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
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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’.
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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
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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
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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
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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’’.
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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.
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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
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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.
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11. Designing the polymer drug conjugates
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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
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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
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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
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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
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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.
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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
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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.
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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
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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
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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
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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
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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.
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24. References
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25. References
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26. References
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27. References
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Thank You