Nanomedicine for HIV and TB treatment Admire Dube, Ph.D.

Introduction-Nanotechnology Nanotechnology is defined as the creation of functional devices in the nanometre range and the exploitation of the unique properties of these devices in various fields1 1 Salamanca-Buentello, F., et al. (2005). Nanotechnology and the Developing World. PLoS Med, 2(5), 383-386. Figure from: http://inl.int/what-is-nanotechnology-2

Introduction-Nanotechnology1 Applications of nanotechnology: Energy storage and production Water purification Food processing and storage Medicine For medical applications: Nanomedicine Mostly concerning diagnostics and drug delivery Multi-disciplinary field, utilizing material sciences, pharmacology, medicine, etc. 1 Salamanca-Buentello, F., et al. (2005). Nanotechnology and the Developing World. PLoS Med, 2(5), 383-386.

Nanomedicine A vehicle for delivery of therapeutics into the body Small molecule drug compounds, DNA/genes, proteins, vaccines, etc. 2,3 Administration routes to reach systemic circulation or infected organs and cells: oral, intravenous, inhalation, ocular, topical 2 Ojewole, E., Mackraj, I., Naidoo, P., & Govender, T. (2008). Exploring the use of novel drug delivery systems for antiretroviral drugs. European Journal of Pharmaceutics and Biopharmaceutics, 70(3), 697-710. 3 Pinto Reis, C., et al. (2006). Nanoencapsulation II. Biomedical applications and current status of peptide and protein nanoparticulate delivery systems. Nanomedicine: Nanotechnology, Biology and Medicine, 2(2), 53-65.

Nanoparticles in oral drug delivery4,5,6,7 Improving stability and solubility of drugs in G.I tract Improving solubility of drugs in G.I tract Increasing bioavailability of drugs Alter PK of drugs, e.g. extending half-life Targeting drugs to specific cells, tissues and organs Reducing toxicity of drugs Mitigating metabolism and drug-drug interactions (RIF and P.I’s) Sustained release, imagine if it is an antimalarial formulating releasing the antimalarial prophylaxis over 1 mnth, or the ARV or anti-TB drug over 1 mnth. Through targeted delivery can reduce unwanted systemic absorption or absorption into certain organs Biocompatible, biodegradble, non-toxic Use of ligands on the nanoparticle surface to target drugs to specific cells Reducing toxicities related to the metabolism of current oral formulations. For example, if a nanoformulation is designed to increase active drug levels inside cells while keeping blood levels low this has the potential to reduce toxicities related to systemic drug levels. 4Dube A, Ng K, Nicolazzo JA, Larson I. Effective use of reducing agents and nanoparticle encapsulation in stabilizing catechins in alkaline solution. Food Chemistry. 2010;122(3):662-7. 5Dube A, Nicolazzo JA, Larson I. Chitosan nanoparticles enhance the plasma exposure of (−)-epigallocatechin gallate in mice through an enhancement in intestinal stability. European Journal of Pharmaceutical Sciences. 2011;44(3):422-6. 6Boyd, B. J. (2008). Past and future evolution in colloidal drug delivery systems. Expert Opinion on Drug Delivery, 5, 69-85. 7Delie, F., & Blanco-Príeto, M. (2005). Polymeric particulates to improve oral bioavailability of peptide drugs. Molecules, 10(1), 65-80.

Nanoparticles8 8Re F, Moresco R, Masserini M. Nanoparticles for neuroimaging. Journal of Physics D: Applied Physics. 2012;45(7):073001.

