Organic Pharmaceutical Chemistry IV Lecture 6 (2017-2018) PDF

Organic Pharmaceutical Chemistry IV 1st Semester, Year 5 (2017-2018) Lecture 6 Chemical Delivery Systems (Polymeric Prodrugs) Types and structure of polymers; cross-linking agents and polymeric chemical delivery systems. Dr Asim A. Balakit Pharmaceutical Chemistry Dept., College of Pharmacy,...

Organic Pharmaceutical Chemistry IV 1st Semester, Year 5 (2017-2018) Lecture 6 Chemical Delivery Systems (Polymeric Prodrugs) Types and structure of polymers; cross-linking agents and polymeric chemical delivery systems. Dr Asim A. Balakit Pharmaceutical Chemistry Dept., College of Pharmacy, Babylon University 1 2. Controlled Drug Release After administration, it is necessary that the macromolecular prodrug is stable during circulation in the bloodstream but the cytotoxic drug should be released from the macromolecular drug conjugate intracellulary in the lysosomes (lysosomotropic drug delivery) and/or intratumorally (tumoritropic drug delivery). This controlled release from polymeric drug conjugates by enzymatic or hydrolytic cleavage can only be achieved by proper selection of linkage between drug and polymeric carrier. In the development of spacers, the most interest has been focussed on pH- sensitive spacers (pH-controlled drug release) and oligopeptide spacers (enzyme- assisted drug release). 2 pH Controlled Drug Release: When the macromolecular drug conjugate is taken up by the cell through endocytosis, the conjugate is predestined to be exposed to the acidic pH of the lysosome. Also in or near the tumor tissue the pH is slightly acidic in comparison with healthy tissue. This relatively low pH can be exploited to design pH-sensitive spacers. The hydrazon linkage and the N-cis-aconityl spacer are examples for such controlled release: 3 Structures of Acid Sensitive Linkers 4 Drug Release by Lysosomal and/or Tumor-Associated Enzymes: After the cell uptake of the polymeric prodrug through endocytosis and after fusion of the endosome with the lysosome, the drug conjugate is not only exposed to the acid environment but also to the degrading nature of the lysosomal enzymes. When the lysosomal hydrolases degrade the spacer—most likely an oligopeptide spacer—the drug is released inside the cell. The lysozymes are not only present in normal cells but are often overexpressed in tumor tissues. If the substrate is a specific oligopeptide for lysosomal proteases, the cytostatic drug can be released by these enzymes in or near the tumor tissue. Subsequently, the tumor cells can be selectively destroyed. For the design of a specific polymer drug conjugate, the site and the rate of the cleavage will then depend on the amino acid composition of the oligopeptide. 5 3. The “Enhanced Permeability and Retention Effect” In 1980’s, Maeda and his colleagues found that macromolecules such as polymers and proteins with molecular weight larger than 40-50 kDa showed selective accumulation in tumor tissues, far more than that observed in normal tissues, moreover, they retained in tumor tissues for long periods, i.e., > 24 h. They coined this unique phenomenon enhanced permeability and retention (EPR) effect. Accordingly, an EPR based tumor targeting strategy (macromolecular therapy) was developed by using polymer modification, nanoparticles, micelles, liposome and so on, all of which exhibited more than 10-200 times higher concentrations in tumor than that in normal tissues, such as skin, muscle, heart, and kidney, after systemic administration. These findings led to generalization of the concept of the EPR effect. 6 Biological rationale for the design of polymeric anticancer therapeutics. Tumour targeting of long-circulating polymer therapeutics occurs passively by the ‘enhanced permeability and retention’ (EPR) effect. Hyperpermeable angiogenic tumour vasculature allows preferential extravasation of circulating macromolecules and polymeric micelles. Once present in the tumour interstitium, polymer therapeutics act either after endocytic internalization or extracellularly. 7 Polymer–drug conjugates designed for lysosomotropic delivery of small-molecule drugs. Also shown is the use of bioresponsive, endosomolytic polymers to facilitate cytosolic access of genes and proteins from the endosome. 8 Use of polymer-based systems to deliver drug within the tumour interstitium, or to destroy tumour cells following interaction with the cell membrane. Polymer-directed enzyme prodrug therapy (PDEPT) is a two-step approach that relies on activation of a polymer–drug conjugate by a complementary polymer–enzyme conjugate. Polymer–enzyme liposome therapy (PELT) relies on the liberation of drug from liposomes by the action of a polymer– phospholipase conjugate. Polymers that are conjugated to membrane active peptides or drugs that are known to activate the apoptosis pathway also have the potential to act at the 9 level of the plasma membrane. 4. Alteration of the body distribution and the cell uptake by active targeting: Antibody conjugates The use of monoclonal antibodies to direct drug conjugates is based on the fact that surfaces of tumors contain a wide variety of proteins, some of which are specific to the tumor type. The monoclonal antibodies used as targeting group selectively seek out the tumor cells by binding to such tumor-specific antigens. As a result, the drug conjugate should bind very specifically these tumor cells. Frequently, however, the quantity of drug that can be selectively targeted is limited by the number of antigens available. Hence, in cancer therapy the targeted-drug approach has been most successful for extremely potent agents such as the plant toxins, which in conjugation with antibodies have been termed the ‘immunotoxins’. Further problems associated with the use of monoclonal antibodies as targeting moiety are lack of tumor selectivity, tumor access and immunogenecity. 10 One antibody-based targeting strategy is antibody directed enzyme prodrug therapy (ADEPT). An enzyme, capable of converting a non-toxic prodrug into a potent cytotoxic drug, is covalently attached to a tumor selective monoclonal antibody. Following localisation of the antibody enzyme conjugate at the tumor site and clearance of residual conjugate from the bloodstream, the prodrug is administered. This prodrug can be converted by the enzyme into a potent cytotoxic drug at the tumor site, so minimising non-specific toxicity. One major advantage over conventional antibodytargeting is the inherent amplification stage, meaning that for every successful enzyme-targeting event a very large number of prodrug molecules can be activated. 11 References: The material of this lecture is collected the following references: 1. K. Hoste, K. De Winne, E. Schacht, Polymeric prodrugs, International Journal of Pharmaceutics 277 (2004) 119–131. 2. Jayant Khandare, Tamara Minko, Polymer–drug conjugates: Progress in polymeric prodrugs, Prog. Polym. Sci. 31 (2006) 359–397. 3. Alexander T Florence, David Attwood, Physicochemical Principles of Pharmacy FOURTH EDITION, Pharmaceutical Press 2006 (USA). 4. Haesun Park, Kinam Park, Waleed S.W. Shalaby, Biodegradable Hydrogels for Drug Delivery, Technomic Publications, 1993 (USA). 5. Rohini, Neeraj Agrawal, Anupam Joseph and Alok Mukerji, Polymeric Prodrugs: Recent Achievements and General Strategies, J Antivir Antiretrovir 2013, S15 6. Heidi L. Perez et. al. Antibody–Drug Conjugates: Current Status and Future Directions, Drug Discovery Today _ Volume 00, Number 00 _ December 2013. 7. Ruth Duncan the Dawning Era of Polymer Therapeutics, Nature Reviews | Drug Discovery, Volume 2 | May 2003 | 347. 12