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Development of Nanoparticles

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Current Medicinal Chemistry, 2010, 17, 585-594 585 0929-8673/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd. Development of Nanoparticles for Antimicrobial Drug Delivery L. Zhang*,1,2, D. Pornpattananangkul2,3, C.-M.J. Hu2,3 and C.-M. Huang*,2,4 1Department of Nanoengineering; 2Moores Cancer Center; 3Department of Bioengineering and 4Division of Derma-tology, University of California San Diego, La Jolla, CA 92093, USA Abstract: This review focuses on the development of nanoparticle systems for antimicrobial drug delivery. Numerous an-timicrobial drugs have been prescribed to kill or inhibit the growth of microbes such as bacteria, fungi and viruses. Even though the therapeutic efficacy of these drugs has been well established, inefficient delivery could result in inadequate therapeutic index and local and systemic side effects including cutaneous irritation, peeling, scaling and gut flora reduc-tion. Nanostructured biomaterials, nanoparticles in particular, have unique physicochemical properties such as ultra small and controllable size, large surface area to mass ratio, high reactivity, and functionalizable structure. These properties can be applied to facilitate the administration of antimicrobial drugs, thereby overcoming some of the limitations in traditional antimicrobial therapeutics. In recent years, encapsulation of antimicrobial drugs in nanoparticle systems has emerged as an innovative and promising alternative that enhances therapeutic effectiveness and minimizes undesirable side effects of the drugs. Here the current progress and challenges in synthesizing nanoparticle platforms for delivering various antimi-crobial drugs are reviewed. We also call attention to the need to unite the shared interest between nanoengineers and mi-crobiologists in developing nanotechnology for the treatment of microbial diseases. Keywords: Antimicrobial delivery, microbes, liposomes, polymeric nanoparticles, solid lipid nanoparticles, dendrimers. INTRODUCTION Upon invasion of the epithelial surfaces, infectious mi-croorganisms spread throughout the body via the circulatory system. They are then removed from the blood by macro-phages which are present in all major organs such as liver, spleen and bone marrow [1]. After being phagocytosed by macrophages, the infectious microorganisms are trapped in phagosomes, which then fuse with lysosomal granules inside cell cytoplasm forming phagolysosomes. Subsequently, oxy-gen-dependent or oxygen-independent bacterial killing mechanisms induced by enzymes inside the phagolysosomes occur to digest the trapped microorganisms. However, many microorganisms are able to evade the macrophage digestion via escaping from the phagosomes, inhibiting the phagosome-lysosome fusion, withstanding the lysosomal enzymes, or resisting oxidative and non-oxidative killing mechanisms. These bacterial defense mechanisms make in-tracellular infections difficult to eradicate resulting in infec-tious diseases that range from staph infections to tuberculosis [1]. An antimicrobial refers to a substance that kills or inhib-its the growth of microorganisms. Since the discovery of antimicrobial drugs in the 1960s [2], many infectious dis-eases have been overcome. Typically, antimicrobials kill bacteria by binding to some vital compounds of bacterial metabolism, thereby inhibiting the synthesis of functional biomolecules or impeding normal cellular activities. For in-stance, -lactams such as penicillins and cephalosporins in-hibit bacteria cell wall synthesis; tetracyclines, macrolides, and clindamycin inhibit protein synthesis; metronidazole and quinolones inhibit nucleic acid synthesis; and sulphonamides and trimethoprim have an inhibitory effect on enzyme *Address correspondence to these authors at the Department of Nanoengi-neering, University of California San Diego, 9500 Gilman Drive, MC-0815, La Jolla, CA 92093, USA; Tel: 1-858-246-0999; E-mail: [email protected] Division of Dermatology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Tel: 1-858-822-4627; E-mail: [email protected] synthesis. Some antimicrobials such as penicillin are only effective against a narrow range of bacteria, whereas others, like ampicillin, kill a broad spectrum of Gram-positive and Gram-negative bacteria [3]. Despite the great progress in antimicrobial development, many infectious diseases, espe-cially intracellular infections, remain difficult to treat. One major reason is that many antimicrobials are difficult to transport through cell membranes and have low activity in-side the cells, thereby imposing negligible inhibitory or bac-tericidal effects on the intracellular bacteria. In addition, an-timicrobial toxicity to healthy tissues poses a significant limitation to their use. Aminoglycosides, for instance, cause ototoxicity and nephrotoxicity and have to be given in con-trolled dosages. Another major issue with antimicrobials stems from the acquired resistance of infectious microbes. In 2002, more than 70% of bacteria causing hospital-acquired infections were resistant to at least one common antimicro-bial in the United States. To address these issues, alternative antimicrobial drug delivery strategies have been proposed. Over the last few decades, the applications of nanotech-nology in medicine have been extensively explored in many medical areas, especially in drug delivery. Nanotechnology concerns the understanding and control of matters in the 1-100 nm range, at which scale materials have unique physico-chemical properties including ultra small size, large surface to mass ratio, high reactivity and unique interactions with biological systems [4]. By loading drugs into nanoparticles through physical encapsulation, adsorption, or chemical con-jugation, the pharmacokinetics and therapeutic index of the drugs can be significantly improved in contrast to the free drug counterparts. Many advantages of nanoparticle-based drug delivery have been recognized, including improving serum solubility of the drugs, prolonging the systemic circu-lation lifetime, releasing drugs at a sustained and controlled manner, preferentially delivering drugs to the tissues and cells of interest, and concurrently delivering multiple therapeutic agents to the same cells for combination therapy [4-6]. Moreover, drug-loaded nanoparticles can enter host cells through endocytosis and then release drug payloads to treat microbes-induced intracellular infections. As a result,


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