Unexpected behaviors in molecular transport through size-controlled nanochannels down to the ultra-nanoscale

Bruno, Giacomo; Trani, Nicola Di; Hood, R. Lyle; Zabre, Erika; Filgueira, Carly S.; Canavese, Giancarlo; Jain, Priya; Smith, Zachary W.; Demarchi, Danilo; Hosali, Sharath; Pimpinelli, Alberto; Ferrari, Mauro; Grattoni, Alessandro

doi:10.1038/s41467-018-04133-8

Cited by 74 publications

(99 citation statements)

References 47 publications

(52 reference statements)

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“…Specifically, the concentration difference between the drug reservoir and the subcutaneous space drives drug diffusion across the membrane. The nanometric channel size and related interplay of steric and electrostatic forces acting on molecules diffusing through the nanochannels alters free Fickian diffusion [ 35 ]. As a result, a constant and sustained release that is quasi-independent of the concentration difference across the membrane [ 32 , 35 ] is achieved for a significant percentage of drug contained in the implanted reservoir (~85–95%).…”

Section: Resultsmentioning

confidence: 99%

“…The nanometric channel size and related interplay of steric and electrostatic forces acting on molecules diffusing through the nanochannels alters free Fickian diffusion [ 35 ]. As a result, a constant and sustained release that is quasi-independent of the concentration difference across the membrane [ 32 , 35 ] is achieved for a significant percentage of drug contained in the implanted reservoir (~85–95%). In this scenario, the release rate can be finely tuned by changing the nanochannels’ number and size [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

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Viral load Reduction in SHIV-Positive Nonhuman Primates via Long-Acting Subcutaneous Tenofovir Alafenamide Fumarate Release from a Nanofluidic Implant

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HIV-1 is a chronic disease managed by strictly adhering to daily antiretroviral therapy (ART). However, not all people living with HIV-1 have access to ART, and those with access may not adhere to treatment regimens increasing viral load and disease progression. Here, a subcutaneous nanofluidic implant was used as a long-acting (LA) drug delivery platform to address these issues. The device was loaded with tenofovir alafenamide (TAF) and implanted in treatment-naïve simian HIV (SHIV)-positive nonhuman primates (NHP) for a month. We monitored intracellular tenofovir-diphosphate (TFV-DP) concentration in the target cells, peripheral blood mononuclear cells (PBMC). The concentrations of TFV-DP were maintained at a median of 391.0 fmol/106 cells (IQR, 243.0 to 509.0 fmol/106 cells) for the duration of the study. Further, we achieved drug penetration into lymphatic tissues, known for persistent HIV-1 replication. Moreover, we observed a first-phase viral load decay of −1.14 ± 0.81 log10 copies/mL (95% CI, −0.30 to −2.23 log10 copies/mL), similar to −1.08 log10 copies/mL decay observed in humans. Thus, LA TAF delivered from our nanofluidic implant had similar effects as oral TAF dosing with a lower dose, with potential as a platform for LA ART.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Viral load Reduction in SHIV-Positive Nonhuman Primates via Long-Acting Subcutaneous Tenofovir Alafenamide Fumarate Release from a Nanofluidic Implant

et al. 2020

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“…Molecular diffusion in nanoconfinement exhibits peculiar phenomena which are typical of the nanoscale. 48,49 Charged particles electrostatically interact with the charged surfaces of the nanochannel walls creating an ionic distribution known as electric double layer (EDL). The EDL can extend several nanometers into the solution depending on parameters such as ionic strength and surface charge.…”

Section: Mechanism Of Electrostatically Gated Diffusion In Nanochannelsmentioning

confidence: 99%

Electrostatically gated nanofluidic membrane for ultra-low power controlled drug delivery

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“…The size of nanochannels is selected to saturate drug transport, rendering it steady and independent from the concentration gradient. [24,25]…”

Section: Nanofluidic Implant Assemblymentioning

confidence: 99%

Preventive efficacy of a tenofovir alafenamide fumarate nanofluidic implant in SHIV-challenged nonhuman primates

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Shelton

et al. 2020

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36Pre-exposure prophylaxis (PrEP) using antiretroviral oral drugs is effective at preventing HIV 37 transmission when individuals adhere to the dosing regimen. Tenofovir alafenamide (TAF) is a 38 potent antiretroviral drug, with numerous long-acting (LA) delivery systems under development 39 to improve PrEP adherence. However, none has undergone preventive efficacy assessment. Here 40 we show that LA TAF using a novel subcutaneous nanofluidic implant (nTAF) confers 41 protection from HIV transmission. We demonstrate that sustained subcutaneous delivery through 42 nTAF in rhesus macaques maintained tenofovir diphosphate concentration at a median of 390.00 43 fmol/10 6 peripheral blood mononuclear cells, 9 times above clinically protective levels. In a non-44 blinded, placebo-controlled rhesus macaque study with repeated low-dose rectal SHIVSF162P3 45 3 challenge, the nTAF cohort had a 62.50% reduction in risk of infection per exposure compared 46 to the control. Our finding mirrors that of tenofovir disoproxil fumarate (TDF) monotherapy, 47 where 60.00% protective efficacy was observed in macaques, and clinically, 67% reduction in 48 risk with 86.00% preventive efficacy in individuals with detectable drug in the plasma. Overall, 49 our nanofluidic technology shows potential as a subcutaneous delivery platform for long-term 50PrEP and provides insights for clinical implementation of LA TAF for HIV prevention. 51 52 65 Long-acting (LA) antiretroviral (ARV) formulations and delivery systems offer systemic 66 delivery for prolonged periods, obviating the need for frequent dosing. Currently, LA ARV 67 strategies for HIV PrEP are largely geared towards developing single-agent drugs for prevention 68 mg of TAF over 10 days (Fig. 1i). However, an increase of TAF degradation products was 131 observed throughout the study, attributable to decrease in TAF stability ( Supplementary Fig. 1). 132 133 nTAF pharmacokinetic profile in NHP 134For in vivo evaluation of pharmacokinetic (PK) and PrEP efficacy, rhesus macaques were 135 subcutaneously implanted with either nTAF (n=8) or control nPBS (n=6) in the dorsum for 4 136 months. We used TFV-DP concentration in PBMC of 100.00 fmol/10 6 cells as the benchmark 137 phase 2a trial. Lancet HIV 4, e331-e340 (2017). 595

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Unexpected behaviors in molecular transport through size-controlled nanochannels down to the ultra-nanoscale

Cited by 74 publications

References 47 publications

Viral load Reduction in SHIV-Positive Nonhuman Primates via Long-Acting Subcutaneous Tenofovir Alafenamide Fumarate Release from a Nanofluidic Implant

Viral load Reduction in SHIV-Positive Nonhuman Primates via Long-Acting Subcutaneous Tenofovir Alafenamide Fumarate Release from a Nanofluidic Implant

Electrostatically gated nanofluidic membrane for ultra-low power controlled drug delivery

Preventive efficacy of a tenofovir alafenamide fumarate nanofluidic implant in SHIV-challenged nonhuman primates

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