Mitochondrial metabolism blockade nanoadjuvant reversed immune-resistance microenvironment to sensitize albumin-bound paclitaxel-based chemo-immunotherapy

Currently, the efficacy of albumin-bound paclitaxel (PTX@Alb) is still limited due to theimpaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution. Meanwhile,acquired immune resistance always occurs due to the enhanced programmed cell death-ligand 1(PD-L1) expression after PTX@Alb treatment, which then leads to immune tolerance. To fill these gaps,we newly revealed that tamoxifen (TAM), a clinically widely used adjuvant therapy for breast cancer withmitochondrial metabolism blockade capacity, could also be used as a novel effective PD-L1 and TGF-bdual-inhibitor via inducing the phosphorylation of adenosine 5ʹ-monophosphate-activated protein kinase(AMPK) protein. Following this, to obtain a more significant effect, TPP-TAM was prepared by conjugatingmitochondria-targeted triphenylphosphine (TPP) with TAM, which then further self-assembledwith albumin (Alb) to form TPP-TAM@Alb nanoparticles. By doing this, TPP-TAM@Alb nanoparticleseffectively decreased the expression of collagen in vitro, which then led to the enhanced accumulation ofPTX@Alb in 4T1 tumors. Besides, TPP-TAM@Alb also effectively decreased the expression of PD-L1 and TGF-b in tumors to better sensitize PTX@Alb-mediated chemo-immunotherapy by enhancing T cellinfiltration. All in all, we newly put forward a novel mitochondrial metabolism blockade strategy toinhibit PTX@Alb-resistant tumors, further supporting its better clinical application。

Pharmacokinetics of lipoic acid in healthy Chinese volunteers after single and multiple doses of Lipoic acid dispersible tablets

This study aimed to evaluate the pharmacokinetics for lipoic acid （LA） after oral administration of 12 healthy Chinese volunteers with single and multiple-dose of lipoic acid dispersal tablets using a liquid chromatography-temdend mass spectrometry （LC-MS/MS） methods. In single-dose study, healthy Chinese male and female volunteers received three dose levels at 0.2, 0.3, and 0.4 g of LA dispersal tablets with a 3 x3 Latina square design. In multiple-dose study, 12 healthy Chinese volunteers received orally a 0.1 g of LA dispersible tablet three times daily for 6 consecutive days and 0.3 g once on day 7. The results showed that pharmacokinetics of LA fitted a two-compartment open model. The values of area under the curve （A UC） increased proportionally within the range of 0.2-0.4 g, while the Vd/F, CL/F, MRT, t1/2 and tmax of LA were similar at three dose levels. The steady-state pharmacokinetic parameters of LA were similar to those following a single dose and no accumulation was found following multiple-dose of LA dispersal tablets.