Biology subjects

Sizovs, A.

Publications and source records attributed to Sizovs, A..

3 recordsLinked to original sources

bioRxiv2024

Exploring the Limits of EPR-driven Tumor Accumulation with Non-opsonizing Nanomaterials

The Enhanced Permeability and Retention (EPR) effect is a foundational concept used to rationalize nanomedicine development for cancer treatment and diagnostics. The attainable efficacy of passive tumor targeting due to EPR remains ambiguous owing to pervasive opsonization of nanoparticles. To address this, we developed nanomaterials with complete resistance to opsonization, exceptionally long systemic circulation, and used them to study the limits of the EPR in triple-negative breast cancer. Tumors exerted no impact on pharmacokinetic profiles, which were indistinguishable between healthy and tumor-bearing mice. Tumors were the primary accumulation sites and our data revealed that the maximum average achievable tumor accumulation via EPR is proximate to 60 %ID/g, tumor- to-liver selectivity is 4-to-1, and the optimal DH to fully exploit EPR lies between 18 and 54 nm. The significant heterogeneity observed in tumor accumulation, however, indicates that nanomedicines cannot achieve consistent efficacy across different patients by relying solely on EPR.

bioengineering↗

bioRxiv2020

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

Pre-exposure prophylaxis (PrEP) using antiretroviral oral drugs is effective at preventing HIV transmission when individuals adhere to the dosing regimen. Tenofovir alafenamide (TAF) is a potent antiretroviral drug, with numerous long-acting (LA) delivery systems under development to improve PrEP adherence. However, none has undergone preventive efficacy assessment. Here we show that LA TAF using a novel subcutaneous nanofluidic implant (nTAF) confers partial protection from HIV transmission. We demonstrate that sustained subcutaneous delivery through nTAF in rhesus macaques maintained tenofovir diphosphate concentration at a median of 390.00 fmol/106 peripheral blood mononuclear cells, 9 times above clinically protective levels. In a non-blinded, placebo-controlled rhesus macaque study with repeated low-dose rectal SHIVSF162P3 challenge, the nTAF cohort had a 62.50% reduction (95% CI: 1.72% to 85.69%; p=0.068) in risk of infection per exposure compared to the control. Our finding mirrors that of tenofovir disoproxil fumarate (TDF) monotherapy, where 60.00% protective efficacy was observed in macaques, and clinically, 67.00% reduction in risk with 86.00% preventive efficacy in individuals with detectable drug in the plasma. Overall, our nanofluidic technology shows potential as a subcutaneous delivery platform for long-term PrEP and provides insights for clinical implementation of LA TAF for HIV prevention.

bioengineering↗

bioRxiv2017

The N-terminal domain of ALS-linked TDP-43 assembles without misfolding

TDP-43 forms inclusions in several neurodegenerative diseases, and both its N- and C-terminal domains are implicated in this process. We show that the folded TDP-43 N-terminal domain oligomerizes under physiological conditions and propose that, in full-length TDP-43, association between folded N-terminal domains enhances the propensity of the intrinsically unfolded C-terminal domains to drive pathological aggregation.

biophysics↗