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A doxorubicin (Dox) and curcumin (Cur) combination treatment regimen has been widely studied in pre-clinical research. However, the nanoparticles developed for this combination therapy require a consecutive drug loading process because of the different water-solubility of these drugs. The present study provides a strategy for the 'one-step' formation of nanoparticles encapsulating both Dox and Cur. We took advantage of polyacrylic acid (PAA) and calcium carbonate (CaCO 3 ) to realise a high drug entrapment efficiency and pH-sensitive drug release using a simplified preparation method. Optimisation of lipid ratios and concentrations of CaCO 3 was conducted. Under optimal conditions, the mean diameter of PEGylated lipid/PAA/CaCO 3 nanoparticles with encapsulated Cur and Dox (LPCCD) was less than 100 nm. An obvious pH-sensitive release of both drugs was observed, with different Dox and Cur release rates. Successful codelivery of Cur and Dox was achieved via LPCCD on HepG2 cells. LPCCD altered the bio-distribution of Dox and Cur in vivo and decreased Dox-induced cardiotoxicity. The current investigation has developed an efficient ternary system for co-delivery of Dox and Cur to tumours, using a 'one-step' formation resulting in nanoparticles possessing remarkable pH-sensitive drug release behaviour, which may be valuable for further clinical studies and eventual clinical application.

Abstract:The present treatments for HIV transfection include chemical agents and gene therapies. Although many chemical drugs, peptides and genes have been developed for HIV inhibition, a variety of non-ignorable drawbacks limited the efficiency of these materials. In this review, we discuss the application of dendrimers as both therapeutic agents and non-viral vectors of chemical agents and genes for HIV treatment. On the one hand, dendrimers with functional end groups combine with the gp120 of HIV and CD4 molecule of host cell to suppress the attachment of HIV to the host cell. Some of the dendrimers are capable of intruding into the cell and interfere with the later stages of HIV replication as well. On the other hand, dendrimers are also able to transfer chemical drugs and genes into the host cells, which conspicuously increase the anti-HIV activity of these materials. Dendrimers as therapeutic tools provide a potential treatment for HIV infection.

BackgroundEndoplasmic reticulum (ER) stress-mediated phenotypic switching of vascular smooth muscle cells (VSMCs) is key to vascular calci cation (VC) in patients with chronic kidney disease (CKD). Terpinen-4-ol exerts protective effect against cardiovascular disease, but its role and speci c mechanism in VC remain unclear. We explored whether terpinen-4-ol alleviates ER stress-mediated VC through sirtuin 1 (sirt1) and elucidated its mechanism to provide evidence for its application in the clinical prevention and treatment of VC. MethodsIn this study, CKD-related VC animal model and β-glycerophosphate (β-GP)-induced VSMCs calci cation model were established. We investigated the part of terpinen-4-ol in ER stress-induced VC in vitro and in vivo. However, in order to clarify whether terpinen-4-ol inhibits the molecular mechanism of ERs-induced VC through sirt1, we further veri ed the above signal transduction by knocking down sirt1 in vitro and in vivo. ResultsTerpinen-4-ol inhibited calcium deposition, phenotypic switching, and ER stress of VSMCs in vitro and in vivo. Furthermore, pre-incubation with terpinen-4-ol or a sirt1 agonist and transfection with lentivirus overexpressing sirt1 decreased β-GP-induced calcium salt deposition, increased sirt1 protein level, and inhibited PERK-eIF2α-ATF4 pathway activation in VSMCs, thus, alleviating VC. The opposite results were obtained in sirt1-knockdown models. Moreover, sirt1 physically interacted with and deacetylated PERK.Mass spectrometry analysis identi ed lysine K889 as the acetylation site of sirt1, which regulates PERK.Finally, inhibition of sirt1 reduced the effect of terpinen-4-ol on the deacetylation of PERK in vitro and in vivo and weakened the inhibitory effect of terpinen-4-ol against ER stress-mediated VC. ConclusionsTerpinen-4-ol inhibits the post-transcriptional modi cation of PERK at the lysine K889 acetylation site by upregulating sirt1 expression level, thereby ameliorating VC by regulating ER stress. This provides evidence of the molecular mechanism of terpinen-4-ol, which supports its development as a promising therapeutic agent for CKD-VC.