Polymer Drug Conjugate

A polymer-drug conjugate (PDCs) was designed by Helmut Ringsdorf (1975) to overcome the curbs of traditional chemotherapy, in which drug molecules covalently connected to the hydrophilic polymer (back bone as vehicle) via linkages that are specially designed to liberate drug at specific site or within structures.

Advantages of PDCs:

• 1. Enhance the drug targeting; reduce the dose size, provided sustained release profile and helpful in developing a multifunctional drug delivery system (Chandna et ah, 2010).
• 2. To enhance drug solubility, in-vivo stability, pharmacokinetics properties and protect drug molecules against deactivation (Luo et ah, 2012; Pang et ah, 2014).

FIGURE 9.9 Antigen target in solid tumor: (a) Antigen target over-expressed in tumor cell, (b) antigen target expressed in tumor vasculature, (c) antigen target expressed in tumor stroma, and (d) tumor growth factors.

FIGURE 9.10 Antigen target in different types of cancer.

• 3. Enhanced therapeutic efficacy by prolonged plasma exposure, plasma half-life of drug and accumulation of drug in tumor tissue using EPR effect as well as reduced local and systemic side effects (Chau et al., 2006).
• 4. Polymer drug conjugation enhances the drug loading capacity of nanocarrier systems (Park et al.. 2006).
• 5. PDCs is also a unique system which overcome the “burst drug release” problems associated with other polymeric drug carriers (Liposomes, ethosomes, niosomes etc.) in which drug is physically encapsulated by polymer (Allocati et al., 2018).

Methods for PDCs:

There are three different strategies for synthesize polymer-drug conjugates

• 1. Conjugating synthesized polymers to the drug molecules,
• 2. Conjugating a monomer to the drug, then polymerized by using reversible addition- fragmentation transfer polymerization, ring-opening metathesis polymerization or ringopening polymerization.
• 3. Drug molecule having multifunctional groups Use as a monomer for poly-drug polymerization (Feng and Tong, 2016; Zelikin et al., 2016).

Polymers in PDCs

N-(2-hydroxypropyl) Methacrylamide (HPMA) Copolymer-Drug Conjugates

HPMA is a synthetic nonimmunogenic, nontoxic, and water-soluble copolymer, widely used in PDCs because it is not absorbed by plasma proteins and having extended period of systemic circulation. 20 to 30 kDa HPMA copolymers with the acid labile linkers or peptide cleavable linker are suitable for the synthesis of PDCs because HPM А-drug conjugates less than 40 kDA molecular weight can easily accumulates in tumor tissues by passive targeting and eliminated from the body through renal filtration. HPMA has also immune-modulatory effects, it inhibits the expression of Fas ligand by modifying cell- surface properties of tumor cells, Fas actively involved in the neutralization of leukocytes which attack or kill cancer cells (Rihova and Kovar, 2010). Immuno-modulatory effect of HPMA encourage its use in the development of PDCs, because immune system plays a essential role in the complete eradication of cancer cells. Thus, HPMA conjugation with anticancer drug provides dual advantage (Kovar et al., 2003).

Various HPMA-anticancer drug conjugates have been developed and entered in the clinical trial which have provided the promising results and safety of HPMC copolymer as a new platform for chemotherapy (Duncan and Vicent, 2010). After that PDCs of other cytotoxic drugs like camptoth- ecin (CPT), paclitaxel (PTX), and dichloro(l,2-diaminocyclohexane)platinum(II) (DACHP) was also developed. All conjugates showed tolerable toxicity and bioavailability in phase I and II clinical trials (Vogus et ah. 2017).

Polysaccharide-Drug Conjugates

Polysaccharides are water-soluble, biodegradable and biocompatible polymer; it is one the best choice for the synthesis of PDCs due to having many functional groups for conjugation with drug molecule. Pharmacokinetic property of polysaccharides depends upon its molecular weight, electrical charge, branching and polydispersity (Mehvar, 2003).

There are various types of naturally or synthetic water-soluble polysaccharides such as hyaluronic acid, dextran, chitosan, and heparin which have been exploited for development of PDCs of water- insoluble or hydrophobic drugs.

Hyaluronic acid: It is an anionic high molecular weight (>250 kDa) polysaccharides composed by (1—>4) interglycosidic linkages between alternating units of N-acetyl-d-glucosamine and d-glucuronic acid, having anti-inflammatory effects. Carboxylic and hydroxyl groups at hyaluro- nate backbone provides specific sites for drug conjugation, it has also property to form hydrogel by absorbing water and great affinity to bind with CD44 and RHAMM (cell-surface markers). CD44 is specific cell-surface protein manly overexpressed at various types of cancer cells.

Dextran: Dextran is macromolecule, composed by repeating unit of glucose, was used as plasma expander. Primary and secondary hydroxyl groups of glucose are functional and active site for conjugation with drug molecules.

Chitosan: It is de-acetylated derivative of natural polysaccharide chitin; amino moieties of chitosan backbone is responsible for polymer drug conjugations. Chitosan has mucoadhesive properties which enhance the retention time of conjugated drugs in the respiratory mucosa (Yamamoto et al., 2005).

