The platinum (Pt) drugs cisplatin and carboplatin are heavily employed in chemotherapy regimens; however, similar to other classes of drugs, a number of intrinsic and acquired resistance mechanisms hamper their effectiveness. The method by which Pt drugs enter cells has traditionally been attributed to simple passive diffusion. However, recent evidence suggests a number of active uptake and efflux mechanisms are at play, and altered regulation of these transporters is responsible for the reduced accumulation of drug in resistant cells. This review suggests a model that helps reconcile the disparate literature by describing multiple pathways for Pt-containing drugs into and out of the cell.

Sensitivity and specificity are two most important factors to take into account for molecule sensing, chemical detection and disease diagnosis. A perfect sensitivity is to reach the level where a single molecule can be detected. An ideal specificity is to reach the level where the substance can be detected in the presence of many contaminants. The rapidly progressing nanopore technology is approaching this threshold. A wide assortment of biomotors and cellular pores in living organisms perform diverse biological functions. The elegant design of these transportation machineries has inspired the development of single molecule detection based on modulations of the individual current blockage events. The dynamic growth of nanotechnology and nanobiotechnology has stimulated rapid advances in the study of nanopore based instrumentation over the last decade, and inspired great interest in sensing of single molecules including ions, nucleotides, enantiomers, drugs, and polymers such as PEG, RNA, DNA, and polypeptides. This sensing technology has been extended to medical diagnostics and third generation high throughput DNA sequencing. This review covers current nanopore detection platforms including both biological pores and solid state counterparts. Several biological nanopores have been studied over the years, but this review will focus on the three best characterized systems including α-hemolysin and MspA, both containing a smaller channel for the detection of single-strand DNA, as well as bacteriophage phi29 DNA packaging motor connector that contains a larger channel for the passing of double stranded DNA. The advantage and disadvantage of each system are compared; their current and potential applications in nanomedicine, biotechnology, and nanotechnology are discussed.

This review, a sequel to part 1 in the series, collects about 107 chemical entities separated from the roots, leaves and flower buds of Panax ginseng, quinquefolius and notoginseng, and categorizes these entities into about 18 groups based on their structural similarity. The bioactivities of these chemical entities are described. The ‘Yin and Yang’ theory and the fundamentals of the ‘five elements’ applied to the traditional Chinese medicine (TCM) are concisely introduced to help readers understand how ginseng balances the dynamic equilibrium of human physiological processes from the TCM perspectives. This paper concerns the observation and experimental investigation of biological activities of ginseng used in the TCM of past and present cultures. The current biological findings of ginseng and its medical applications are narrated and critically discussed, including 1) its antihyperglycemic effect that may benefit type II diabetics; in vitro and in vivo studies demonstrated protection of ginseng on beta-cells and obese diabetic mouse models. The related clinical trial results are stated. 2) its aphrodisiac effect and cardiovascular effect that partially attribute to ginseng’s bioactivity on nitric oxide (NO); 3) its cognitive effect and neuropharmacological effect that are intensively tested in various rat models using purified ginsenosides and show a hope to treat Parkinson’s disease (PD); 4) its uses as an adjuvant or immunotherapeutic agent to enhance immune activity, appetite and life quality of cancer patients during their chemotherapy and radiation. Although the apoptotic effect of ginsenosides, especially Rh2, Rg3 and Compound K, on various tumor cells has been shown via different pathways, their clinical effectiveness remains to be tested. This paper also updates the antioxidant, anti-inflammatory, anti-apoptotic and immune-stimulatory activities of ginseng, its ingredients and commercial products, as well as common side effects of ginseng mainly due to its overdose, and its pharmacokinetics.

