Development of a macrophage-based nanoparticle platform for antiretroviral drug delivery

Abstract

Complex dosing regimens, costs, side effects, biodistribution limitations, and variable drug pharmacokinetic patterns have affected the long-term efficacy of antiretroviral medicines. To address these problems, a nanoparticle indinavir (NP-IDV) formulation packaged into carrier bone marrow-derived macrophages (BMMs) was developed. Drug distribution and disease outcomes were assessed in immune-competent and human immunodeficiency virus type 1 (HIV-1)-infected humanized immune-deficient mice, respectively. In the former, NP-IDV formulation contained within BMMs was adoptively transferred. After a single administration, single-photon emission computed tomography, histology, and reverse-phasehigh-performance liquid chromatography (RP-HPLC) demonstrated robust lung, liver, and spleen BMMs and drug distribution. Tissue and sera IDV levels were greater than or equal to 50 M for 2 weeks. NP-IDV-BMMs administered to HIV-1-challenged humanized mice revealed reduced numbers of virus-infected cells in plasma, lymph nodes, spleen, liver, and lung, as well as, CD4 ؉ T-cell protection. We conclude that a single dose of NP-IDV, using BMMs as a carrier, is effective and warrants consideration for human testing. ( IntroductionDespite the significant impact of antiretroviral therapy (ART), the worldwide human immunodeficiency virus type 1 (HIV-1) pandemic continues to grow. [1][2][3] An estimated 40 million people globally are virus infected, with the majority from the developing world. [4][5][6] Although ART has reduced disease morbidity and increased life expectancy, drug expenses, treatment failures, and dosing complexities limit global access. [7][8][9] Multiple daily dosing regimens and untoward secondary side effects diminish achievement of significant long-term HIV-1 suppression in infected people. [10][11][12] Additionally, continuous viral suppression requires maintenance of therapeutically effective drug concentrations. [13][14][15] Most significantly, elimination of viral reservoirs in the infected human host has not yet been achieved. 16,17 To address these challenges to effective antiretroviral delivery, we designed a novel bone marrow-derived macrophage (BMM) pharmacologic nanoparticle (NP) delivery system. This system could provide a strategy to achieve therapeutic efficacy, improve drug distribution to areas of active viral replication, and extend dosing intervals. Because of the small size of the NPs and their highly stable nature, NPs could be packaged within macrophages for subsequent systemic trafficking and sustained drug distribution. We reasoned that such a cell-based drug delivery system could reflect the patterns of viral replication and improve therapeutic outcomes.To test this idea, we loaded indinavir (IDV) nanosuspension into BMMs and administered intravenously into naive mice. Cell tissue distribution was tracked by single-photon emission computed tomography (SPECT) and T 2 * weighted magnetic resonance imaging (MRI) of radio-and superparamagnetic iron oxide (SPIO; Feridex)-labeled BMMs, and confirme...

A Macrophage−Nanozyme Delivery System for Parkinson's Disease

“…To this end, we examined whether BMM could be used as vehicles for delivery of a potent antioxidant, catalase. Indeed, it has long been known that macrophages and microglia as well as other mononuclear phagocytes can endocytose colloidal nanomaterials, for example, liposomes or nanosuspensions, and subsequently carry and release the drug to site of tissue injury, infection, or disease (32,33,35,46,86).…”

“…Bone marrow cells extracted from murine femurs (C57BL/6, female mice) as described (32) were cultured for 10 days in the media supplemented with 1000 U/mL macrophage colonystimulating factor (MCSF) (a generous gift from Wyeth Pharmaceutical, Cambridge, MA). The purity of monocyte culture was determined by flow cytometry using FACSCalibur (BD Biosciences, San Jose, CA).…”

“…Recent works from our laboratories demonstrate that bone-marrow derived monocytes (BMM) can be used as carriers of nanoformulated drugs, both in the periphery and across the BBB (32,33). Entry into the brain occurs as a consequence of the establishment of a chemokine gradient induced through neuroinflammatory responses (34,35).…”

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

“…Studies done in our laboratory using indinavir (IDV) nanosuspensions highlighted the importance of cell-based drug delivery for treatment of HIV disease [275][276][277]. When in an alkaline environment, IDV can be fabricated into nanosuspensions and remain stable.…”

Polymeric Nanoparticles for Enhancing Antiretroviral Drug Therapy

“…This in vitro in vivo study confirmed that PEO-PCL nanoparticles can incorporate SQN and deliver it intracellularly in Mo/Mac. In a novel follow-up to the concept of targeting nanoparticles to Mo/Mac, Dou et al (2006Dou et al ( , 2007 postulated that the mononuclear phagocytes, as the principal reservoir for viral dissemination, could also serve as a transporter of antiretroviral drugs themselves since they are responsible for dissemination of HIV that is, macrophages can enter into tissues that limit entry of many ARV drugs. In this novel study, they chose indinavir (IDV) to prove their concept of using a macrophage-based nanoparticulate system as a drug carrier itself.…”