Heparin: It is an anticoagulant having the property to deactivates heparanase, prevents cancer cell adhesion, activates NK cells to attack and prevents tumor angiogenesis and metastasis by inhibits the activity of growth factors such as bFGF and VEGF. Heparin is the combination of 2-amino-deoxyglucopyranose (glucosamine) and pyranosyluronic acid residues (Li et al., 2012). Heparin-drug conjugate offers better solubility, long systemic circulation as well as more cytotoxicity than free drug. Heparin-drug conjugation reduces the anticoagulant property of heparin which decreases the risk of hemorrhagic complications in patients. Heparin- PTX conjugates was developed which exhibited more water solubility and cytotoxicity than free drug (Goodarzi et al., 2013).

PEG-Drug Conjugates

PEG is a hydrophilic FDA-approved polysaccharide for biological applications (Knop et ah, 2010). “PEGylation” is an approach proposed by Davis and Abuchowski in the 1970s (Pelegri-O'Day et ah, 2014), in which drug or protein molecules are conjugated with PEG to enhance the therapeutic index or plasma half-life by reducing reticulo-endothelial system (RES) uptake.

“PEGylation” also promote passive-targeting, EPR (enhanced permeability and retention) effects (Ajazuddin et ah, 2013) and reduce the host cytotoxicity. “PEG-amino-acid-oligopeptide-irinotecan” drug conjugate was developed and patented by Xu et ah (2011), during the in-vivo study using human ovarian cancer cells (SKOV-3) in nude mice they founded that this conjugate inhibits the growth of tumor cells at low dose (45 mg/kg) and reduce host cytotoxicity of irrinotecan (Khan et ah, 2018; Xu et ah, 2014). “PEGylation” or PEG-drug conjugation improves the solubility of drug as well as drug carrying capacity of nanocarrier or nanomaterial. Solubility of anticancer drug SN38 was enhanced by preparation of micelle of PEG-drug conjugation (Kurzrock et ah, 2012).

PG-Drug Conjugates

Poly(a,L-glutamic acid) (PG) is negatively charged, highly water-soluble naturally polypeptide of L-glutamic acid. PG degrades by lysosomal enzyme and mostly cleared by renal pathway so PG is an excellent polymeric carrier of therapeutic agents. Carboxylic group at glutamate backbone is responsible for PG-drug Conjugation. PG- drug conjugation enhances the solubility of poorly water-soluble drug.

Solubility of PTX (Taxol®. TXL) was improved by developing PG-TXL conjugate, in which PTX was conjugated via an ester linkage through 2'-hydroxyl group of poly(l -glutamic acid) (PG). Result of pre- clinical studies revealed that this conjugate has high water solubility, better antitumor efficacy and was more safe as compared PTX (Li et ah, 1998).

Camptothecins is a broad-spectrum anticancer drug inhibit topoisomerase-1 activity, but having limited therapeutic efficacy due to poor aqueous solubility and in instability of the lactone ring in systemic fluid, for the enhance stability and solubility PG-Camptothecins conjugate was developed by coupling the carboxylic acid of PG with hydroxy group of camptothecins. This conjugation also stuck the growth of growth of established H322 human lung tumors grown subcutaneously in nude mice when administered intravenously (Zou et ah, 2001).

Others

Prodrug with Other Therapeutic Agents

The prodrug nanoparticles can also be used for delivery of anticancer drugs along with the other therapeutic agents for enhancing chemotherapeutic effects, this combination also shows synergists effects of both (Luo et ah, 2014). For example, micelles of doxorubicin and disulfiram was developed by employing polymer poly (styrene-co-maleic anhydride) and acid cleavable linker adipic- di-hydrazide for the treatment of MDR cancer, disulfiram was encapsulated in the DOX conjugate polymer (SMA-ADH-DOX), this combination enhances the accumulation of doxorubicin in tumor by fast release of DSF, DSF reduce the pumping out of the chemotherapeutic drug from the tumor (Duan et ah, 2013).

Prodrug with Nucleic Acid

Combination of anticancer drug with nucleic acid like plasmid DNA, small interfering RNA, and anti- sense oligonucleotides reduce the side effects as well as drug resistance of anticancer drug and enhance the efficacy of cytotoxic drug by targeting the different pathways of disease (Li et ah, 2013). Cationic polymer or lipids are used for the development of polymer-drug-nucleic acid complex. Cationic polymer-based drug delivery system cyclodextrin-polyethylenimine-doxorubicin conjugates were developed for the gene delivery, which deliver both p53 plasmid and doxorubicin. Tumor suppressor gene p53 induces apoptosis as well as increases the sensitivity of tumor cells to anticancer drugs through the P-gp inhibition (Lu et ah, 2011).

Combination Chemotherapy and Phototherapy

Photodynamic therapy is a new approach for the cancer treatment where light-sensitive agents are used. They produce a reactive oxygen species in the presence of specific wavelength cause cell necrosis or apoptosis. The combination therapy of chemotherapy and phototherapy has synergistic therapeutic effects (Ge et al., 2016). For example, a prodrug nanoparticle-based chemo-photodynamic combination TCAD@Ce6 nanoparticles was developed in which photosensitizer chlorine e6 (Ce6) and acid-sensitive cis-aconitic anhydride modified doxorubicin was encapsulated in prodrug nanoparticle. System was easily hydrolyzed in TME and enhance cellular uptake of Ce6 and doxorubicin, Ce6 induce inhibition of A549 tumor in the presence near-infrared light irradiation (Hou et al., 2016).