjugate, there are at least three major components..... 1. a soluble polymer backbone 2. a biodegradable linker, and 3. a covalently linked drug which is deactivated as a conjugate. 21/06/2012 10G.I.P.S.
  10. 10. Designing the polymer drug conjugates 21/06/2012 11G.I.P.S. HPMA-doxorubin-galactosamine
  11. 11.  Three major types of polymeric prodrug are currently being used.... 1. Prodrug of the first type are broken-down inside cells to form active substance or substances. 2. The second type of prodrug is usually the combination of two or more substances. Under specific intracellular conditions, these substances react forming an active drug. 3. The third type of prodrug, targeted drug delivery systems, usually includes three components: a targeting moiety, a carrier, and one or more active component(s). Designing the polymer drug conjugates 21/06/2012 12G.I.P.S.
  12. 12.  The targeting ability of the delivery system depends on the several variables including: receptor expression; ligands internalization; choice of antibody, antibody fragments or non-antibody ligands; and binding affinity of the ligand.  Therefore, the selection of a suitable polymer and a targeting moiety is vital to the effectiveness of prodrugs.  It is essential that the polymer used is neither inherently toxic nor immunogenic. If the polymer is non-degradable in main chain the carrier must have a molecular weight sufficiently low to allow renal elimination (i.e. less than 30– 40 kDa) and thus prevent progressive accumulation in the body. Designing the polymer drug conjugates 21/06/2012 13G.I.P.S.
  13. 13.  Unless the drug bound to the polymeric chain is membrane active, a non biodégradable polymère drug linker will yield an inactive conjugate. Preferably the linker chosen should be stable in the circulation but amenable to specific enzymatic or hydrolytic cleavage intra-tumourally.  The cleavage of the polymer drug linker results in the release and re-activation of the attached drug molecules.  Despite the variety of novel drug targets and sophisticated chemistries available, only four drugs (doxorubicin, camptothecin, paclitaxel, and platinate) and four polymers {N-(2-hydroxylpropyl)methacrylamide (HPMA) copolymer, poly-L-glutamic acid, poly(ethylene glycol) (PEG), and Dextran} have been repeatedly used to develop polymer– drug conjugates. Designing the polymer drug conjugates 21/06/2012 14G.I.P.S.
  14. 14.  To date, at least 11 polymer–drug conjugates have entered Phase I and II clinical trials and are especially useful for targeting blood vessels in tumors. Designing the polymer drug conjugates 21/06/2012 15G.I.P.S.
  15. 15. Polymers for drug conjugation Many polymers have been investigated as candidates for the delivery of natural or synthetic drugs. In general, an ideal polymer for drug delivery should be characterized by..... 1. biodegradability or adequate molecular weight that allows elimination from the body to avoid progressive accumulation in vivo; 2. low poly dispersity, to ensure an acceptable homogeneity of the final conjugates; 3. Longer body residence time either to prolong the conjugate action or to allow distribution and accumulation in the desired body compartments; and 4. for protein conjugation, only one reactive group to avoid cross-linking, whereas for small drug conjugation, many reactive groups to achieve a satisfactory drug loading. 21/06/2012 16G.I.P.S.
  16. 16.  Synthetic polymers: PEG, N-(2-hydroxypropyl)- methacrylamide copolymers (HPMA), poly(ethy-leneimine) (PEI), poly(acroloylmorpholine) (PAcM), poly(vinylpyrrolidone) (PVP), polyamidoamines, divinylethermaleic anhydride/acid co-polymer (DIVEMA), poly(styrene-co-maleic acid/anhydride) (SMA), polyvinylalcohol (PVA);  Natural polymers: dextran, pullulan, mannan, dextrin, chitosans, hyaluronic acid, proteins;  Pseudosynthetic polymers: PGA, poly(L-lysine), poly(malic acid), poly(aspartamides), poly((N-hydroxyethyl)- L-glutamine) (PHEG). Polymers for drug conjugation 21/06/2012 17G.I.P.S.
