Vascular-confined multi-passage discoidal nanoconstructs for the low-dose docetaxel inhibition of triple-negative breast cancer growth

Taxane efficacy in triple negative breast cancer(TNBC)is limited by insufficient tumor accumulation and severe off-target effects.Nanomedicines offer a unique opportunity to enhance the anti-cancer potency of this drug.Here,1,000 nm×400 nm discoidal polymeric nanoconstructs(DPN)encapsulating docetaxel(DTXL)and the near infrared compound Iipid-Cy5 were engineered.DPN were obtained by filling multiple times cylindrical wells in a poly(vinyl alcohol)template with a polymer mixture comprising poly(lactic-co-glycolic acid)(PLGA)and poly(ethylene glycol)diacrylate(PEG-DA)chains together with therapeutic and imaging agents.The resulting“multi-passage”DPN exhibited higher DTXL loading,Iipid-Cy5 stability,and stiffness as compared to the conventional"single-passage"approach.Confocal microscopy confirmed that DTXL-DPN were not taken up by MDA-MB-231 cells but would rather sit next to the cell membrane and slowly release DTXL thereof.Empty DPN had no toxicity on TNBC cells,whereas DTXL-DPN presented a cytotoxic potential comparable to free DTXL(IC_(50)=2.6 nM±1.0 nM vs.7.0 nM±1.09 nM at 72 h).In orthotopic murine models,DPN accumulated in TNBC more efficiently than free-DTXL.With only 2 mg/kg DTXL,intravenously administered every 2 days for a total of 13 treatments,DTXL-DPN induced tumor regression and were associated to an overall 80%survival rate as opposed to a 30%survival rate for free-DTXL,at 120 days.All untreated mice succumbed before 90 days.Collectively,this data demonstrates that vascular confined multi-passage DPN,biomimicking the behavior of circulating platelets,can efficiently deliver chemotherapeutic molecules to malignant tissues and effectively treat orthotopic TNBC at minimal taxane doses.

Tribological behavior of shape-specific microplate-enriched synovial fluids on a linear two-axis tribometer

Nano-and micro-particles are being increasingly used to tune interfacial frictional properties in diverse applications,from friction modifiers in industrial lubrication to enhanced biological fluids in human osteoarthritic joints.Here,we assessed the tribological properties of a simulated synovial fluid enriched with non-spherical,poly lactic-co-glycolic acid(PLGA)microparticles(μPL)that have been previously demonstrated for the pharmacological management of osteoarthritis(OA).Three different μPL configurations were fabricated presenting a 20μm×20μm square base and a thickness of 5μm(thin,5H μPL),10μm(10H μPL),and 20μm(cubical,20H μPL).After extensive morphological and physicochemical characterizations,the apparent Young’s modulus of the μPL was quantified under compressive loading returning an average value of~6 kPa,independently of the particle morphology.Then,using a linear two-axis tribometer,the static(μ_(s))and dynamic(μ_(d))friction coefficients of the μPL-enriched simulated synovial fluid were determined in terms of particle configuration and concentration,varying from 0(fluid only)to 6×10^(5) μPL/mL.The particle morphology had a modest influence on friction,possibly because the μPL were fully squeezed between two mating surfaces by a 5.8 N normal load realizing boundary-like lubrication conditions.Differently,friction was observed to depend on the dimensionless parameterW,defined as the ratio between the total volume of the μPL enriching the simulated synovial fluid and the volume of the fluid itself.Both coefficients of friction were documented to grow withWreaching a plateau of μ_(s)~0.4 and μ_(d)~0.15,already at Ω~2×10^(-3).Future investigations will have to systematically analyze the effect of sliding velocity,normal load,and rigidity of the mating surfaces to elucidate in full the tribological behavior of μPL in the context of osteoarthritis.