Typical nanoparticle design Cell targeting molecule/ligand Surface modifier to achieve prolonged circulation of particle, e.g. Poly(ethylene glycol) Drug

Improved physico-chemical properties of HIV drugs9 Effective oral administration of Saquinavir is a challenge Saquinavir has poor solubility (35 µg/ml) 5 Solubility increased 400 fold through encapsulation in cyclodextrin and polyalkylcyanoacrylate nanoparticles (15.8 mg/ml)5 9Boudad, H., Legrand, P., Lebas, G., Cheron, M., Duchêne, D., & Ponchel, G. (2001). Combined hydroxypropyl-β-cyclodextrin and poly(alkylcyanoacrylate) nanoparticles intended for oral administration of saquinavir. International Journal of Pharmaceutics, 218(1-2), 113-124.

Modulation of PK profiles of HIV drugs10 Indinavir has elimination half-life of 11.5 min (free drug) and 71 h for nanoparticle formulation at 10 mg/kg10 10Kingsley, J., Dou, H., Morehead, J., Rabinow, B., Gendelman, H., & Destache, C. (2006). Nanotechnology: A Focus on Nanoparticles as a Drug Delivery System. Journal of Neuroimmune Pharmacology, 1(3), 340-350.

Improved cellular and organ concentrations of HIV drugs11 Mannose receptors are present at the surface of monocyte macrophages Intracellular concentrations of saquinavir as a function of dose administered (A) and time of incubation (B) to THP-1 monocyte/ macrophage cells. 18 fold increase in uptake of Didanosine in macrophages following encapsulation in nanoparticles (mannosylated) 11 Jain, S. K., Gupta, Y., Jain, A., Saxena, A. R., Khare, P., & Jain, A. (2008). Mannosylated gelatin nanoparticles bearing an anti-HIV drug didanosine for site-specific delivery. Nanomedicine : nanotechnology, biology, and medicine, 4(1), 41-48.

Modulation of PK profiles of TB drugs12 12 Sharma, A., R. Pandey, et al. (2004). "Chemotherapeutic efficacy of poly (DL-lactide-co-glycolide) nanoparticle encapsulated antitubercular drugs at sub-therapeutic dose against experimental tuberculosis." Int J Antimicrob Agents 24(6): 599-604.

Improved the tissue concentrations of TB drugs12 TB drugs present at MIC levels at Day 7 and Day 9. In the case of free drugs, no drug could be detected in these tissues after 48 h 12 Sharma, A., R. Pandey, et al. (2004). "Chemotherapeutic efficacy of poly (DL-lactide-co-glycolide) nanoparticle encapsulated antitubercular drugs at sub-therapeutic dose against experimental tuberculosis." Int J Antimicrob Agents 24(6): 599-604.

Some PK considerations for nanoparticle drug delivery systems Conventional drug delivery system PK: Designed to control input rate into central compartment (k1) Determines rate of tissue uptake (k2) leading to PD effect k1 k2 Drug delivery device Central compartment Tissue compartment

PK aspects of nanoparticle drug delivery systems The drug delivery system itself enters the central compartment with the drug onboard and distributes to tissues Extent of central compartment and tissue distribution controlled by particle characteristics kS-4 Central compartment Tissue compartment Nanoparticle drug delivery system kS-1 kS-3 ‘Special’ drug delivery system kS-2 ‘Special’ drug delivery system kS-1 kS-1 kS-2

Examples of HIV nanomedicines in development (2010)13 13 Mamo, T., Moseman, E. A., Kolishetti, N., Salvador-Morales, C., Shi, J., Kuritzkes, D. R., Langer, R., Andrian, U. v., & Farokhzad, O. C. (2010). Emerging nanotechnology approaches for HIV/AIDS treatment and prevention. Nanomedicine, 5(2), 269-285.

Conclusion Nanomedicine offers new prospects for HIV and TB medicines PK and efficacy Changes the way we currently view and understand drug PK Further study is required including collaborative efforts to deliver nanomedicines (HIV and TB) to the clinic

Acknowledgements Fogarty International Center University of Zimbabwe The content is solely the responsibility of the authors and does not necessarily represent the official views of the Fogarty International Center or the National Institutes of Health. University of Zimbabwe Council for Scientific and Industrial Research South Africa