This study develops novel pH and reduction dual-sensitive micelles for the anticancer drug doxorubicin (DOX) delivery owing to the fact that the tumor tissues show low pH and high reduction environment. These sub-100 nm micelles present a core-shell structure under physiological conditions, but quickly release the loaded drugs responding to acidic and reductive stimuli. With disulfide bonds in each repeat unit of poly(β-amino ester)s, the novel copolymer was synthesized via Michael addition polymerization from 2,2'-dithiodiethanol diacrylate, 4,4'-trimethylene dipiperidine, and methoxy-PEG-NH(2). DOX released faster from micelles in a weakly acidic environment (pH 6.5) than at pH 7.4 or in the presence of a higher concentration (5 mM) of reducing agent (DTT). The release is even more effective in a scenario of both stimuli (pH 6.5 and 5 mM DTT). MTT assay showed that the DOX-loaded micelles had a higher cytotoxicity for HepG2 tumor cells than DOX at higher concentrations, and that blank micelles had a very low cytotoxicity to the tumor cells. Confocal microscopy observation showed that the micelles can be quickly internalized, effectively deliver the drugs into nuclei, and inhibit cell growth. These results present the copolymer as a novel and effective pH and reduction dual-responsive nanocarrier to enhance drug efficacy for cancer cells.

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Recently, carbon nanotubes together with other types of conductive materials have been used to enhance the viability and function of cardiomyocytes in vitro. Here we demonstrated a paradigm to construct ECTs for cardiac repair using conductive nanomaterials. Single walled carbon nanotubes (SWNTs) were incorporated into gelatin hydrogel scaffolds to construct three-dimensional ECTs. We found that SWNTs could provide cellular microenvironment in vitro favorable for cardiac contraction and the expression of electrochemical associated proteins. Upon implantation into the infarct hearts in rats, ECTs structurally integrated with the host myocardium, with different types of cells observed to mutually invade into implants and host tissues. The functional measurements showed that SWNTs were essential to improve the performance of ECTs in inhibiting pathological deterioration of myocardium. This work suggested that conductive nanomaterials hold therapeutic potential in engineering cardiac tissues to repair myocardial infarction.

A series of reducible hyperbranched poly(amido amine)s (RHB) with high transfection efficiency were designed and synthesized as non-viral gene delivery vectors. The polycations were synthesized by Michael addition copolymerization of N,N-dimethylaminodipropylenetriamine (DMDPTA) and two bisacrylamide monomers N,N′-hexamethylene bisacrylamide (HMBA) and N,N′-cystamine bisacrylamide (CBA). The density of disulfide linkages in the synthesized hyperbranched polymers was tuned by varying the feed molar ratio of the bisacrylamide monomers. The results demonstrate that disulfide content in RHB controls the molecular weight of the polycation degradation products, ease of polyplex disassembly, polycation cytotoxicity, and polyplex transfection activity. Due to their lower cytotoxicity, polyplexes based on reducible polycations could be used safely in a wider range of DNA doses than non-reducible controls. As a result, significantly increased transfection activity is achieved with optimized formulations of reducible polyplexes compared with non-reducible controls.

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Nanocarriers-derived anticancer therapeutics typically suffers from poor tumor penetration and suboptimal antitumor efficacy. Although PEGylation improves the stability of nanoparticles and prolongs drug circulation, it further increases the size of nanoparticles and adversely affects the tumor penetration. Here, we developed a light-triggered PEGylation/dePEGylation strategy, whereby near-infrared (NIR)-/pH-dual responsive dePEGylation activates iRGD for tumor targeting. The embedded up-conversion nanoparticles (UCNPs) could efficiently convert NIR to UV−vis which cleaved the linker to remove PEG. NIR-induced dePEGylation remarkably improved vascular extravasation of drugs and deep tumor penetration. Therefore, the stimuli-responsive nanocarriers facilitated the tumor-targeted delivery of drugs through blood circulation and enhanced the antitumor effects.

As a key regulator of cell metabolism and survival, mechanistic target of rapamycin (mTOR) emerges as a novel therapeutic target for Parkinson's disease (PD). A growing body of research indicates that restoring perturbed mTOR signaling in PD models can prevent neuronal cell death. Nevertheless, molecular mechanisms underlying mTOR-mediated effects in PD have not been fully understood yet. Here, we review recent progress in characterizing the association of mTOR signaling with PD risk factors and further discuss the potential roles of mTOR in PD.

Cross-linked polymeric micelles have gained increasing research interest in the past decade due to the instability of existing polymeric micelles when used in vivo. In this study, we reported a series of covalently cross-linked pH-sensitive biodegradable micelles based on the poly(ethylene glycol)-hyperbranched poly(β-aminoester)s with acrylate group terminals (PEG-HBPAE-A) copolymers for intracellular delivery of doxorubicin (DOX). PEG-HBPAE-A can be self-assembled to form micellar nanoparticles in aqueous solution with diameters of approximately 160 nm. The non-cross-linked micelles (NCLMs) were cross-linked upon UV irradiation to form cross-linked micelles (CLMs). (1)H NMR, FT-IR and dynamic light scattering (DLS) were utilized to investigate the process of the UV cross-linking and the stability of CLMs. The results showed the significantly enhanced stability for CLMs in comparison to NCLMs. pH sensitivity of CLMs and NCLMs were also estimated by DLS. In vitro drug release studies confirmed that DOX release from DOX-loaded CLMs was greatly inhibited upon the neutral pH environment, whereas DOX underwent faster release in acidic conditions. MTT assays showed that DOX-loaded micelles had a similar inhibition rate for HepG-2 and MCF-7 cell lines compared with free DOX, whereas the blank CLMs and NCLMs showed very low cytotoxicity. Laser scanning confocal microscopy and real-time in situ fluorescence microscopy were exploited to investigate drug uptake in cells and drug distribution in the interior of cells. These results showed a promising nanocarrier for intracellular DOX delivery with great potential for cancer therapy.