Cancer treatment that uses a combination of approaches with the ability to affect multiple disease pathways has been proven highly effective in the treatment of many cancers. Combination therapy can include multiple chemotherapeutics or combinations of chemotherapeutics with other treatment modalities like surgery or radiation. However, despite the widespread clinical use of combination therapies, relatively little attention has been given to the potential of modern nanocarrier delivery methods, like liposomes, micelles, and nanoparticles, to enhance the efficacy of combination treatments. This lack of knowledge is particularly notable in the limited success of vectors for the delivery of combinations of nucleic acids with traditional small molecule drugs. The delivery of drug-nucleic acid combinations is particularly challenging due to differences in the physicochemical properties of the two types of agents. This review discusses recent advances in the development of delivery methods using combinations of small molecule drugs and nucleic acid therapeutics to treat cancer. This review primarily focuses on the rationale used for selecting appropriate drug-nucleic acid combinations as well as progress in the development of nanocarriers suitable for simultaneous delivery of drug-nucleic acid combinations.

Redox-responsive polyplexes represent a promising class of non-viral gene delivery vectors. The reducible disulfide bonds in the polyplexes undergo intracellular reduction owing to the presence of high concentrations of reduced glutathione (GSH). Available evidence suggests improved transfection activity of redox-sensitive polyplexes upon artificial modulation of intracellular GSH. This study investigates the effect of innate differences in GSH concentration in a panel of human pancreatic cancer cell lines on activity of reducible polyplexes of the four major classes of nucleic acid therapeutics: plasmid DNA (pDNA), messenger RNA (mRNA), antisense oligodeoxynucleotides (AON) and siRNA. In general, reducible polyplexes of linear poly(amido amines) (PAA) show improved activity compared to non-reducible polyplexes of PAA. Results demonstrate that increased GSH levels are associated with improved transfection of mRNA polyplexes but no clear trend is observed for pDNA, AON and siRNA polyplexes.

A bicyclam-based biodegradable polycation with CXCR4 antagonistic activity was developed with potential for combined drug/gene cancer therapies. The dual-function polycation prevents cancer cell invasion by inhibiting CXCL12 stimulated CXCR4 activation, while at the same time efficiently and safely delivers plasmid DNA into cancer cells.

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STAT6 participates in classical IL-4/IL-13 signaling and stimulator of interferon genes-mediated antiviral innate immune responses. Aberrations in STAT6-mediated signaling are linked to development of asthma and diseases of the immune system. In addition, STAT6 remains constitutively active in multiple types of cancer. Therefore, targeting STAT6 is an attractive proposition for treating related diseases. Although a lot is known about the role of STAT6 in transcriptional regulation, molecular details on how STAT6 recognizes and binds specific segments of DNA to exert its function are not clearly understood. Here, we report the crystal structures of a homodimer of phosphorylated STAT6 core fragment (STAT6 CF ) alone and bound with the N3 and N4 DNA binding site. Analysis of the structures reveals that STAT6 undergoes a dramatic conformational change on DNA binding, which was further validated by performing molecular dynamics simulation studies and small angle X-ray scattering analysis. Our data show that a larger angle at the intersection where the two protomers of STAT meet and the presence of a unique residue, H415, in the DNAbinding domain play important roles in discrimination of the N4 site DNA from the N3 site by STAT6. H415N mutation of STAT6 CF decreased affinity of the protein for the N4 site DNA, but increased its affinity for N3 site DNA, both in vitro and in vivo. Results of our structure-function studies on STAT6 shed light on mechanism of DNA recognition by STATs in general and explain the reasons underlying STAT6's preference for N4 site DNA over N3.STAT6 | N4 site DNA recognition | JAK-STAT pathway | antiviral innate immunity | crystal structure P roteins belonging to the STAT family mediate transmission of signals of numerous cytokines and growth factors from the cell membrane to the nucleus via the classical JAK-STAT pathway (1). Malfunctions in this pathway are known to result in immune system disorder and cancers. Therefore, the JAK-STAT pathway is considered to be of great importance in the development of therapeutic interventions (2). The mammalian STAT family is made up of seven structurally and functionally related proteins named STAT1, 2, 3, 4, 5a, 5b, and 6 (3). All of the STAT proteins share a conserved domain organization (Fig. 1A).STAT6, an important member of the STAT family, plays a crucial role in the differentiation of Th2 cells and has been implicated in the development of asthma (4). This STAT is primarily stimulated by IL-4 and IL-13. A recent study reported that STAT6 plays a pivotal role in antiviral signaling initiated by host cells in response to viral infections (5). STAT6 could be activated by the stimulator of interferon genes/TBK1 cascade via phosphorylation of Y641. Intriguingly, residue S407 located in the DNA-binding domain (DBD) of STAT6 has been shown to be phosphorylated by TBK1. However, its implication for biological function of STAT6 is currently unknown (5). Thus, structural studies on STAT6 and its complex with DNA are essential to address several unanswered q...