sruthi-polymer drug conjugates

A Seminar onPolymer-drug conjugates: current status and future trends : 

A Seminar onPolymer-drug conjugates: current status and future trends

Contents : 

Contents INTRODUCTION POLYMER-DRUG CONJUGATES POLYMERS FOR USE IN POLYMERIC THERAPEUTICS PROTEIN-POLYMER CONJUGATES CLINICAL STATUS OF POLYMER-DRUG CONJUGATES NOVEL POLYMERIC ANTICANCER AGENTS CONCLUSION REFERENCES

Polymer Therapeutics : 

Polymer Therapeutics The term ‘polymer therapeutics’ describes several distinct classes of agents, including polymeric drugs, polymer–drug conjugates, polymer–protein conjugates, polymeric micelles to which drug is covalently bound, and the multicomponent polyplexes that are now being developed as non-viral vectors.

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To maximize the outcomes and better tailor the polymer conjugation, a number of different polymers and chemical approaches were also developed, yielding a selection of new structures like Dendrimers Dendronized polymers Graft polymers Block copolymers Branched polymers Multivalent polymers Stars Hybrid glycol and peptide derivatives .

STRATEGIES FOR POLYMER-DRUG CONJUGATES : 

STRATEGIES FOR POLYMER-DRUG CONJUGATES In the field of anticancer therapy, two strategies for improving the therapeutic efficacy of anticancer agents have emerged over the past several decades. First approach is the design and development of agents that modulate the molecular processes and pathways specifically associated with tumor progression. In second approach existing anticancer agents can be made more effective by using nanocarriers that bring more drug molecules to the tumor site, compared with the conventional formulation, while reducing exposure of normal tissues to the drug. These nanosized hybrid systems often combine a drug, protein or antibody with a polymer or polymer-coated liposome and they can rightly be viewed as the first ‘nanomedicines’.

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Schematic illustration of the therapeutics and technologies in clinical development and/or on the market as treatment for cancer that can be viewed as nanomedicines

POLYMER–DRUG CONJUGATES: RATIONALE FOR DESIGN : 

POLYMER–DRUG CONJUGATES: RATIONALE FOR DESIGN To prolong the plasma half-life of therapeutically active agents by increasing their hydrodynamic volume and hence decreasing their excretion rate. Careful design of the polymer drug linker so that it is stable in transit and degraded at a suitable rate intratumourally. Whichever linking chemistry is used, it is important to note that there is a clear influence of drug loading on conjugate conformation in solution. This in turn governs drug release rate and consequently therapeutic index. High loading with hydrophobic drugs can reduce the rate of prodrug activation .

Advantages of polymer-drug conjugates : 

Advantages of polymer-drug conjugates Improve therapeutic properties of peptides, proteins, small molecules or oligonucleotides. Exhibit prolonged half-life. Higher stability Water solubility Lower immunogenicity and antigenicity and Specific targeting to tissues or cells. Ease of drug adminitration Improved Patient Compliance.

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Polymer-Drug Conjugates Polymer anticancer drug conjugates are designed to enhance the physico-chemical properties of the drug and to administer the drug specifically to the tumor site. They are prepared by conjugating anticancer drug to a polymeric backbone via covalent linkage. Biodegradable spacer is inserted in the conjugate to insure stability during systemic circulation and to facilitate specific enzymatic or hydrolytic release of the drug. Eg: Doxorubicin-HPMA conjugate. The polymer used is N (2-hydroxyp-ropyl) methacrylamide copolymer.

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Mechanism of action : Targeting of polymeric drugs Conjugation of low molecular weight drugs to high molecular weight carriers results in high molecular weight prodrugs. Such conjugation substantially changes the mechanisms of cellular drug entrance. While small molecular weight drugs enter cells primarily by diffusion, high molecular weight drugs are internalized mainly by endocytosis. Two approaches are generally used to target polymeric anticancer drugs to the tumor or cancer cells: (1) passive targeting and (2) active targeting

Passive Targeting : 

Passive Targeting The macromolecular carriers offers ‘‘per se’’ a passive targeting to solid tumors due to the anatomical and physiological modifications of such tissues. In particular tumors have (i) an increased vascular density (the result of highly active angiogenesis); (ii) vessels with both wide fenestrations and lack of smooth muscle layer; (iii) a decreased lymphatic drainage.

