Smart pH-responsive polyhydralazine/bortezomib nanoparticles for remodeling tumor microenvironment and enhancing chemotherapy.

The clinical translation of nanomedicines has been impeded by the unfavorable tumor microenvironment (TME), particularly the tortuous vasculature networks, which significantly influence the transport and distribution of nanomedicines into tumors. In this work, a smart pH-responsive bortezomib (BTZ)-loaded polyhydralazine nanoparticle (PHDZ/BTZ) is presented, which has a great capacity to augment the accumulation of BTZ in tumors by dilating tumor blood vessels via specific release of vasodilator hydralazine (HDZ). The Lewis acid-base coordination effect between the boronic bond of BTZ and amino of HDZ empowered PHDZ/BTZ nanoparticles with great stability and high drug loading contents. Once triggered by the acidic tumor environment, HDZ could be released quickly to remodel TME through tumor vessel dilation, hypoxia attenuation, and lead to an increased intratumoral BTZ accumulation. Additionally, our investigation revealed that this pH-responsive nanoparticle dramatically suppressed tumor growth, inhibited the occurrence of lung metastasis with fewer side effects and induced immunogenic cell death (ICD), thereby eliciting immune activation including massive cytotoxic T lymphocytes (CTLs) infiltration in tumors and efficient serum proinflammatory cytokine secretion compared with free BTZ treatment. Thus, with efficient drug loading capacity and potent immune activation, PHDZ nanoparticles exhibit great potential in the delivery of boronic acid-containing drugs aimed at a wide range of diseases.

A dendronised polymer architecture breaks the conventional inverse relationship between porosity and mechanical properties of hydrogels.

We present a series of synthetic polymer hydrogels which break the traditional correlation between pore size and mechanical properties. The hydrogels are prepared from a dendronised polymer architecture based on a methacrylate copolymer to which poly(amido amine) dendrons are attached. Our approach will be useful in tailoring hydrogels for tissue engineering, controlled drug release, and flexible electronics.

Genetic Variation of the Kalirin Gene is Associated with ICAS in the Chinese Population.

Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of ischemic stroke (IS), especially in recurrent patients. Several studies have demonstrated an intimate association between the genetic mutation of the KALRN gene and IS. The main aim of this study was to clarify the relationship between three single nucleotide polymorphisms (SNPs) of KALRN and ICAS in a northern Chinese population and further explore the underlining mechanism. The relationship between each SNP and ICAS and the related components were examined in five models (co-dominant, dominant, recessive, heterozygous, and additive). Multivariate logistic regression models were applied and adjusted for 10,000 permutation tests. Haplotype regression analysis was performed to determine the associations between haplotypes and the severity of ICAS. qRT-PCR was used to confirm the mRNA level of Kalirin. SNP rs6438833 of the Kalirin gene in the additive model was associated with ICAS (OR = 1.642, 95%CI: 1.129-2.388, PDom = 0.048). After performing 10,000 permutations, the result showed a trend toward statistical significance (Pper = 0.048). Haplotypes of the KALRN gene were not significantly associated with ICAS (global significance, p = 0.090). qRT-PCR showed that the expression of KALRN 9 in IS patients was almost threefold the control group (p < 0.0005). SNPs of the KALRN gene are associated with ICAS in the northern Chinese population.