Polymeric Prodrugs Lecture 3 PDF

Polymeric Prodrugs Lec: 3  Polymeric prodrug A conjugation of a drug with a polymer forms so-called ‘polymeric prodrug’. The conjugation of a biologically active compound with a polymer is one of the many methods for altering and controlling the pharmacokinetics...

Polymeric Prodrugs Lec: 3  Polymeric prodrug A conjugation of a drug with a polymer forms so-called ‘polymeric prodrug’. The conjugation of a biologically active compound with a polymer is one of the many methods for altering and controlling the pharmacokinetics, biodistribution, and often the toxicity of various drugs. Prof. H. Ringsdorf developed a rational model of polymeric prodrug for the first time in 1975. The proposed model consists mainly of five components: the polymeric backbone, the drug, the spacer, the targeting group and the solubilising agent.  ‫مو بس ربط‬ Polymeric prodrug ‫يتكسر‬ The polymeric carrier can be either an inert or a biodegradable polymer. The role of spacer is to control the site and the rate of release of the active drug from the conjugate by hydrolytic or enzymatic cleavage. The drug must be covalently bonded to the polymer and must remain attached to it until the macromolecule reaches the desired site of action. The choice of drug for use in this system is based on three criteria. ‫االدوية قوية فقط‬ ‫تقييد فقط لالدوية كبيرة‬ i. First, only potent drug can be used because there is restriction on the amount of drug that can be administered. ii. Second, the drug should have a functional group by which it can bind with the polymer backbone directly or by means of spacer molecule. iii. Third, the drug must be sufficiently stable and should not be excreted in this conjugate form until it is released at the desired site.  Polymeric prodrug ‫هدفه مكان معني‬ The targeting moiety or homing device guide the entire drug-polymer conjugate to the targeted tissue. The targeting ability of the delivery system depends on the several variables including: ‫كميتها عالقتها طردية الزيادة ونقصان‬ 1. receptor expression; ‫دواء اله قدرة يدخل داخل الخلية‬ ‫دواء او اي مركب‬ 2. ligands internalization; 3. choice of antibody, antibody fragments or non-antibody ligands; 4. binding affinity of the ligand. ‫ارتباطه قوي او ال‬  Polymeric prodrug The targeting moiety or homing device guide the entire drug-polymer conjugate to the targeted tissue. The targeting ability of the delivery system depends on the several variables including: 1. receptor expression; 2. ligands internalization; 3. choice of antibody, antibody fragments or non-antibody ligands; 4. binding affinity of the ligand.  Advantages of Polymeric Prodrugs 1. Prolongation of drug action The polymer-drug conjugates results in a slower renal excretion, longer blood circulation and an endocytotic cell uptake. 2. Controlled drug release The controlled release from polymeric prodrug can only be achieved by proper selection of linkage between drug and polymeric carrier. i. pH controlled drug release: The therapeutic effect is achieved only when the macromolecular drug from the polymeric prodrug is released intracellularly in the lysosomes or tumour tissue which are slightly acidic in comparison to the healthy tissues. ‫تنفصل فقط‬ ‫هنا‬  Advantages of Polymeric Prodrugs ii. Enzymes for drug release: When the polymeric prodrug is up taken intracellularly, it enters the lysosomes which are present in normal as well as tumor tissues. In the lysosomes, the polymeric prodrug is acted upon by lysosomal enzymes such as cathepsins and metalloproteinases to release the macromolecular drug. ‫بيها انزيمات فقط بهاي االنزيمات يال ينفصل‬ 3. Enhanced permeability and retention effect ‫بقاء دواء بدون خروج‬ The polymeric prodrugs are taken up by solid tumors by pinocytosis and this passive tumor uptake increases the targeting of drug due to their characteristic feature of enhanced permeability and retention effect. This effect is due to increased tumor vascular permeability and poor tissue ‫تقلل خروجها‬ drainage from the tumor cells which increase the duration of action and targeting