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Nanomedicine for HIV and TB treatment

Admire Dube, Ph.D.

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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

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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.

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NanomedicineA 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.

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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)

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.

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Nanoparticles8

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

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Typical nanoparticle designCell 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.

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Improved cellular and organ concentrations of HIV drugs11

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.

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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.

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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

k1

Drug delivery device Central compartment Tissue compartment

k2

Designed to control input rate into central compartment (k1)

Determines rate of tissue uptake (k2) leading to PD effect

Conventional drug delivery system PK:

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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

‘Special’ drug

delivery system

Central compartment Tissue compartment

‘Special’ drug

delivery system

Nanoparticle drug delivery

systemkS-2

kS-4

kS-3

kS-1

kS-2

kS-1

kS-1

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.

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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

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Acknowledgements

• Fogarty International CenterThe 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