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A simple nanocarrier coated with chitosan and the pH-responsive charge-reversible polymer, PAH-Cit, was constructed using layer-by-layer assembly to deliver siRNA. Gold nanoparticles (AuNPs) were di-rectly reduced and stabilized by chitosan (CS), forming a positively charged AuNP-CS core. Charge-reversible PAH-Cit and polyethylenimine (PEI) were sequentially deposited onto the surface of AuNP-CS through electrostatic interaction, forming a PEI/PAH-Cit/AuNP-CS shell/core structure. After loading siRNA, the cytotoxicity of siRNA/PEI/PAH-Cit/AuNP-CS against HeLa and MCF-7R cells was negligible. This vehicle completely protected siRNA against enzymatic degradation at vector/RNA mass ratios of 2.5:1 and above. An in vitro release profile demonstrated an efficient siRNA release (79%) from siRNA/PEI/PAH-Cit/AuNP-CS at pH 5.5, suggesting a pH-induced charge-reversing action of PAH-Cit. This mechanism also worked in vivo and facilitated the escape of siRNA from endosomes. Using this carrier, the uptake of cy5-siRNA by HeLa cells was significantly increased compared to PEI, an efficient polycationic transfection reagent. In drug-resistant MCF-7 cells, specific gene silencing effectively reduced expression of MDR1, the gene encoding the drug exporter P-gp, and consequently promoted the uptake of doxorubicin. This simple charge-reversal polymer assembly nanosystem has three essential benefits (protection, efficient uptake, and facilitated escape) and provides a safe strategy with good biocompatibility for enhanced siRNA delivery and silencing.

New strategies with high antimicrobial efficacy against multidrug-resistant bacteria are urgently desired. Herein, we describe a smart triple-functional nanostructure, namely TRIDENT (Thermo-Responsive-Inspired Drug-Delivery Nano-Transporter), for reliable bacterial eradication. The robust antibacterial effectiveness is attributed to the integrated fluorescence monitoring and synergistic chemo-photothermal killing. We notice that temperature rises generated by near-infrared irradiation did not only melt the nanotransporter via a phase change mechanism, but also irreversibly damaged bacterial membranes to facilitate imipenem permeation, thus interfering with cell wall biosynthesis and eventually leading to rapid bacterial death. Both in vitro and in vivo evidence demonstrate that even low doses of imipenem-encapsulated TRIDENT could eradicate clinical methicillin-resistant Staphylococcus aureus, whereas imipenem alone had limited effect. Due to rapid recovery of infected sites and good biosafety we envision a universal antimicrobial platform to fight against multidrug-resistant or extremely drug-resistant bacteria.

Rheumatoid arthritis (RA) is one of the most common chronic autoimmune diseases. Despite considerable advances in clinical treatment of RA, suboptimal response to therapy and treatment discontinuation are still unresolved challenges due to systemic toxicity. It is of crucial importance to actively target and deliver therapeutic agents to inflamed joints in order to promote in situ activity and decrease systemic toxicity. In this study, we found that SPARC (secreted protein acidic and rich in cysteine) was overexpressed in the synovial fluid and synovium of RA patients as well as mice with collagen-induced arthritis (CIA), which has been scarcely reported. Building upon the SPARC signature of RA joint microenvironment and the intrinsic high affinity of SPARC for albumin, we fabricated methotrexate-loaded human serum albumin nanomedicines (MTX@HSA NMs) and explored them as biomimetic drug delivery systems for RA therapy. Upon intravenous injection of chlorin e6-labeled MTX@HSA NMs into CIA mice, the fluorescence/magnetic resonance dual-modal imaging revealed higher accumulations and longer retention of MTX@HSA NMs in inflamed joints with respect to free MTX molecules. In vivo therapeutic evaluations suggested that the MTX@HSA NMs were able to attenuate the progression of RA with better efficacy and fewer side effects even at half  dose of administrated MTX in comparison with free MTX. By unraveling the mechanism driving the efficient accumulation of MTX@HSA NMs in RA joints and showing their ability to improve the safety and therapeutic efficacy of MTX, our work sheds light on the development of innovative anti-RA nanomedicines with a strong potential for clinical translation.