of the macromolecular drug. ‫وتوصل للخاليا املصابة‬  Advantages of Polymeric Prodrugs ii. Enzymes for drug release: When the polymeric prodrug is up taken intracellularly, it enters the lysosomes which are present in normal as well as tumor tissues. In the lysosomes, the polymeric prodrug is acted upon by lysosomal enzymes such as cathepsins and metalloproteinases to release the macromolecular drug. 3. Enhanced permeability and retention effect The polymeric prodrugs are taken up by solid tumors by pinocytosis and this passive tumor uptake increases the targeting of drug due to their characteristic feature of enhanced permeability and retention effect. This effect is due to increased tumor vascular permeability and poor tissue drainage from the tumor cells which increase the duration of action and targeting of the macromolecular drug.  Advantages of Polymeric Prodrugs The tumor cells contain permeability enhancing factors such as vascular endothelial growth factor (VEGF), bradykinin etc., which increase the permeability of polymeric prodrugs towards tumor tissue and also, lack of effective lymphatic drainage from the tumor tissue increases its retention.  Advantages of Polymeric Prodrugs 4. Active targeting by Polymeric prodrug ‫يستهدف خلية سرطانية‬ i. Monoclonal antibodies The monoclonal antibodies can be used as targeting group for coupling with the drug to increase the specific targeting of the prodrug on the tumor cells. These antibodies bind very specifically to tumor cells and this approach has been successfully used in cancer therapy. For example ‫يستهدف الخاليا ويقتلها‬ a) Conjugate of plant toxins and antibodies, referred as immunotoxin is a very potent antitumor therapy. b) Tumor selective monoclonal antibody is covalently attached to an enzyme which converts non toxic prodrug into potent cytotoxic drug after specific targeting at the tumor site. This approach minimizes non specific toxicity. ‫يكشف انزيم معني بالخلية الرطانية يشتغل ك تاركت لخلية معينة‬  Advantages of Polymeric Prodrugs 4. Active targeting by Polymeric prodrug i. Monoclonal antibodies The monoclonal antibodies can be used as targeting group for coupling with the drug to increase the specific targeting of the prodrug on the tumor cells. These antibodies bind very specifically to tumor cells and this approach has been successfully used in cancer therapy. For example a) Conjugate of plant toxins and antibodies, referred as immunotoxin is a very potent antitumor therapy. b) Tumor selective monoclonal antibody is covalently attached to an enzyme which converts non toxic prodrug into potent cytotoxic drug after specific targeting at the tumor site. This approach minimizes non specific toxicity.  Advantages of Polymeric Prodrugs ‫تاركت للكبد‬ ii. Lectins The sugar specific receptors present on the plasma membrane are called lectins and they have been characterized mainly on hepatocytes. Galactose specifically targets these lectins and this targeting seems to be an attractive approach for target specific drug delivery especially for treatment of liver diseases such as hepatitis, parasitic infections and liver metastasis. Drug delivery to macrophages (e.g. Kupffer cells) can be employed for targeted treatment of various malfunctions such as leishmaniasis, Gaucher’s syndrome etc.  Advantages of Polymeric Prodrugs iii. Angiogenic vessels of tumor cells The endothelial cells in angiogenic vessels of tumors show increased expression of cell surface proteins. These proteins include receptors for vascular endothelial growth factor (VEGF) and integrin receptors. The peptides which specifically bind to these receptors can be used as targeting moiety for drug delivery such as RGD (arginine-glycine-aspartic acid) containing peptides that specifically bind with integrin receptors. The conjugation of RGD peptides and poly(ethylene glycol) (PEG) showed increased efficacy of drug against breast cancer.  