ࡱ> 3v47 ?'bjbjUU U7|7|"'%l8:NTdZ(KKKYYYYYYY$[ :] ZKK^KKK ZR3ZRRRKl8YRKYRRX:sY,Y Rx>_PVY Y4Z0dZY ]R]YRDelivery Systems for Cancer Drugs Dr M.C Garnett, School of Pharmaceutical Sciences. Tel ext 15045, e-mail martin.garnett@nottingham.ac.uk Aims of lecture To examine why they may be of advantage in comparison to the more usual drug formulations To look at delivery systems currently available for cancer therapy To explore what delivery systems have been investigated or are being developed for cancer therapy To look briefly at the background and mechanisms for selected drug delivery systems. Why drug delivery systems? Most anti-cancer drugs are based on a differential killing of cancer cells. Development of cancer therapy has largely been driven by the assumption that if we screen enough drugs we will find drugs with a mechanism of action which allows a greater discrimination between normal cells and cancer cells. From a biochemical (or pharmacological) viewpoint - very little difference between normal and cancer cells, i.e. pharmacological specificity of anticancer agents very low for most cancers. Side effects are usually dose limiting. Conventional formulations have been optimised by: Careful timing, slow infusions, monitoring of serum drug levels, multi-drug regimes etc. Alternative view for cancer therapy Delivery systems to try to exploit differences between cancer and normal cells because of differences in accessibility - physiological/anatomical factors. Delivery systems could improve treatment either by increasing efficacy or reducing side effects Enhancing delivery of current drugs, e.g. enhancing the time for which tumour is exposed to therapeutic agent, increasing the amount of drug at the tumour site and/or local delivery. Promoting the effectiveness of products of biotechnology, e.g. peptides New delivery systems to allow the use of agents which would otherwise not be useable for cancer therapy. Types of Drug Delivery Systems 1. Matrix delivery systems A solid matrix of polymer containing dispersed drug can be used as a matrix system. Two such systems are currently clinically available for cancer treatment local or systemic. i. Zoladex - (goserelin, a gonaderelin analogue [peptide]) Formulated as a rod of polylactide co glycolide (PLGA) containing dispersed drug. Injected as an implant into the abdominal wall. For treatment of prostate cancer ii. Gliadel Wafer of polyanhydride polymer and Carmustine, (CCNU). The polymer is a copolymer of sebacic acid and carboxyphenoxypropane in 80/20 ratio. Polymer is hydrophobic and prevents decomposition of drug until it is released Polymer and drug are dissolved in a solvent, spray dried to form microspheres and compressed into discs of 14mm diameter 1mm thick For treatment of gliomas. Aggressive brain tumour. Surgery cannot remove all traces of tumour, allowing tumour to regrow. Requires adjuvant chemotherapy. After surgery discs of Gliadel are lodged in the space left by excision of brain tissue to give a slow release of drug over a period of months. Gives some improvement in survival time, but significantly reduces systemic side effects. 2. Drug targeting systems Increasing the amount or concentration of drug delivery to tumour cells Decreasing the amount or concentration of drug delivered to normal tissues Targeting can be: -passive -active - e.g. antibody targeting Depends on exploitable differences between tumour and normal tissues: i. Leakiness of capillaries Normal endothelium has tight junctions, no gaps between cells and low permeability to large or hydrophilic molecules. Permeability to conventional drugs (small, lipophilic molecules) occurs through partition/diffusion processes. Access to all cells Generally macromolecules exit the circulation by a transcytosis mechanism - slow in comparison to diffusion. Particles are retained in circulation. In tumours, endothelium tends to be leaky - to high molecular weight polymers and smaller particles. It has been proposed that this may be exploited through a mechanism known as the Enhanced Permeability and Retention effect (EPR) [Hiroshi Maeda.]  