  17. 17. Recent studies 1. Anti-diabetic γ-PGA–Phloridzin conjugates :  Yusuke Ikumi et. al. studied Polymer (γ-PGA)–Phloridzin conjugates for anti-diabetic action that Inhibits glucose absorption through the Na+/glucose co-transporter (SGLT1).  They used γ-PGA of weight-average molecular weight: 382,000 as the polymer for conjugation.  The strong inhibitory effect of PGA-PRZ may be explained by considering that bulky γ-PGA chains prevent the Phloridzin moiety of PGA-PRZ from degrading in the small intestine. 21/06/2012 18G.I.P.S.
  18. 18. 2. Anti cancer MPEG-b-PCL-b-PLL Cisplatin conjugate:  Haihua Xiao et. al. studied the conjugate of Cisplatin with MPEG-b-PCL-b-PLL.  They assembled the conjugate into nano-micelles.  In vitro release experiments showed that drug release from the polymer - Cisplatin micelles follows an acid responsive and oxidation-reduction sensitive kinetics.  HPLC-ICP-MS analysis revealed that Cisplatin can be released from the conjugate under an acidic plus a reductive condition which is available inside a cancerous cell. Recent studies 21/06/2012 19G.I.P.S.
  19. 19.  In vitro MTT assay demonstrated that the polymer- Cisplatin micelles display higher cytotoxicity against SKOV-3 tumor cells than pure Cisplatin.  This enhanced cytotoxicity is attributed to effective internalization of the micelles by the cells via endocytosis mechanism, which was observed by fluorescence imaging and by direct determination of the platinum uptake by the cells.  This polymer- Cisplatin conjugate is a promising polymeric pro-drug of Cisplatin in micellar form. It can protect the drug against blood clearance. It can enter cancerous cells via endocytosis mechanism and then Cisplatin can be released.  Therefore, this polymeric pro-drug of cisplatin is expected to find clinical applications in the future. Recent studies 21/06/2012 20G.I.P.S.
  20. 20. 3. Rotem Erez et. al. have synthesized an N-(2 hydroxypropyl)-meth-acrylamide (HPMA) copolymer– paclitaxel conjugate with an AB3 self-immolative dendritic linker.  The water-soluble polymer–drug conjugate was designed to release a triple payload of the hydrophobic drug paclitaxel as a result of cleavage by the endogenous enzyme cathepsin B.  The polymer–drug conjugate exhibited enhanced cytotoxicity on murine prostate adeno-carcinoma (TRAMP C2) cells in comparison to a classic monomeric drug– polymer conjugate. Recent studies 21/06/2012 21G.I.P.S.
  21. 21. 4. A novel folate-decorated maleilated pullulan–doxorubicin conjugate (abbreviated as FA–MP–DOX) for active tumor targeting was set up by Haitao Zhang et. al.  Based on the IC50 values, the conjugate was found more effective with ovarian carcinoma A2780 cells than the parent drug.  These results suggested that FA–MP–DOX conjugate could be a promising doxorubicin carrier for its targeted and intracellular delivery. Recent studies 21/06/2012 22G.I.P.S.
  22. 22. Conclusion  Use of polymeric materials and their implications in delivering bio- components seems to be crucial in therapeutics. It is well accepted that the bioactive components can be delivered more efficiently by being converted into a prodrug form. However, such polymeric bio-conjugates need extensive structural and clinical studies. To date, poly(ethylene glycol) continues to be a highly investigated polymer for the covalent modification of biological macromolecules and has evolved as a successful candidate for many pharmaceutical and biotechnical applications. Modification of biological macromolecules, anticancer drugs, peptides, and proteins in the form of prodrugs are of extreme importance in therapeutics. Selection of a suitable polymer and methodology to conjugate the same with different bioactive components is a critical step. The prodrug conjugation approach is a fascinating field and appears to have a bright future in therapeutics. 21/06/2012 23G.I.P.S.