Advantages of Polymeric Prodrugs iii. Angiogenic vessels of tumor cells The endothelial cells in angiogenic vessels of tumors show increased expression of cell surface proteins. These proteins include receptors for vascular endothelial growth factor (VEGF) and integrin receptors. The peptides which specifically bind to these receptors can be used as targeting moiety for drug delivery such as RGD (arginine-glycine-aspartic acid) containing peptides that specifically bind with integrin receptors. The conjugation of RGD peptides and poly(ethylene glycol) (PEG) showed increased efficacy of drug against breast cancer.  ‫لكن بيها‬ ‫مشكلة مو‬ Advantages of Polymeric Prodrugs ‫سبيسفك لذلك‬ ‫ممكن تشتغل‬ ‫ع كل خاليا‬ 5. Immunoprotection by polymeric prodrugs ‫وتضعف جهاز‬ ‫مناعي‬ Treatment of cancer by polymeric prodrug can remarkably protect the patient’s immunity owing to a mechanism known as Fas-Fas ligand interaction. Fas and Fas ligand (Fas L) are present on cancer as well as immune cells. Interaction between Fas and Fas ligand (Fas L) triggers a cascade of signals, that eventually ‫يحفزها‬ results in apoptosis i.e. programmed cell death. ‫بالتالي تقضي عالسرطان‬ ‫ما مرتبطة هنا مشكلة‬ It has been reported that treatment with free anti-tumor drugs promotes induction of Fas ligands on cancer cells whereas their macromolecular derivatives did not increase Fas L. This is an important outcome that might indicate that polymeric prodrugs are able to protect the patient’s immune system. ‫لكن من ربطتها ببوليمر تحل املشكلة‬  Advantages of Polymeric Prodrugs 5. Immunoprotection by polymeric prodrugs Treatment of cancer by polymeric prodrug can remarkably protect the patient’s immunity owing to a mechanism known as Fas-Fas ligand interaction. Fas and Fas ligand (Fas L) are present on cancer as well as immune cells. Interaction between Fas and Fas ligand (Fas L) triggers a cascade of signals, that eventually results in apoptosis i.e. programmed cell death. It has been reported that treatment with free anti-tumor drugs promotes induction of Fas ligands on cancer cells whereas their macromolecular derivatives did not increase Fas L. This is an important outcome that might indicate that polymeric prodrugs are able to protect the patient’s immune system.  Requirements for Selecting Polymers as Candidate Drug Carriers: i. Availability of suitable functional groups -COOH, -OH, -SH, or -NH2 for covalent coupling with drugs ii. Biocompatibility: preferably nontoxic, nonimmunogenic ‫جزيئات صغيرة‬ iii. Biodegradability or a molecular weight below the renal excretion limit ‫مو مكلف‬ iv. Availability: reproducibly manufactured and conveniently administered to patients v. Water solubility: hydrophilic to ensure water solubility vi. Low polydispersity, to ensure an acceptable homogeneity of the final conjugates. ‫جزيئات الزم نفس وزن جزيئي‬  Classification of Polymers Used for Bioconjugation Based on their origin polymers used for bioconjugation are classified as either synthetic or natural. Synthetic polymers can be widely used because the properties of these molecules can be modified by varying their structures.  Polymers Used for Bioconjugation A. SYNTHETIC POLYMERS 1. Polyethylene glycol (PEG) polyethylene glycol (PEG), is a linear polyether compound with ethylene glycol repeats.‫تنتهي‬ PEG terminates with hydroxyl group, and can readily be covalently conjugated to many peptides, proteins or drugs.  Polymers Used for Bioconjugation 1. Polyethylene glycol (PEG) The incorporation of PEG with a drug has the advantage of increasing solubility and therefore bioavailability of the resulting conjugates. ‫سوي حماية‬ Additionally, immunogenic responses upon exposure to peptides/proteins may be diminished by the presence of PEG, which mask peptide/protein recognition by the reticuloendothelial system (RES). The main problem with using PEG lies in its poor drug-loading efficiency, with the limited number of reactive groups in PEG often restricting its broad applications as a drug carrier. ‫ما اكدر احمل دواء كبير الن مجاميع وظيفية قليلة‬  Polymers Used for Bioconjugation 2. The N-(2-hydroxypropyl) Methacrylamide (HPMA) Copolymer HPMA, like PEG, is a water-soluble, biocompatible, non-immunogenic polymer. Unlike PEG, it contains large number of pendent functional groups which permits the conjugation of many drugs. Further, HPMA facilitates activating or releasing the compound from the polymer backbone within a targeted region by manipulation of their bond, a degradable linker.  