Polymer-drug conjugates are a novel class of nanocarriers for drug delivery, which can protect the drug from premature degradation, prevent the drug from premature 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. Conjugation of a drug with a polymer forms so-called ‘Polymeric Prodrug’.

1. G.I.P.S. 1
Tapash Chakraborty
Assistant Professor
Girijananda Chowdhury Institute of Pharmaceutical Science (GIPS)

2. 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
2G.I.P.S.

3. Introduction
 Polymer-drug conjugates are a novel class of nanocarriers
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’.
3G.I.P.S.

4.  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
4G.I.P.S.

5.  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
5G.I.P.S.

6. 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
6G.I.P.S.

7. 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’’.
7G.I.P.S.

8. 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.
8G.I.P.S.

9. 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
9G.I.P.S.

10. 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.
10G.I.P.S.

11. Designing the polymer drug conjugates
11G.I.P.S.
HPMA-doxorubin-galactosamine

12.  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
12G.I.P.S.

13.  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
13G.I.P.S.

14.  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
14G.I.P.S.

15.  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
15G.I.P.S.

16. 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.
16G.I.P.S.

17.  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
17G.I.P.S.

18. 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.
18G.I.P.S.

19. 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
19G.I.P.S.

20.  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
20G.I.P.S.

21. 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
21G.I.P.S.

22. 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
22G.I.P.S.

23. 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.
23G.I.P.S.

24. 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 nanomedicines 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
galactosamine, in methacrylamide polymer-drug conjugates 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
leishmaniasis Original Research Article; Bioorganic & Medicinal Chemistry, Volume 18,
Issue 7, 1 April 2010, Pages 2559-2565; Salvatore Nicoletti, Karin Seifert, Ian H. Gilbert.
24G.I.P.S.

25. References
7. E-selectin binding peptide–polymer–drug conjugates and their selective cytotoxicity against
vascular endothelial cells 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 the Na+/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-
tumor efficacy 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.
25G.I.P.S.

26. 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 laboratory to clinic 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 the polymer 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.
26G.I.P.S.

27. 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.
27G.I.P.S.

28. 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.
28G.I.P.S.

29. 29G.I.P.S.
Thank You