  23. 23. References 1. Polymer-drug conjugates: Recent development in clinical oncology Review Article; Advanced Drug Delivery Reviews, Volume 60, Issue 8, 22 May 2008, Pages 886-898; Chun Li, Sidney Wallace. 2. Combination therapy: Opportunities and challenges for polymer–drug conjugates as anticancer Review Article; Advanced Drug Delivery Reviews, Volume 61, Issue 13, 12 November 2009, Pages 1203-1213; Francesca Greco, María J. Vicent. 3. Polymer conjugates of the highly potent cytostatic drug 2-pyrrolinodoxorubicin Original Research Article; European Journal of Pharmaceutical Sciences, Volume 42, Issues 1–2, 18 January 2011, Pages 156-163; M. Studenovsky, K. Ulbrich, M. Ibrahimova, B. Rihova. 4. Biodegradable polymer − cisplatin(IV) conjugate as a pro-drug of cisplatin(II) Original Research Article; Biomaterials, Volume 32, Issue 30, October 2011, Pages 7732-7739; Haihua Xiao, Ruogu Qi, Shi Liu, Xiuli Hu, Taicheng Duan, Yonghui Zheng, Yubin Huang, Xiabin Jing. 5. HPLC methods for the determination of bound and free doxorubicin, and of bound and free gala Original Research Article; Journal of Pharmaceutical and Biomedical Analysis, Volume 15, Issue 1, October 1996, Pages 123-129; E. Configliacchi, G. Razzano, V. Rizzo, A. Vigevani. 6. Water-soluble polymer–drug conjugates for combination chemotherapy against visceral leishma Original Research Article; Bioorganic & Medicinal Chemistry, Volume 18, Issue 7, 1 April 2010, Pages 2559-2565; Salvatore Nicoletti, Karin Seifert, Ian H. Gilbert. 21/06/2012 24G.I.P.S.
  24. 24. References 7. E-selectin binding peptide–polymer–drug conjugates and their selective cytotoxicity against vas Original Research Article; Biomaterials, Volume 30, Issue 32, November 2009, Pages 6460-6468; Yosi Shamay, Denise Paulin, Gonen Ashkenasy, Ayelet David. 8. Polymer–phloridzin conjugates as an anti-diabetic drug that Inhibits glucose absorption through +/glucose cotransporter (SGLT1) in the small intestine Original Research Article; Journal of Controlled Release, Volume 125, Issue 1, 4 January 2008, Pages 42-49; Yusuke Ikumi, Toshiyuki Kida, Shinji Sakuma, Shinji Yamashita, Mitsuru Akashi. 9. Polymer–drug conjugates: Progress in polymeric prodrugs Review Article; Progress in Polymer Science, Volume 31, Issue 4, April 2006, Pages 359-397; Jayant Khandare, Tamara Minko. 10. Enhanced cytotoxicity of a polymer–drug conjugate with triple payload of paclitaxel Original Research Article; Bioorganic & Medicinal Chemistry, Volume 17, Issue 13, 1 July 2009, Pages 4327-4335; Rotem Erez, Ehud Segal, Keren Miller, Ronit Satchi-Fainaro, Doron Shabat. 11. Biodegradable star HPMA polymer–drug conjugates: Biodegradability, distribution and anti-tum Original Research Article; Journal of Controlled Release, Volume 154, Issue 3, 25 September 2011, Pages 241-248; Tomáš Etrych, Lubomír Kovář, Jiří Strohalm, Petr Chytil, Blanka Říhová, Karel Ulbrich. 21/06/2012 25G.I.P.S.