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EPR effect plays a crucial role in drug accumulation (EPR-Enhanced Permeation and Retention)

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Hyperpermeable angiogenic tumour vessels allow preferential extravasation of circulating macromolecules and liposomes, and once in the interstitium they are retained there by lack of intratumoural lymphatic drainage. This leads to significant tumour targeting (>10-100-fold compared to free drug) . Both polymer- and tumour-related characteristics govern the extent of EPR-mediated targeting. Smaller tumours exhibit the highest concentration of polymer–drug. Tumour uptake of polymers (usual molecular diameter 5–20 nm) had broad size tolerance and good intratumoural penetration compared with that reported for liposomes and nanoparticles

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Conjugates have also been synthesised to contain ligands that might promote receptor-mediated targeting (including antibodies, peptides and saccharides) Although this is an attractive possibility, so far only one such conjugate has progressed into phase I trial, and this was HPMA copolymer-doxorubicin- galactosamine, which was designed as a treatment for hepatocellular carcinoma or secondary liver disease.

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Contd., Passive targeting increases the concentration of the conjugate in the tumor environment and therefore ‘passively’ forces the polymeric drug to enter the cells by means of the concentration gradient between the intracellular and extracellular spaces and therefore is not very efficient. The more efficient way to provide targeting is so-called ‘active targeting’

Active Targeting : 

Active Targeting Active targeting of a drug delivery system is usually achieved by adding, to DDS, a targeting component that provides preferential accumulation of the whole system or drug in a targeted organ, tissue,cells, intracellular organelles or certain molecules in specific cells. The active targeting approach is based on the interactions between a ligand and a receptor or between a specific biological pair (e.g. avidin–biotin, antibody–antigen, lectin–carbohydrate, etc.). This process can be divided into several distinct steps as schematically presented here..

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Main stages of receptor-mediated endocytosis: Interaction of a targeted carrier with a corresponding receptor leads to the engulfing of the plasma membrane inside the cells and the formation of a coated pit. The pit then pinches off from the plasma membrane and forms an endocytic vesicle and endosomes-membrane-limited transport vesicles with a polymeric delivery system inside. Endosomes move deep inside the cell and fuse with lysosomes forming secondary lysosomes. Lysosomal enzymes are capable of breaking the bond and the drug is released from the drug delivery complex and might exit a lysosome by diffusion.

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Contd., As a result of receptor mediated endocytosis and transport inside cells in membrane-limited organelles, targeted polymeric drugs no longer require a higher concentration gradient across the plasma membrane. They are protected from degradation inside the cell and therefore the specific efficacy is substantially higher than non-targeted conjugates and free drugs.

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An Ideal polymer for drug delivery should be characterized by (i) biodegradability or adequate molecular weight that allows elimination from the body to avoid progressive accumulation in vivo; (ii) low polydispersity, to ensure an acceptable homogeneity of the final conjugates; (iii) longer body residence time either to prolong the conjugate action or to allow distribution and accumulation in the desired body compartments; (iv) for protein conjugation, only one reactive group to avoid crosslinking, whereas for small drug conjugation, many reactive groups to achieve a satisfactory drug loading.

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Popular polymers for use in polymeric therapeutics Synthetic polymers: PEG, N-(2-hydroxypropyl)-methacrylamide copolymers (HPMA), poly(ethyleneimine) (PEI), poly(acroloylmorpholine)(PAcM), poly(vinylpyrrolidone) (PVP), polyamidoamines, divinylethermaleic anhydride/acid copolymer (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((Nhydroxyethyl)-L-glutamine) (PHEG).

Proteins– polymer conjugates : 

Proteins– polymer conjugates In the field of protein–polymer conjugation, the first pioneering studies were carried out by Torchilinet al. with dextran. There since, a number of alternative polymers have been explored for polymer conjugation and poly(ethylene glycol) (PEG) emerged as the best candidate for protein modification Indeed, its leading position reflects the fact that the majority of conjugates on the market are PEGylated products and that many others are already in advanced clinical investigation

Low molecular weight drug– polymer conjugates : 

Low molecular weight drug– polymer conjugates Polymer–low molecular weight drugs conjugates are well described by the model that Ringsdorf proposed in 1975. Small drug–polymer conjugate model according to Ringsdorf

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. Contd., Many steps have been made in the understanding of their mechanism of action both at cellular level and in vivo that allowed an improved design of each conjugate component (i.e.,polymer backbone, spacers, targeting agents and solubilising agents). Although, a large number of studies have been carried out for the preparation of small-drug conjugates, unfortunately none has yet reached the market. At present, XYOTAXTM (paclitaxel conjugated to polyglutamic acid (PGA)) will be the first of its class to reach the market: it is now under phase III clinical trials for the treatment of non-small cell lung cancer (NSCLC) in combination with carboplatin. Usually, a covalent and strategically positioned linkage with the polymer prevents the activity of small drugs. To ensure drug release several methods have been developed primarily based on either hydrolytically unstable bond or enzymatically labile spacers between the drug and the polymer.

