Platinum Drug Delivery Vehicle - History and Mechanism of Action - Research Paper Example

Platinum Drug Delivery Vehicle: History and Mechanism of Action [Name] [Professor Name] [Course] [Date] Table of Contents Table of Contents 1 Introduction 3 History of the development of Liposomes 3 Mechanism of action of Liposomal drugs 7 Quantitative structure-activity relationships 12 Conclusion 14 References 14 Introduction Platinum-based anticancer agents have found extensive clinical use despite of the fact that they are associated to numerous side effects (Kirkpatrick 2010, 1). When the delivery of cytotoxic platinum compounds is improved, it may reduce the side effects hence achieving a greater efficacy of the drugs when taken at a comparatively less dosage. These side effects can be overcome by developing delivery vehicles for the platinum-based drugs. Polymer-based remedies or treatments have been found to work as drug delivery vehicles for platinum-based drugs. This paper examines the history of the development of liposomes, the mechanism of their action and a review of Quantitative structure-activity relationships (QSAR). History of the development of Liposomes Liposome is among the most used drug delivery vehicles with several clinical products. It is made up of amphiphilic lipid molecules that amass into bilayered spherical vesicles (Fig 1). They are non-toxic in nature, non-immunogenic and non-hemolytic even with repeated injections. In addition, they are also biodegradable and biocompatible and can be designed further to prevent clearance mechanisms, enzymatic and chemical inactivation. Their major problem when used in the body is their speedy uptake and clearance by the RES system as well as low stability when used externally (Egbara and Weiner 1990, 288-289). Figure 1: Schematic representation of liposome (Bergstrand 2003, 7) Liposome was first discovered by British haematologist Dr. Alec Bangham in 1961 when testing a new electron microscope by adding a negative stain to desiccated phospholipids. Bangham realised that the semblance to plasmalemma was obvious, and that the pictures of the microscope showed that the cell membrane had a bilayer lipid structure (Heap and Grogoridias 2011, 35-36). The possibility of using liposome as drug delivery vehicles for anti-cancer platinum drugs however gathered momentum during the 1st International Conference concerning liposome that was held in New York in 1977. At the conference, Brenda Ryman discussed the possibility of injecting vesicles into the human body. Her key argument was that “when liposomal administration of therapeutic agents is at a commonplace, the biophysicist’s membrane model and the liposome will come of age” (Heap and Grogoridias 2011, 36). Thereafter, pharmacists attending the conference left the hall convinced that liposome could be exploited to address delivery of anti-cancer drugs (Heap and Grogoridias 2011, 36). At that time however, it was basically hypothetical that phospholipid assemblies had the capacity to form bilayer structures in a similar manner like the red blood cells, and that they could capture molecules such as nucleic acids and enzymes (Lasic 1998, 307). David Deamer at the National Institute of General Medical Sciences pursued the theory and established that phospholipids could be synthesized in prebiotic conditions. The suggestion and subsequent demonstration that liposome had the potential to serve as a carrier system for drug delivery was indeed a milestone after the determining discovery of liposome in 1961 and its immediate application as a model of study for cell membranes. In 1976, work and focus on demonstration of the concept on humans and animals started. This attracted attention from the pharmaceutical industry and the academia leading to the adoption of liposomes as a criterion drug delivery system (Egbara and Weiner 1990, 288-289). Further applications included; delivery of drugs for anti-cancer and antimicrobial chemotherapy, treatment of lysosomal storage disease and short interfering RNA (siRNA) therapies. Such applications in the late 1970s were promoted by two divergent developments. The first involved technological developments which involved techniques formulated for the efficient entrapment of a variety of agents. The agents consisted of active pharmacologically; such as nucleic acids, proteins and conventional drugs into fairly-priced liposomes produced on industrial scale. The second development involved the maximisation of behaviour of liposomes used within the body (in vivo) in regards to the nature of their stability in the blood circulation hence reducing leakage of entrapped agents (Heap and Grogoridias 2011, 38). Liposomes were first used as drug-delivery vehicles in the 1970s. Initial results were rather disappointing because of the biological and colloidal stability in addition to their rather unstable and inefficient encapsulation of