  25. 25. References 12. Poly(L-glutamic acid)–anticancer drug conjugates Review Article; Advanced Drug Delivery Reviews, Volume 54, Issue 5, 13 September 2002, Pages 695-713; Chun Li. Relevance of folic acid/polymer ratio in targeted PEG–epirubicin conjugates Original Research Article; Journal of Controlled Release, Volume 146, Issue 3, 15 September 2010, Pages 388-399; Fabiana Canal, María J. Vicent, Gianfranco Pasut, Oddone Schiavon. 13. Polymer–drug conjugates, PDEPT and PELT: basic principles for design and transfer from the Original Research Article; Journal of Controlled Release, Volume 74, Issues 1–3, 6 July 2001, Pages 135-146; R. Duncan, S. Gac-Breton, R. Keane, R. Musila, Y.N. Sat, R. Satchi, F. Searle. 14. Macromolecular prodrugs. VII. Polymer-dopamine conjugates Original Research Article International Journal of Pharmaceutics, Volume 136, Issues 1–2, 14 June 1996, Pages 31- 36; I. Kalčić, B. Zorc, I. Butula. 15. Manipulation of the rate of hydrolysis of polymer-drug conjugates: The secondary structure of th Original Research Article; Journal of Controlled Release, Volume 39, Issues 2–3, May 1996, Pages 221-229; Colin G. Pitt, Subodh S. Shah. 16. 4.423 - Polymeric Drug Conjugates by Controlled Radical Polymerization Comprehensive Biomaterials, Volume 4, 2011, Pages 377-388; S.-H. Kim, T.H. Nguyen, H.D. Maynard. 21/06/2012 26G.I.P.S.
  26. 26. References 17. Polymer platforms for drug delivery and biomedical imaging Original Research Article; Journal of Controlled Release, Volume 122, Issue 3, 8 October 2007, Pages 269-277; Zheng-Rong Lu, Furong Ye, Anagha Vaidya. 18. Folate-decorated maleilated pullulan–doxorubicin conjugate for active tumor-targeted drug delivery Original Research Article; European Journal of Pharmaceutical Sciences, Volume 42, Issue 5, 18 April 2011, Pages 517-526; Haitao Zhang, Fei Li, Jun Yi, Chunhu Gu, Li Fan, Youbei Qiao, Yangchun Tao, Chong Cheng, Hong Wu. 19. Polymer–drug conjugation, recent achievements and general strategies Review Article Progress in Polymer Science, Volume 32, Issues 8–9, August–September 2007, Pages 933-961; G. Pasut, F.M. Veronese. 20. Polymer-drug conjugates: manipulating drug delivery kinetics using model LCST systems Original Research Article; Journal of Controlled Release, Volume 45, Issue 1, 3 March 1997, Pages 95-101; S.S Shah, J Wertheim, C.T Wang, C.G Pitt. 21. Polymer conjugates for tumour targeting and intracytoplasmic delivery. The EPR effect as a common gateway? Review Article; Pharmaceutical Science & Technology Today, Volume 2, Issue 11, 1 November 1999, Pages 441-449; Ruth Duncan. 21/06/2012 27G.I.P.S.
  27. 27. References 22. Curcumin polymers as anticancer conjugates Original Research Article; Biomaterials, Volume 31, Issue 27, September 2010, Pages 7139-7149; Huadong Tang, Caitlin J. Murphy, Bo Zhang, Youqing Shen, Edward A. Van Kirk, William J. Murdoch, Maciej Radosz. 23. Conjugates of stimuli-responsive polymers and proteins Review Article; Progress in Polymer Science, Volume 32, Issues 8–9, August–September 2007, Pages 922-932; Allan S. Hoffman, Patrick S. Stayton. 24. Effective drug delivery by PEGylated drug conjugates Original Research Article; Advanced Drug Delivery Reviews, Volume 55, Issue 2, 10 February 2003, Pages 217-250; Richard B. Greenwald, Yun H. Choe, Jeffrey McGuire, Charles D. Conover. 21/06/2012 28G.I.P.S.
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