Apoptosis induction by siRNA targeting integrin-ß1 and regorafenib/DDAB-mPEG-PCL hybrid nanoparticles in regorafenib-resistant colon cancer cells.

Colorectal cancer (CRC) is regarded as the third most common cancer worldwide. Although Regorafenib as a receptor tyrosine kinase inhibitor (RTKI) disrupts tumor growth and angiogenesis in metastatic CRC (mCRC) patients, drug resistance leads to poor prognosis and survival. Integrin-ß1 overexpression has been proposed to be the major player in this regard. Herein, the Regorafenib-resistant human colon cancer cell line (SW-48) was induced, and the Integrin-ß1 gene expression, as well as apoptosis, was assessed through the combination of small interfering RNA (siRNA) targeting Integrin-ß1 and Regorafenib/Dimethyldioctadecylammonium bromide (DDAB)-methoxy poly (ethylene glycol) (mPEG)-poly-ε-caprolactone (PCL) hybrid nanoparticles (HNPs). In the current study, Regorafenib-resistant SW-48 cell line was generated in which the Regorafenib half-maximal inhibitory concentration (IC50) for non-resistant and resistant cells was 13.5±1.5 µM and 55.1±0.8 µM, respectively. The results of DLS also demonstrated that the size and the charge of the HNPs were equal to 66.56±0.5 nm and +29.5±1.2 mv, respectively. In addition, the Integrin-ß1 gene expression was significantly higher in resistant cells than in non-resistant ones (P<0.05). The siRNA/HNP complexes in combination with Regorafenib/HNPs were accordingly identified as the most effective treatment to decrease the Integrin-ß1 gene expression and to enhance the apoptosis rate in resistant cells (P<0.001). Overall, the study indicated that combination therapy using siRNA/HNP and Regorafenib/HNPs complex could down-regulate the Integrin-ß1 gene expression and consequently trigger apoptosis, and this may potentially induce drug sensitivity.

Multidirectional Strategies for Targeted Delivery of Oncolytic Viruses by Tumor Infiltrating Immune Cells.

Oncolytic virus (OV) immunotherapy has demonstrated to be a promising approach in cancer treatment due to tumor-specific oncolysis. However, their clinical use so far has been largely limited due to the lack of suitable delivery strategies with high efficacy. Direct 'intratumoral' injection is the way to cross the hurdles of systemic toxicity, while providing local effects. Progress in this field has enabled the development of alternative way using 'systemic' oncolytic virotherapy for producing better results. One major potential roadblock to systemic OV delivery is the low virus persistence in the face of hostile immune system. The delivery challenge is even greater when attempting to target the oncolytic viruses into the entire tumor mass, where not all tumor cells are equally exposed to exactly the same microenvironment. The microenvironment of many tumors is known to be massively infiltrated with various types of leucocytes in both primary and metastatic sites. Interestingly, this intratumoral immune cell heterogeneity exhibits a degree of organized distribution inside the tumor bed as evidenced, for example, by the hypoxic tumor microenviroment where predominantly recruits tumor-associated macrophages. Although in vivo OV delivery seems complicated and challenging, recent results are encouraging for decreasing the limitations of systemically administered oncolytic viruses and an improved efficiency of oncolytic viral therapy in targeting cancerous tissues in vitro. Here, we review the latest developments of carrier cell-based oncolytic virus delivery using tumor-infiltrating immune cells with a focus on the main features of each cellular vehicle.

Vaccine development and therapeutic design for 2019-nCoV/SARS-CoV-2: Challenges and chances.

The ongoing outbreak of the recently emerged 2019 novel coronavirus (nCoV), which has seriously threatened global health security, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with high morbidity and mortality. Despite the burden of the disease worldwide, still, no licensed vaccine or any specific drug against 2019-nCoV is available. Data from several countries show that few repurposed drugs using existing antiviral drugs have not (so far) been satisfactory and more recently were proven to be even highly toxic. These findings underline an urgent need for preventative and therapeutic interventions designed to target specific aspects of 2019-nCoV. Again the major factor in this urgency is that the process of data acquisition by physical experiment is time-consuming and expensive to obtain. Scientific simulations and more in-depth data analysis permit to validate or refute drug repurposing opportunities predicted via target similarity profiling to speed up the development of a new more effective anti-2019-nCoV therapy especially where in vitro and/or in vivo data are not yet available. In addition, several research programs are being developed, aiming at the exploration of vaccines to prevent and treat the 2019-nCoV. Computational-based technology has given us the tools to explore and identify potentially effective drug and/or vaccine candidates which can effectively shorten the time and reduce the operating cost. The aim of the present review is to address the available information on molecular determinants in disease pathobiology modules and define the computational approaches employed in systematic drug repositioning and vaccine development settings for SARS-CoV-2.