drug molecules. Their use was however improved after basic research that improved understanding of their interaction properties and stability. Conversely, several pharmaceutical companies were established that managed to survive the rejects in the commercial appreciation of liposomes in the late 1980s and early 1990s. With time however, this put a number of commercial liposome products in the market (Lasic 1998, 307). In the early 1980s, a number of liposome-based manufacturing plants were established with the main ones including; Liposome Technology, Liposome Company and Vestar. All the three were based in the United States. Following comprehensive clinical trials, a number of injectable liposome-based drugs were approved for marketing. This included Doxil and AmBisome. Both of the drugs had the potential to significantly reduce the toxicity of platinum-based anticancer drugs in treating tumours. It was generally accepted that AmBisome and Doxil extended the lives of cancer patients, and in some cases, led to their cure (Fig. 2). In the early 1990s, all the three liposome-based companies were bought by a larger pharmaceutical company at between US$500 and 700 million. Later developments saw newer pharmaceutical companies design liposomal formulations for siRNA therapy, genetics vaccine and gene therapy (Zhang 2013, 324). Cancer is still a major devastating disease globally with over 1 million new cases globally. Nevertheless, mortality from cancer has decreased over the last decade because of milestones in diagnostic and treatment of tumour (Peer et al 2007; 751). The emergence of liposomes has made substantial impacts on clinical therapeutics since 1960s. Indeed, improvements in biocompatible nanoscale drug carriers have facilitated more safe delivery of antic-cancer platinum-based drugs (Zhang 2013, 323). To date, over fifty years since the discovery of liposome, it remains a leading drug delivery vehicle in the continuing battle against the disease. Today, a number of liposomal products have been approved in the market (Fig 2) with even more still waiting approval. Figure 2: Available liposomal drugs in the market (Dua, Rana & Bhandari 2012, 5). Mechanism of action of Liposomal drugs Liposomes are essential for drug delivery given their unique properties. Liposome envelopes a region of aqueous solution within a hydrophobic membrane, consequently hydrophobic solutes cannot penetrate voluntarily through the lipids. However, hydrophobic chemicals are dissoluble in the membrane. This allows the membrane to carry both hydrophilic and hydrophobic molecules. For delivery of molecules to the action sites, the lipid bilayer can join with other bilayers, including the cell membrane enabling delivery of the contents of the liposome (Dua, Rana & Bhandari 2012, 4). When liposomes are made in the solution of the DNA of platinum-based drugs such as; cisplatin, that often have side-effects to the patients since they are not diffusible through the membrane, they can be delivered selectively through the lipid bilayer (Fig 3). In any case, a liposome does not necessarily have lipophobic content like water even as it often does (Dua, Ranam and Bhandari 2012, 5). Figure 3: Schematic diagram of liposome cross section Liposome are utilised as models for artificial cells. They can further be designed to deliver drugs in various ways. Liposomes containing high or low pH can be designed in a way that dissolves aqueous platinum-based drugs which become charged in the solution (such as when the pH is not within the pI range of the drug). Since the pH inherently neutralised inside the liposome (since protons are able to pass through the membranes), the drug becomes neutralised enabling it to readily pass through the membrane. The liposomes therefore are able to deliver the drugs through diffusion instead of through direct cell fusion (Bergstrand 2003, 7). Figure 4: Liposome for drug delivery (Wikipedia) Similarly, biodetoxication drugs in cancer treatment can work in a similar manner when empty liposomes are injected with a transmembrane pH gradient. Here, the vesicles will function as a sink that scavenge the drugs in the blood circulation reducing its toxic effects. Another mechanism in which liposome works in delivery of drugs is by targeting endocytosis incidences. Towards this end, liposome can be designed in certain sizes making them to be viable targets for macrophage phagocytosis (Fig 4). Here, the liposomes are ingested while they are in the phagosome of the microphage enabling it to release its drug. Liposomes may as well be garnished with ligands and opsonins hence activating endocytosis in other cell types (Bergstrand 2003, 7). The major components of liposomes that enable them to be biocompatible, less toxic and biodegradable are phospholipids (Fig 5). The bilayer of the phospholipids also prevents the active form of platinum-based anti-cancer drugs from breaking down