Polymers Used for Bioconjugation 3. Poly (Styrene-Co-Maleic Acid/Anhydride) (SMA) SMA is an alternating copolymer composed of styrene and maleic anhydride: Since SMA forms micelles with a hydrophobic styrenic core and a hydrophilic maleic acid surface, a stable and rate-controllable release of micelles can allow surface modification for use in tissue targeting.  Polymers Used for Bioconjugation 4. The Polyglutamic Acid Polymer Poly (γ-glutamic acid) (γ-PGA), a highly anionic polymer which exhibits excellent biocompatibility and non-cytotoxicity. ‫اذا ضفناه‬ Thiolated γ-PGA nanogel for doxorubicin delivery that showed controlled drug release behavior and higher toxicity as compared to free doxorubicin. PGA was added with another glutamic acid to each glutamic acid in the polymer backbone producing a poly(L-γ-glutamyl- glutamine) (PGG). This modification shows additional hydrophilicity on a PGG- paclitaxel conjugate as well as improved paclitaxel-loading efficiency in comparison to PGA-paclitaxel conjugates.  Polymers Used for Bioconjugation 4. The Polyglutamic Acid Polymer Poly (γ-glutamic acid) (γ-PGA), a highly anionic polymer which exhibits excellent biocompatibility and non-cytotoxicity. Thiolated γ-PGA nanogel for doxorubicin delivery that showed controlled drug release behavior and higher toxicity as compared to free doxorubicin. PGA was added with another glutamic acid to each glutamic acid in the polymer backbone producing a poly(L-γ-glutamyl- glutamine) (PGG). This modification shows additional hydrophilicity on a PGG- paclitaxel conjugate as well as improved paclitaxel-loading efficiency in comparison to PGA-paclitaxel conjugates.  Classification of Polymers Used for Bioconjugation B. NATURAL POLYMERS: 1. Dextran Dextran, structured of glucose molecules that form a complex branched glucan chain of variable length, is a water soluble polymeric saccharide.  Classification of Polymers Used for Bioconjugation B. NATURAL POLYMERS: 1. Dextran Dextran microspheres exhibit biodegradability and biocompatibility, as well as being non-immunogenic and non-toxic, all important factors for future clinical applications. These microspheres, easily filtered and neutral, are above all water soluble. However, when conjugated to antitumor drugs, dextran is rendered immunogenic and non-biodegradable. ‫اذا‬ ‫ضفته‬ ‫اله‬ Other negative effects of dextran polymer use currently include platelet ‫راح‬ ‫يتحو‬ dysfunction, anaphylaxis, and pulmonary, as well as cerebral edema. ‫ل‬  Classification of Polymers Used for Bioconjugation B. NATURAL POLYMERS: 2. Chitosan is Chitosan, a linear polymer composed of interchangeably organized, deacetylated β-(1-4)-linked D glucosamine units and of acetylated N-acetyl-D-glucosamine units is widely used in drug delivery systems. The sole polysaccharide polycation used as a polymer, chitosan binds to negatively charged moieties.  Classification of Polymers Used for Bioconjugation B. NATURAL POLYMERS: 2. Pullulan Pullulan, a natural polysaccharide composed of maltotriose units structured as α- 1-4; α-1-6-glucan and a liver specific biopolymer, is biodegradable, nontoxic, non- mutagenic, and noncarcinogenic. ‫اقل تاثير عاملناعة‬ Its low immunogenicity and satisfactory solubility in aqueous and several organic solvents have together led to a range of applications in cancer drug delivery. & 6 D 14 J  Polymeric prodrugs and targeting Two approaches are mainly used for targeting polymeric prodrugs: i. Passive targeting Enhanced permeability and retention effect is the main approach in passive targeting. Passive targeting is not very efficient as the polymeric drug enter the cells by means of the concentration gradient between the intracellular and extracellular spaces. ii. Active targeting 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.).