Exosomes are naturally occurring membranous vesicles secreted by various types of cells. Given their unique and important biological and pharmacological properties, exosomes have been emerging as a promising form of nanomedicine acting via efficient delivery of endogenous and exogenous therapeutics. Here we explore a new concept of utilizing endogenously derived exosomes as artificial controllers of cellular immunity to redirect and activate cytotoxic T cells toward cancer cells for killing. This was achieved through genetically displaying two distinct types of antibodies on exosomal surface. The resulting synthetic multivalent antibodies retargeted exosomes (SMART-Exos), which express monoclonal antibodies specific for T-cell CD3 and cancer cell-associated epidermal growth factor receptor (EGFR), were shown to not only induce cross-linking of T cells and EGFR-expressing breast cancer cells but also elicit potent antitumor immunity both in vitro and in vivo. This proof-of-concept study demonstrates a novel application of exosomes in cancer immunotherapy and may provide a general and versatile approach for the development of a new class of cell-free therapy.
Asplatin, a fusion of aspirin and cisplatin, exhibits significant cytotoxicity in tumor cells and almost fully overcomes the drug resistance of cisplatin resistant cells. Asplatin is highly accumulated in cancer cells and is activated upon the reduction by ascorbic acid.
Nicotinamide adenine dinucleotide (NAD+)-dependent ADP-ribosylation plays important roles in physiology and pathophysiology. It has been challenging to study this key type of enzymatic post-translational modification in particular for protein poly-ADP-ribosylation (PARylation). Here we explore chemical and chemoenzymatic synthesis of NAD+ analogues with ribose functionalized by terminal alkyne and azido groups. Our results demonstrate that azido substitution at 3′-OH of nicotinamide riboside enables enzymatic synthesis of an NAD+ analogue with high efficiency and yields. Notably, the generated 3′-azido NAD+ exhibits unexpected high activity and specificity for protein PARylation catalyzed by human poly-ADP-ribose polymerase 1 (PARP1) and PARP2. And its derived poly-ADP-ribose polymers show increased resistance to human poly(ADP-ribose) glycohydrolase-mediated degradation. These unique properties lead to enhanced labeling of protein PARylation by 3′-azido NAD+ in the cellular contexts and facilitate direct visualization and labeling of mitochondrial protein PARylation. The 3′-azido NAD+ provides an important tool for studying cellular PARylation.
Platinum-based anticancer drugs play a central role in current cancer therapy. However, their applicability and efficacy are limited by drug resistance and adverse effects. Nanocarrier-based platinum drug delivery systems are promising alternatives to circumvent the disadvantages of bare platinum drugs. The various properties of nanoparticle chemistry allow for the trend toward multiple functionality. Nanoparticles preferentially accumulate at the tumor site through passive targeting, and the attachment of tumor targeting moieties further enhances their tumor-specific localization as well as tumor cell uptake. The introduction of stimuli-responsive groups into drug delivery systems can further achieve spatially and temporally controlled drug release in response to specific stimuli. Combination therapy strategies have been used to promote synergetic efficacy and overcome the resistance of platinum drugs. The tumor-localized drug delivery strategies exhibit benefits for preventing local tumor recurrence. In addition, the combination of platinum drugs and imaging agents in one unity allows the cancer diagnostics for real-time monitoring the distribution of drug-loaded nanoparticles inside the body and tumor. This review discusses recent scientific advances in multifunctional nanoparticle formulations of platinum drugs, and these designs exhibit new potential of multifunctional nanoparticles for delivering platinum-based anticancer drugs. WIREs Nanomed Nanobiotechnol 2017, 9:e1410. doi: 10.1002/wnan.1410 For further resources related to this article, please visit the WIREs website.
Self-assembled cholesterol-asplatin-incorporated nanoparticles (SCANs) were prepared for oral delivery of a Pt(IV) prodrug. SCANs exhibit high gastrointestinal stability, sustained drug release and enhanced cell uptake. The oral bioavailability of SCANs was 4.32-fold higher than that of free Pt(IV) prodrugs. The oral administration of SCANs efficaciously inhibits tumor growth with negligible toxicity.
Aspirin, a widely used anti-inflammatory drug, has been shown to be effective for the prevention and remission of cancers (Science, 2012, 337(21) 1471-1473). Asplatin, a Pt(iv) prodrug of cisplatin with the ligation of aspirin (c,c,t-[PtCl2(NH3)2(OH)(aspirin)]), demonstrates significantly higher cytotoxicity than cisplatin towards tumor cells and almost fully overcomes the drug resistance of cisplatin resistant cells. In this work, we have studied the molecular mechanism of asplatin by investigating the cellular response to this compound in order to understand the prominent inhibitory effect on the proliferation of cancer cells. The apoptosis analyses and the related gene expression measurements show that aspirin released from asplatin significantly modulates the cellular response to the platinum agent. Asplatin promotes the apoptosis via the BCL-2 associated mitochondrial pathway. The down-regulation of BCL-2 along with the up-regulation of BAX and BAK enhances the mitochondrial outer membrane permeability, resulting in the cytochrome c release from mitochondria into the cytosol. This event promotes the apoptosis by activation of caspase processing. Consequently, the ligation of aspirin significantly enhances the drug efficacy of the platinum complex in the low micromolar range. The alteration of the cellular response is probably responsible for the circumvention of the cisplatin resistance by asplatin. These results provide an insight into the mechanism of asplatin and provide information for designing new classic platinum drugs.
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