before they reach the tissues of the tumour (Lao 2013, np). Hence, the exposure of normal tissue to platinum-based drugs such as cisplastin is reduced. Thereafter, the therapeutic index of the drug rises by two mechanisms. Figure 5: Liposome formed by phospholipidsin an aqueous solution (Dua, Ranam and Bhandari 2012). The first mechanism is occurs when a larger amount of the drug penetrates the tumour cells and increased cytotoxic effect is achieved (Lao 2013, np). Such cytotoxic effects have been recently studied in diamine-platinum (II) complexes (Kostova 2006, 7; Gupta et al 2008, 3984). The study examined the cytotoxic activities of diamine-platinum (II) in resistant and parental ovarian cancer cells (McWhinney, Goldberg and McLeod 2009, n.p; Staropoli 2013, np). The diamine-platinum (II) complexes were found to represent structures of conjugates between the active vectors and the cytotoxic moieties inside the drug delivery and targeting strategy (Kostova 2006, 7). In such a case, the therapeutic index of diamine-platinum (II) complexes is increased (Dua, Rana & Bhandari 2012, 4-5). The second mechanism occurs when the side effects are reduced as a result of the drug encapsulation. Liposomal formulations also have other effects on the metabolism of platinum-based anticancer drugs by reducing their enzymatic degradation. Drug encapsulation in liposomes is achievable through two mechanisms (Dua, Rana & Bhandari 2012, 4-5). In the first option the drugs can be dissolved in aqueous solution in order to hydrate lipid films resulting in formation of drug-loaded multilamellar liposomes which can be squeezed out through filters that have a set preset pore size to create unilamellar liposomes. In the second option, unilamellar liposomes are initially synthesised and afterwards incubated in an aqueous drug solution. Here, the drug molecules are diffused passively through the liposomal membranes until eventual saturation of the aqueous solution happens (Hu, Aryal and Zhang 2010, 324). The unloaded drugs will then be extracted from the drug-loaded liposome solution via centrifugation, chromatography and dialysis. Given their unique structures, liposomes can at the same time load hydrophobic drugs inside their bilayer lipid membrane. Their additional interesting property includes a natural ability to target cancer (Fiegl et al 2011, 2). The endothelial wall of the blood vessels is enveloped by endothelial cells bound tightly by tight junctions. The tightened junction stops any large particles in the blood from penetrating out of the vessel. Tumour vessels do not have a similar level of sealing between cells. Further, they are also leaky. This property in known as ‘enhanced permeability and retention effect. Liposomes of particular sizes of less than 400nm can enter the sites of the tumour readily. However, they are maintained in the blood stream by the endothelial walls. The hydrophobic and hydrophilic drugs are therefore readily encapsulated in liposomes. These liposomes are further comparatively biodegradable and not-toxic (Dua, Rana & Bhandari 2012, 4-5). Quantitative structure-activity relationships Because of the special properties of liposomes, QSRA studies have been conducted to determine their applications in various cancer treatments. Recombinant-DNA technology and QSAR studies of how the gene functions have been conducted in an attempt to determine how liposomes can be exploited fully. The study found that although the vitro techniques depend on a several chemical and physical methods, the vivo delivery of the drugs was more challenging. DNA-carrier systems consisted of colloidal particles (or cationic liposomes) and similar complexes transfected cells in vitro. This resulted to the expression of proteins that were encoded in the DNA plasmid inside the target cells. Observably, for gene therapy, vivo treatment was preferred. The QSAR studies further found that cationic lipid-based DNA complexes could transfect particular cells inside the body upon system or localised administration. In any case, the first series of in vivo QSAR studies bore relatively low level gene expression. Advancements were sought on the molecular level, where a number of novel lipids were synthesised and different mix of lips tested and colloidal level (Lasic 1998, 318). Despite the fact that quantitative structure-activity relations (QSAR) are still scarcely understood, development in the DNA-plasmid design still remains uncertain. Improvements in the colloidal structures have resulted to significant increases in gene expression over the initial experiments. Despite these developments being impressive, the real expression levels are still low. In fact, the tissue specificity of expression on the time of expression is short. Advancements in the lipid-based carriers may involve coating reactive cationic surfaces using bilayers that are negatively charged. Another option includes