Connexin and gap junctions: perspectives from biology to nanotechnology based therapeutics.

The concept of gap junctions and their role in intercellular communication has been known for around 50 years. Considerable progress has been made in understanding the fundamental biology of connexins in mediating gap junction intercellular communication (GJIC) and their role in various cellular processes including pathological conditions. However, this understanding has not led to development of advanced therapeutics utilizing GJIC. Inadequacies in strategies that target specific connexin protein in the affected tissue, with minimal or no collateral damage, are the primary reason for the lack of development of efficient therapeutic models. Herein, nanotechnology has a role to play, giving plenty of scope to circumvent these problems and develop more efficient connexin based therapeutics. AsODN, antisense oligodeoxynucleotides; BMPs, bone morphogenetic proteins; BMSCs, bone marrow stem cells; BG, bioglass; Cx, Connexin; CxRE, connexin-responsive elements; CoCr NPs, cobalt-chromium nanoparticles; cGAMP, cyclic guanosine monophosphate-adenosine monophosphate; cAMP, cyclic adenosine monophosphate; ERK1/2, extracellular signal-regulated kinase 1/2; EMT, epithelial-mesenchymal transition; EPA, eicosapentaenoic acids; FGFR1, fibroblast growth factor receptor 1; FRAP, fluorescence recovery after photobleaching; 5-FU, 5-fluorouracil; GJ, gap junction; GJIC, gap junctional intercellular communication; HGPRTase, hypoxanthine phosphoribosyltransferase; HSV-TK, herpes virus thymidine kinase; HSA, human serum albumin; HA, hyaluronic acid; HDAC, histone deacetylase; IRI, ischemia reperfusion injury; IL-6, interleukin-6; IL-8, interleukin-8; IONPs, iron-oxide nanoparticles; JNK, c-Jun N-terminal kinase; LAMP, local activation of molecular fluorescent probe; MSCs, mesenchymal stem cells; MMP, matrix metalloproteinase; MI, myocardial infarction; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; NO, nitric oxide; PKC, protein kinase C; QDs, quantum dots; ROI, region of interest; RGO, reduced graphene oxide; siRNA, small interfering RNA; TGF-ß1, transforming growth factor-ß1; TNF-α, tumor necrosis factor-α; UCN, upconversion nanoparticles; VEGF, vascular endothelial growth factor. In this review, we discuss briefly the role of connexins and gap junctions in various physiological and pathological processes, with special emphasis on cancer. We further discuss the application of nanotechnology and tissue engineering in developing treatments for various connexin based disorders.

Nanomedicine-based cancer immunotherapy: recent trends and future perspectives.

The combination of cancer immunotherapy with efficient functionalized nanosystems has emerged as a beneficial treatment strategy and its use has increased rapidly. The roles of stimuli-responsive nanosystems and nanomedicine-based cancer immunotherapy, a subsidiary discipline in the field of immunology, are pivotal. The present era is witnessing rapid advancements in the use of nanomedicine as a platform for investigating novel therapeutic applications and modern intelligent healthcare management strategies. The development of cancer nanomedicine has posthaste ratified the outcomes of immunotherapy to the subsequent stage in the current era of medical research. This review focuses on key findings with respect to the effectiveness of nanomedicine-based cancer immunotherapies and their applications, which include i) immune checkpoint inhibitors and nanomedicine, ii) CRISPR-Cas nanoparticles (NPs) in cancer immunotherapy, iii) combination cancer immunotherapy with core-shell nanoparticles, iv) biomimetic NPs for cancer immunotherapy, and v) CAR-T cells and cancer nanoimmunotherapy. By evaluating the state-of-the-art tools and taking the challenges involved into consideration, various aspects of the proposed nano-enabled therapeutic approaches have been discussed in this review.

Dual-emission copper nanoclusters-based ratiometric fluorescent probe for intracellular detection of hydroxyl and superoxide anion species.

A fluorescent nanoprobe based on copper nanoclusters (CuNCs) has been developed for ratiometric detection of hydroxyl radicals (•OH) and superoxide anion radicals (O2•-). Two differently luminescent CuNCs, namely cyan-emissive poly(methacrylic acid)-protected copper nanoclusters (PCuNCs) and orange-emissive bovine serum albumin-protected CuNCs (BCuNCs), were conjugated to obtain a hybrid, dual-emission nanoprobe (PCuNCs-BCuNCs) with the corresponding peaks at 445 nm and 652 nm at an excitation wavelength of 360 nm. In particular, the fluorescence peak at 445 nm gradually enhanced with the incremental addition of •OH and O2•-. However, the fluorescence emission at 652 nm was greatly quenched in the presence of •OH, while in case of O2•-, the fluorescence intensity remained constant. The differential response of the PCuNCs-BCuNCs towards •OH and O2•- formed the basis of ratiometric detection. Under optimal conditions, the PCuNCs-BCuNCs exhibited good sensitivity and linearity towards •OH and O2•- with limits of detection of 0.15 µM and 1.8 µM, respectively. Moreover, the nanoprobe exhibited high selectivity for •OH and O2•- over other potential ROS interferences. Besides, PCuNCs-BCuNCs were eventually applied for qualitative and quantitative ratiometric assessment of intracellular •OH and O2•- in L-132 cells. Therefore, this strategy unveils a new potential for copper nanocluster-based sensing of ROS.

Four electrode-based impedimetric biosensors for evaluating cytotoxicity of tamoxifen on cervical cancer cells.

In the current study, novel four electrode-based impedimetric biosensors have been fabricated using photolithography techniques and utilized to evaluate the cytotoxicity of tamoxifen on cervical cancer cell lines. The cell impedance was measured employing the electric cell-substrate impedance sensing (ECIS) method over the frequency range of 100 Hz to 1 MHz. The results obtained from impedimetric biosensors indicate that tamoxifen caused a significant reduction in the number of HeLa cells on the electrode surfaces in a dose-dependent manner. Next, the impedance values recorded by the fabricated biosensors have been compared with the results obtained from the different conventional techniques such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), live-dead cell assay, and flow cytometric analysis to estimate the cytotoxicity of tamoxifen. The impedimetric cytotoxicity of tamoxifen over the growth and proliferation of HeLa cells correlates well with the traditional methods. In addition, the IC50 values obtained from impedimetric data and MTT assay are comparable, signifying that the ECIS technique can be an alternative method to assess the cytotoxicity of different novel drugs. The working principle of the biosensor has been examined by scanning electron microscopy, indicating the detachment of cells from gold surfaces in a dose-dependent manner, signifying the decrease in impedance at higher drug doses.