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Contd., These spacers or bonds may control the release rate which is also important, because ideally the drug has to be released only at the site of action to reduce the drug toxicity. Indeed, a too fast release can abolish the advantages of polymer conjugation and yield conjugates with the same toxicity of the free drugs , whereas a too slow release can impair drug activity.

Clinical status of polymer–drug conjugates : 

Clinical status of polymer–drug conjugates HPMA copolymer- Gly-Phe-Leu-Gly-doxorubicin (PK1) In 1994, the first synthetic polymer – anticancer conjugate entered clinical trial. molecular mass is ~30 000 Da and doxorubicin content is ~8.5 wt% This peptidyl linker was designed to be hydrolysed by thiol-dependent proteases (particularly cathepsin B) after lysosomotropic delivery. In phase I trials, PK1 was administered as a short infusion every 3 weeks, and it had a maximum tolerated dose of 320 mg/m2 (doxorubicin equivalent) . This is approximately fourfold higher than the normal safe clinical dose of doxorubicin. Despite cumulative doses up to 1680 mg/m2 (doxorubicin equivalent), no cardiotoxicity was observed.

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Only targeted conjugate to be tested clinically . It was designed to recognise the hepatocyte asialoglyco-protein receptor and has been explored as a treatment for hepatocellular carcinoma. However, it was estimated that this hepatoma-associated drug was still 12–50 fold higher than could be achieved with administration of free doxorubicin. Antitumour activity was seen in patients with primary hepatocellular carcinoma in this study. HPMA copolymer-paclitaxel conjugates Clinical studies were disappointing. This was probably due to lack of ester linker stability during transport in the circulation and/or renal elimination. HPMA copolymer-paclitaxel showed toxicity consistent with commonly observed paclitaxel toxicities: flu-like symptoms, mild nausea and vomiting, mild haematological toxicity and neuropathy LIGAND-TARGETED POLYMER CONJUGATES HPMA copolymer-doxorubicin-galactosamine PK2

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HPMA copolymer platinates ,polymeric micelles containing doxorubicin and paclitaxel and PEG-camptothecin and paclitaxel conjugates are also undergoing early clinical evaluation. The polymer conjugate most advanced in clinical development is a polyglutamate-paclitaxel conjugate called Xyotax. Earlier phase I/II studies have reported very interesting activity in non small cell lung cancer (NSCLC) and also relapsed ovarian cancer . USA has recently initiated a phase III clinical trial involving Xyotax in ovarian cancer patients.

Novel polymeric anticancer agents and polymer–drug combinations : 

Novel polymeric anticancer agents and polymer–drug combinations Conjugates tested clinically so far have incorporated only established chemotherapeutic agents, including doxorubicin, paclitaxel, camptothecins and platinates. Clinical proof of the concept is now paving the way for synthesis of second-generation conjugates containing experimental chemotherapy and novel polymer-based combinations. Recently synthesised conjugates designed contain novel antitumour agents, such as Ellipticines Geldanamycin 1,5-diazaanthraquinones Wortmannin

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All are based on the premise that the EPR effect will promote tumour selective delivery of polymeric anticancer conjugates to tumour tissue in humans

Conclusion : 

Conclusion Results from early clinical trials of about a dozen polymer-drug conjugates have demonstrated several advantages over the corresponding parent drugs, including fewer side effects, enhanced therapeutic efficacy, ease of drug administration, and improved patient compliance. Clinical data collected over the last decade warrant further development of polymer-drug conjugates as a new class of anticancer agents. Future generation of polymer-drug conjugates will have to meet a number of challenges, including the development of novel polymers with modulated rates of degradation, versatile conjugation chemistry allowing site-specific attachment of targeting moieties, and polymerization methods that allow accurate control of polymer molecular weights and molecular weight distributions.

References : 

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