Targeting TNFα Ameliorated Cationic PAMAM Dendrimer-Induced Hepatotoxicity via Regulating NLRP3 Inflammasomes Pathway

Hepatotoxicity of cationic poly amidoamine (PAMAM) dendrimers is one of the most urgent challenges to their medicinal application. Recent studies have indicated that proinflammatory cytokines were critical in nanomaterials-induced toxicity. However, little is known about the roles and underlying regulatory mechanisms of proinflammatory cytokines in cationic PAMAM dendrimer-induced hepatotoxicity. Thus, the aim of the current study was to explore the role of proinflammatory cytokine tumor necrosis factor alpha (TNFα) in cationic PAMAM dendrimer-induced liver injury and its underlying mechanism and develop novel strategies to reduce hepatotoxicity of cationic PAMAM dendrimers through regulating TNFα. In this study, we verified the significant overexpression of TNFα in cationic PAMAM dendrimer-induced hepatotoxicity in mice and found that targeting TNFα by etanercept could protect against cationic PAMAM dendrimer-induced liver injury. Interestingly, etanercept suppressed cationic PAMAM dendrimer-induced inflammasome signaling as demonstrated by reduced activation of NALP3, cleavage of Caspase-1, and maturation of interleukin (IL)-1β. Moreover, suppression of NLRP3 inflammasomes by belnacasan could also protect against cationic PAMAM dendrimer-induced hepatotoxicity and TNFα-induced acute hepatotoxicity. Notably, targeting either TNFα or inflammasomes reduced autophagy activation in hepatotoxicity triggered by cationic PAMAM dendrimers. In general, these findings revealed that targeting TNFα could ameliorate cationic PAMAM dendrimer-induced hepatotoxicity via regulating NLRP3 inflammasome pathway, underscoring that TNFα antagonism by etanercept could be used as an effective pharmacological approach to control hepatotoxicity of cationic PAMAM dendrimers and thus providing novel therapeutic strategies for managing liver toxicity of nanomaterials via regulating inflammatory mediators

Stapled RGD Peptide Enables Glioma-Targeted Drug Delivery by Overcoming Multiple Barriers

Malignant glioma, the most frequent and aggressive central nervous system (CNS) tumor, severely threatens human health. One reason for its poor prognosis and short survival is the presence of the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB), which restrict the penetration of therapeutics into the brain at different stages of glioma. Herein, inspired by the peptide stapling technique, we designed a cyclic RGD ligand via an all-hydrocarbon staple (stapled RGD, sRGD) to facilitate BBB penetration while retaining the capacity of BBTB penetration and targeting ability to glioma cells. As expected, sRGD-modified micelles were able to penetrate the in vitro BBB model while retaining the glioma targeted capability. The results of the in vivo imaging studies further revealed that this nanocarrier could not only efficiently transverse the intact BBB of normal mice, but also could specifically target glioma cells of intracranial glioma-bearing nude mice. Furthermore, Paclitaxel-loaded sRGD-modified micelles exhibited improved antiglioma efficacy in vitro and significantly prolonged survival time of glioma-bearing nude mice. Overall, this sRGD peptide showed potency for glioma-targeted drug delivery by overcoming multiple barriers