Tumour endothelium leaky ii. Permeability of extracellular matrix by macromolecules - extracellular matrix is a glycoprotein matrix containing water channels - acts like a molecular sieve -macromolecules traverse more quickly than small drug molecules iii. Lysosomotropic uptake Macromolecules are only taken up into cells by vesicular uptake processes, e.g. receptor mediated endocytosis, pinocytosis. Pinocytosis is a continuous process in all cells - non-specific uptake Pinocytosis is generally though to be more active in tumour cells iv. Increased release of degradative enzymes (cathepsins) v. Change in pH in extracellular matrix iv. and v. have so far been less exploited, but a number of delivery systems have been proposed to take advantage of the above differences: A. Colloidal drug delivery systems Particulates - includes liposomes, microparticles, microcapsules, nanoparticles etc. Liposomes, microcapsules, essentially a small container for drugs Micro and nanoparticles, a matrix containing dispersed drug Drugs mostly released by diffusion - slow release delivery system Delivery system may enhance T1/2 of drug, protect some tissues from exposure to drug. i. Larger particles - microspheres, microcapsules - may be used as a depot formulation e.g. gonaderelin analogues (peptides) - similar to matrix systems Prostap, (Leuprorelin acetate s.c. injection) De-capeptyl (Triptorelin s.c. injection) ii. Colloidal delivery systems can also be used as parenteral delivery systems. However, particulates cannot be used in an unmodified form. Any particulate materials will be treated as an invading micro-organism. Opsonisation by serum proteins - mediated mainly by hydrophobic interactions Phagocytosed by cells of the Reticulo-Endothelial System (RES) or Mononuclear Phagocytic System (MPS). -Very rapid uptake of particles to liver and spleen (< 5 minutes) Some liposomal formulations have been produced which can partly overcome this problem e.g. Myocet containing Daunorubicin A more efficient method of overcoming MPS uptake is by coating particles with a hydrophilic polymer polyethylene oxide/glycol (PEO/PEG), create a very hydrophilic surface not recognised by macrophages - prevention of opsonisation. - Steric stabilisation - resulting long circulation of particles (hours ( days rather than minutes)  If the particles are small, this may allow accumulation of particles at tumour sites by the EPR effect. Both nanoparticles and liposomes have been created with sterically stabilised PEG surfaces. e.g. Caelyx a sterically stabilised liposome formulation containing Doxorubicin Myocet and Caelyx are available for treatment of Karposis sarcoma in AIDS patients. B. Polymer -drug conjugatesPRIVATE  i. Soluble polymer with drug attached e.g. HPMA - Doxorubicin Conjugates (Duncan/Ulbrich) Doxorubicin (Dox) - potent anti-cancer drug,( IC50 10-8M), clinical use limited by cardiotoxicity - free amino group for conjugation  Attached to polymer Hydroxypropylmethacrylate (HPMA), 20kDa, by tetra peptide spacer HPMA Gly Phe Leu Gly Drug Cleavage by cathepsins but not by serum enzymes - only released at tumour site Properties of HPMA - Dox conjugates Increased solubility of drug Increased T1/2 of drug 5min > 1h Increased amount of drug in tumour (free and conjugated) Large decrease in drug toxicity (cardiotoxicity) Conjugation reduces drug activity - slower uptake but Increased Dose ------> Increased Therapeutic Index [Therapeutic effect/Toxicity] Increased response in animal studies Now in Phase 2 clinical trials ii. SMANCS (H. Maeda) Enhanced delivery of a polymer drug conjugate Neocarzinostatin (NCS) - very potent novel drug IC50 10-9M Protein + Chromophore (Carrier - 11,0000Da) (Cleaves DNA) - Protein carrier protects unstable and reactive chromophore NCS has a short T1/2 drug stability clearance from blood Polymer - polyStyrene Maleic Anhydride (SMA) Mw 1500-2000 developed as a floor polish! NCS has 2-amino groups reacts with 2 molecules of SMA ------> SMANCS Conjugate is hydrophobic - stabilises drug further - now soluble in Lipiodol Lipiodol - iodinated poppy seed oil - agent for imaging lymph nodes using fluoroscopy - i.a. injection to liver found to cause selective accumulation of Lipiodol in some tumours SMANCS in Lipiodol - selective delivery to some tumours via i.a. route Principal action against Hepatocellular carcinoma - very aggressive cancer & a major cancer killer in Japan & far east Typically patients with unresectable tumours die < 6 months, with SMANCS/Lipiodol, survival >90% after 5 years. -Side effects: low grade fever and abdominal pain Now available clinically in Japan. 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