Tapash ChakrabortyM. Pharm (Pharmaceutics)

2nd SemesterRoll No- MP/11/04

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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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’.

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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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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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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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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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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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Conjugate Indication Year of market status

Company

A)High molecular drugSMANCS(ZINOSTIDIN,STIMILAMAN)

PEG adenosine deamainasePEG-anti-TNF Fab (CDP870)

Hepatocelluler carcinomaSCID syndromeRA, CROHN’S DISEASE

1993

19902008

Yamanochi pharmaceuticalEnzonUCB

B)Low molecular Wight drugHPMA 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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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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Designing the polymer drug conjugates

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HPMA-doxorubin-galactosamine

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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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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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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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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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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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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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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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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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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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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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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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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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.

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References

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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.

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References

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References

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References

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