Creation of a Long-Acting Nanoformulated 2′,3′-Dideoxy-3′-Thiacytidine

Guo, Dongwei; Zhou, Tian; Araínga, Mariluz; Palandri, Diana L.; Gautam, Nagsen; Bronich, Tatiana K.; Alnouti, Yazen; McMillan, JoEllyn M; Edagwa, Benson; Gendelman, Howard Eliot

doi:10.1097/qai.0000000000001170

Cited by 41 publications

(59 citation statements)

References 46 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The folate receptor (FR) present on the macrophage surface [33, 34] was engaged by placing folic acid (FA) on the particle surface. This enabled the synthesized particles to seek out the FR and potentially enhance drug delivery in cell culture as was previously demonstrated [6, 9, 20, 21, 35, 36]. These next generation FA decorated probes combine accurate histologic (fluorescent) and magnetic properties to facilitate the utility of multimodal nanoprobes.…”

Section: Introductionmentioning

confidence: 82%

Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging

et al. 2017

Self Cite

View full text Add to dashboard Cite

The size, shape and chemical composition of europium (Eu3+) cobalt ferrite (CFEu) nanoparticles were optimized for use as a “multimodal imaging nanoprobe” for combined fluorescence and magnetic resonance bioimaging. Doping Eu3+ ions into a CF structure imparts unique bioimaging and magnetic properties to the nanostructure that can be used for real-time screening of targeted nanoformulations for tissue biodistribution assessment. The CFEu nanoparticles (size ~7.2 nm) were prepared by solvothermal techniques and encapsulated into poloxamer 407-coated mesoporous silica (Si-P407) to form superparamagnetic monodisperse Si-CFEu nanoparticles with a size of ~ 140 nm. Folic acid (FA) nanoparticle decoration (FA-Si-CFEu, size ~ 140 nm) facilitated monocyte-derived macrophage (MDM) targeting. FA-Si-CFEu MDM uptake and retention was higher than seen with Si-CFEu nanoparticles. The transverse relaxivity of both Si-CFEu and FA-Si-CFEu particles were r2= 433.42 mM−1s−1 and r2= 419.52 mM−1s−1 (in saline) and r2= 736.57 mM−1s−1 and r2= 814.41 mM−1s−1 (in MDM), respectively. The results were greater than a log order-of-magnitude than what was observed at replicate iron concentrations for ultrasmall superparamagnetic iron oxide (USPIO) particles (r2= 31.15 mM−1s−1 in saline) and paralleled data sets obtained for T2 magnetic resonance imaging. We now provide a developmental opportunity to employ these novel particles for theranostic drug distribution and efficacy evaluations.

show abstract

Section: Introductionmentioning

confidence: 82%

Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Antiretroviral activities of EuCF-RPV, NRPV and native RPV were evaluated by measures of reverse transcriptase (RT) activity and HIV-1p24 staining as previously described protocols [34] with the following modifications. In brief, MDM were treated with 6.25 μM, 12.5 μM, or 25 μM (RPV content) native RPV, NRPV or EuCF-RPV particles for 8 hours.…”

Section: Methodsmentioning

confidence: 99%

Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities

et al. 2018

Self Cite

View full text Add to dashboard Cite

Antiretroviral therapy (ART) has changed the outcome of human immunodeficiency virus type one (HIV-1) infection from certain death to a life free of disease co-morbidities. However, infected people must remain on life-long daily ART. ART reduces but fails to eliminate the viral reservoir. In order to improve upon current treatment regimens, our laboratory created long acting slow effective release (LASER) ART nanoformulated prodrugs from native medicines. LASER ART enables antiretroviral drugs (ARVs) to better reach target sites of HIV-1 infection while, at the same time, improve ART's half-life and potency. However, novel ARV design has been slowed by prolonged pharmacokinetic testing requirements. To such ends, tri-modal theranostic nanoparticles were created with single-photon emission computed tomography (SPECT/CT), magnetic resonance imaging (MRI) and fluorescence capabilities to predict LASER ART biodistribution. The created theranostic ARV probes were then employed to monitor drug tissue distribution and potency. Intrinsically Indium (In) radiolabeled, europium doped cobalt-ferrite particles and rilpivirine were encased in a polycaprolactone core surrounded by a lipid shell (InEuCF-RPV). Particle cell and tissue distribution, and antiretroviral activities were sustained in macrophage tissue depots. InEuCF-PCL/RPV particles injected into mice demonstrated co-registration of MRI and SPECT/CT tissue signals with RPV and cobalt. Cell and animal particle biodistribution paralleled ARV activities. We posit that particle selection can predict RPV distribution and potency facilitated by multifunctional theranostic nanoparticles.

