Comment on Dou et al, page 2827

Transfer of autologous macrophages carrying a nanoparticulated protease inhibitor is a novel and fantastic approach to antiretroviral chemotherapy. Dou and colleagues have demonstrated its efficacy in a mouse model.

Nanoparticles, or colloidal particles, are considered to have great potential for selective and controlled drug delivery to target cells and organs. It has been shown that the biologic distribution of compounds, proteins, and DNA is modified at both the cell and organ levels through the use of nanoparticle systems.1  Since drugs are generally encapsulated into biodegradable nanoparticles, several factors, such as particle material and size, are known to be important determinants for their targets.2  Furthermore, the speed of drug release from nanoparticles is also controlled by these factors.

In this issue of Blood, Dou and colleagues describe a novel antiretroviral drug delivery system using bone marrow-derived macrophages (BMMs). To this end, the human immunodeficiency virus type 1 (HIV-1) protease inhibitor indinavir (IDV) was nanoparticulated (NP-IDV). Like other nanoparticles, NP-IDV can be rapidly taken up by BMMs in vitro and gradually released from the cells. After a single administration of NP-IDV-carrying BMMs to mice, the BMMs acted as “Trojan horses” and migrated to several important organs. As a consequence of gradual release of IDV from the migrated BMMs, sufficient tissue and serum IDV levels inhibitory to HIV-1 replication can be maintained for a long period of time. In fact, the authors demonstrated the reduction of infected cell numbers in HIV-1-challenged humanized mice.

The significance of this work is indeed, as also pointed out by the authors, a unique approach to antiretroviral chemotherapy with nanotechnology. It is well known that IDV is very difficult to dissolve in water and physiologic fluids.3  The strong hydrophobicity of IDV has hampered its practical usefulness in the treatment of HIV-1-infected patients. It seems that the authors have converted this disadvantage of IDV into an advantage for nanoparticle formation. In other words, the present approach might be applicable to any hydrophobic compounds, including other HIV-1 protease inhibitors and anticancer agents. Furthermore, if BMMs carrying NP-IDV could cross the blood-brain barrier and reach the brain, this approach would become a rational and effective tool for the treatment of HIV-1-induced brain disorders.4 

However, the limitations of this chemotherapeutic modality should also be considered. First, the effect of NP-IDV-carrying BMMs on host immune responses needs to be extensively investigated. Although it is unlikely that specific immune responses to IDV will be generated as a consequence of antigen presentation by BMMs, such possibilities, including the induction of hypersensitivity to IDV, have to be excluded prior to starting clinical trials. Second, cost effectiveness still remains to be clarified. Nevertheless, the present approach is quite exciting and should be further pursued as a novel strategy for the treatment of HIV-1 infection in humans. ▪

Panyam J, Labhasetwar V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue.
Adv Drug Deliv Rev
Allen TM, Cullis PR. Drug delivery systems: entering the mainstream.
Dieleman JP, Salahuddin S, Hsu YS, et al. Indinavir crystallization around the loop of Henle: experimental evidence.
J Acquir Immune Defic Syndr
Zheng J, Gendelman HE. The HIV-1 associated dementia complex: a metabolic encephalopathy fueled by viral replication in mononuclear phagocytes.
Curr Opin Neurol
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