sterically stabilising coatings. Further QSAR studies have showed that PEG-lipid have the capacity to coat conventional liposomes through transfer from PEG-lipid micelles destined for the liposomes inside the incubation medium (Fig 6). The same approach can be applied to coat DNA-lipid complexes. These kinds of liposomes may possess targeting ligands and in some case may integrate some fusogonic component or function (Lasic 1998, 318). Figure 6: Molecular shape of lipids and conditions in lipid-water (Dua, Ranam and Bhandari 2012) Based on the fact that, liposomes platinum-based drugs for the treatment of cancer such as; carboplatin, cisplatin and oxaliplatin have found extensive use in treatment of numerous solid tumours (See Figure 1). Their therapeutic window is restricted by drug resistance and systematic toxicity of the tumours. For instance, cisplastin produces neurotoxity, nephrotoxicity and causes natural drug resistance (Kelland 2007, 581). These toxicities have been found to be generated by interaction of the platinum drugs with health issues in the event of distribution of the drug inside the body. In this case, the means of reducing the general toxicity and improving the efficacy of the drugs is a critical objective in the development of platinum complex drugs (Kostova, 2006, 1-2). Conclusion Combining nonparticle drug delivery and platinum-based anticancer drugs has significantly improved cancer treatment since the 1970s. The combined therapy facilitates synergism among platinum-based drugs such as cisplastin, as result suppressing drug resistance through their divergent mechanisms of action. Liposomal platinum drug delivery vehicles promote therapeutic effectiveness. They have also reduced the side effects of drug payloads through improved pharmacokinetics. Indeed once the delivery of cytotoxic platinum compounds is improved, side effects are reduced hence achieving greater efficacy of the drug when taken at comparatively less dosage. These side effects can be overcome by developing delivery vehicles for the platinum-based drugs. References Bergstrand, N 2003, Liposomes for Drug Delivery, CTA Universitatis Upsaliensis, Uppsala Dua, J, Ranam A & Bhandari, K 2012, 'Liposome: Methods Of Preparation And Applications,' International Journal of Pharmaceutical Studies and Research Vol 3 Iss 2, pp.1-5 Egbara, K & Weiner, N 1990, 'Liposomes as a topical drug delivery system,' Advanced Drug Delivery Reviews, Vol. 5, pp.287-300 Fiegl M, Mlinertisch, B, Hubalek, M, Bartsch, R, Pluschnig, U & Stegger, G 2011, 'Sine-Agent Pegylated Liposomal Doxurubicin (PLD) In The Treatment Of Metastatic Breast Cancer: Results Of An Austrian Observational Trial,' BMC Cancer Vol 11, pp373 Gupta, A, Mandal, S, Leblanc, V, Descôteaux, C, Asselin, E & Berube, G 2008, 'Synthesis and cytotoxic activity of benzopyran-based platinum(II) complexes,' Bioorganic & Medicinal Chemistry Letters Vol. 18, pp. 3982–3987 Heap, B & Grogoridiasm G 2011, Alec Douglas Bangham. 10 November 1921 −− 9 March 2010, Biogr. Mems Fell. R. Soc. Vol. 57, pp.27-43 Hu, C, Aryal, S & Zhang, L 2010, 'Nanoparticle-assisted combination therapies for effective cancer treatment,' Therapeutic Delivery Vol 1 No. 2, pp. 324-334 McWhinney, S, Goldberg, R & McLeod, H 2009, 'Platinum neurotoxicity pharmacogenetics,' Mol Cancer Ther , Vol 8 No. 10, viewed 4 Nov 2013, http://mct.aacrjournals.org/content/8/1/10.full Misra, A & Shahiwala, A 2003, ‘Drug delivery to the central nervous system: a review,’ J Pharm Pharmaceut Sci Vol 6 No, 2, pp.252-273 Kelland, L 2007, 'The resurgence of platinum-based cancer chemotherapy,' Nature Reviews Cancer, Vol. 7: 573-584 Kostova, I 2006, 'Platinum Complexes as Anticancer Agents,’ Recent Patents on Anti-Cancer Drug Discovery, 1: 1-22 Lasic, D 1998, 'Novel Applications of Liposomes,' TIBTECH Reviews vol 16, pp 308-320 Lao, J, Madani, J, Puertolas, T, alvarez, M, Hernandez, A & Pazo-cid, R 2013, 'Liposomal Doxorubicin in the Treatment of Breast Cancer Patients: A Review,' Journal of Drug Delivery, Vol. 2013, viewed 6 Noc 2013, http://www.hindawi.com/journals/jdd/2013/456409/ Peer, D, Karpi. J, HOng, S, Farokhzad, O, margalit, R & Langer, R 2007, Nanocarriers as an emerging platform for cancer therapy, viewed 6 Nov 2013, http://www.uic.edu/labs/honglab/NatNano_published.pdf Staropoli, N, Ciliberto, D, Botta, C, Fiorilli, L & Gualtieri, S 2013, 'A retrospective analysis of pegylated liposomal doxorubicin in ovarian cancer: do we still need it?,' Journal of Ovarian Research Vol 6 No 10, viewed 6 No 2013, http://www.ovarianresearch.com/content/6/1/10 Vahdani, S & Bayat, Z 2011, 'A Quantitative Structure-Activity Relationship (QSAR) Study of Anti-cancer Drugs,' Der Chemica Sinica, Vol. 2 No. 4, pp.235-243 Zhang, S, Lovejoy K, Shima, J, Lagpacan, M & Shu, Y 2006, 'Organic Cation Transporters Are Determinants of Oxaliplatin Cytotoxicity,' Cancer Res, Vol, 66 No. 17, pp. 8847-8857 Read More