show abstract

“…Cell targeted nanomedicines may offer several advantages over conventional drug delivery methods including enhanced efficacy, reduced side effects, increased drug stability and effective subcellular targeting [27, 53, 54]. To facilitate macrophage targeting, our laboratory developed injectable ART nanoformulations and evaluated drug delivery to macrophage subcellular compartments and tissues, as well as the pharmacokinetic profile [28, 29, 30, 53, 54, 55, 56, 57]. We observed rapid uptake and accumulation of hydrophobic drug nanocrystals throughout the macrophage cytoplasm without notable changes in cell morphology (Figure 2).…”

Section: Targeted Deliverymentioning

confidence: 99%

“…These in vitro data demonstrate that surfactants that exhibit anti-HIV activity could be used in the design of multimodal carriers that might protect cells from invasion by the virus. To overcome limitations of short acting NRTIs, our laboratory recently developed slow release products of 3TC (NMTC) and abacavir (ABC; NMABC) extending their half-lives from hours to weeks [29, 57]. Myristoylated prodrugs of 3TC (M3TC) and ABC (MABC) were produced then encapsulated into poloxamer 407 excipients.…”

Section: Prodrugs and Drug Polymer Conjugatesmentioning

confidence: 99%

Long-acting slow effective release antiretroviral therapy

Edagwa

McMillan

Sillman

et al. 2017

Expert Opinion on Drug Delivery

Self Cite

View full text Add to dashboard Cite

Introduction Advances in the development of long acting antiretroviral therapy (ART) can revolutionize current treatments for HIV/AIDS. We have coined the term long active slow effective release ART (LASER ART) based on properties of slow drug dissolution, poor water-solubility, excellent bioavailability, limited off target systemic toxicities, and excellent patient treatment adherence. Drug carrier technologies characterized by high payload of antiretroviral drugs (ARVs) in a single carrier are being developed to improve the pharmacokinetics and pharmacodynamics of the nanoformulated ART (nanoART). Additionally, surface modification of slow release antiretroviral carriers with targeting ligands has facilitated receptor-mediated transport across physiological barriers serves to improve therapeutic outcomes. Areas covered This review highlights current developments of reservoir targeted LASER ART delivery platforms that have the potential to improve HIV/AIDS therapeutic outcomes. Such nanoART delivery platforms include decorated multifunctional nano- and micro- particles, prodrugs and polymer conjugates. Therapeutic strategies such as anti-inflammatory and neuroprotective agents and CRISPR/Cas 9 based gene-editing technologies that affect drug depots, boost ART effectiveness and facilitate viral clearance are discussed. Expert opinion The persistence of HIV-1 in its lymphoid, gut and nervous system reservoirs poses a major challenge to viral eradication. Emerging innovative strategies for effective medicines and slow release products to target intracellular pathogens, immune based interventions, genome-editing technologies, compounds that sustain drug depots and combinations of nanoART and image contrast agents have the potential to meet the unmet clinical needs of HIV patients. Such efforts will bring the medicines to sites of active viral replication and accelerate viral clearance.

show abstract

Creation of a Long-Acting Nanoformulated 2′,3′-Dideoxy-3′-Thiacytidine

Abstract: Supplemental Digital Content is Available in the Text.

Cited by 41 publications

References 46 publications

Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging

Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging

Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities

Long-acting slow effective release antiretroviral therapy

Contact Info

Product

Resources

About