Physicochemical Stimulus-Responsive Systems Targeted with Antibody Derivatives.

The application of monoclonal antibodies and antibody fragments with the advent of recombinant antibody technology has made notable progress in clinical trials to provide a regulated drug release and extra targeting to the special conditions in the function site. Modification of antibodies has facilitated using mAbs and antibody fragments in numerous models of therapeutic and detection utilizations, such as stimuli-responsive systems. Antibodies and antibody derivatives conjugated with diverse stimuli-responsive materials have been constructed for drug delivery in response to a wide range of endogenous (electric, magnetic, light, radiation, ultrasound) and exogenous (temperature, pH, redox potential, enzymes) stimuli. In this report, we highlighted the recent progress on antibody-conjugated stimuli-responsive and dual/multi-responsive systems that affect modern medicine by improving a multitude of diagnostic and treatment strategies.

Exosomal delivery of 7SK long non-coding RNA suppresses viability, proliferation, aggressiveness and tumorigenicity in triple negative breast cancer cells.

AIMS: RN7SK (7SK), a highly conserved non-coding RNA, serves as a transcription regulator via interaction with a few proteins. Despite increasing evidences which support the cancer-promoting roles of 7SK-interacting proteins, limited reports address the direct link between 7SK and cancer. To test the hypothetic suppression of cancer by overexpression of 7SK, the effects of exosomal 7SK delivery on cancer phenotypes were studied. MATERIALS AND METHODS: Exosomes derived from human mesenchymal stem cells were loaded with 7SK (Exo-7SK). MDA-MB-231, triple negative breast cancer (TNBC), cell line was treated with Exo-7sk. Expression levels of 7SK were evaluated by qPCR. Cell viability was assessed via MTT and Annexin V/PI assays as well as qPCR assessment of apoptosis-regulating genes. Cell proliferation was evaluated by growth curve analysis, colony formation and cell cycle assays. Aggressiveness of TNBCs was evaluated via transwell migration and invasion assays and qPCR assessment of genes regulating epithelial to mesenchymal transition (EMT). Moreover, tumor formation ability was assessed using a nude mice xenograft model. KEY FINDINGS: Treatment of MDA-MB-231 cells with Exo-7SK resulted in efficient overexpression of 7SK; reduced viability; altered transcription levels of apoptosis-regulating genes; reduced proliferation; reduced migration and invasion; altered transcription of EMT-regulating genes; and reduced in vivo tumor formation ability. Finally, Exo-7SK reduced mRNA levels of HMGA1, a 7SK interacting protein with master gene regulatory and cancer promoting roles, and its bioinformatically-selected cancer promoting target genes. SIGNIFICANCE: Altogether, as a proof of the concept, our findings suggest that exosomal delivery of 7SK may suppress cancer phenotypes via downregulation of HMGA1.

RNAa-mediated epigenetic attenuation of the cell senescence via locus specific induction of endogenous SIRT1.

SIRT1, a known regulator of cellular senescence, is a therapeutic target for age related disorders and its upregulation is a strategy to improve the cell therapeutic potentials of human mesenchymal stem cell (MSCs). Knockdown of natural antisense transcripts via small activating RNAs (RNAa) is an emerging approach for safe and locus specific gene regulation. We have recently identified a natural antisense transcript at human SIRT1 locus (SIRT1-NAT), the expression of which shows a negative correlation with that of SIRT1. To test the hypothetic upregulation of SIRT1 via knockdown of SIRT1-NAT, in this study we designed a single stranded oligonucleotide (SIRT1-antagoNAT) against the antisense transcript, transfection of which efficiently knocked down the SIRT1-NAT and induced SIRT1 transcription in human MSCs. In addition, activation of SIRT1 transfection via knockdown of SIRT1-NAT in human MSCs enhanced their proliferation and differentiation potentials, reduced senescence associated ß-galactosidase activity and reversed the senescence associated molecular alterations. Our findings introduce an RNAa mediated approach for epigenetic induction of endogenous SIRT1 and the consequent attenuation of senescence. Further studies should evaluate the therapeutic potentials of this approach against various age related disorders.

Nonviral siRNA delivery systems for pancreatic cancer therapy.

The serious drawbacks of the conventional treatment of pancreatic ductal adenocarcinoma (PDAC) such as nonspecific toxicity and high resistance to chemo and radiation therapy, have prompted the development and application of countless small interfering RNA (siRNA)-based therapeutics. Recent advances in drug delivery systems hold great promise for improving siRNA-based therapeutics and developing a new class of drugs, known as nano-siRNA drugs. However, many fundamental questions, regarding toxicity, immunostimulation, and poor knowledge of nano-bio interactions, need to be addressed before clinical translation. In this review, we provide recent achievements in the design and development of various nonviral delivery vehicles for pancreatic cancer therapy. More importantly, codelivery of conventional anticancer drugs with siRNA as a new revolutionary pancreatic cancer combinational therapy is completely discussed.

Monocyclic Peptides: Types, Synthesis and Applications.

Peptides are considered to be appropriate tools in various biological fields. They can be primarily used for the rational design of bioactive molecules. They can act as ligands in the development of targeted therapeutics as well as diagnostics, can be used in the design of vaccines or can be employed in agriculture. Peptides can be classified in two broad structural classes: linear and cyclic peptides. Monocyclic peptides are a class of polypeptides with one macrocyclic ring that bears advantages, such as more selective binding and uptake by the target receptor, as well as higher potency and stability compared to linear types. This paper provides an overview of the categories, synthesis methods and various applications of cyclic peptides. The various applications of cyclic peptides include their use as pro-apoptotic and anti-microbial agents, their application as targeting ligands in drug delivery and diagnostic agents, as well as agricultural and therapeutics applications that are elaborated and discussed in this paper.

Coinhibition of S1PR1 and GP130 by siRNA-loaded alginate-conjugated trimethyl chitosan nanoparticles robustly blocks development of cancer cells.

There is an interconnected network between S1P/sphingosine-1-phosphate receptor 1 (S1PR1), IL-6/glycoprotein 130 (GP130), and signal transducer and activator of transcription 3 (STAT3) signaling pathways in the tumor microenvironment, which leads to cancer progression. S1P/S1PR1 and IL-6/GP130 signaling pathways phosphorylate and activate STAT3, and it then induces the expression of S1PR1 and interleukin-6 (IL-6) in a positive feedback loop leading to cancer progression. We hypothesized that blockade of this amplification loop can suppress the growth and development of cancer cells. Therefore, we silenced STAT3 upstream molecules including the S1PR1 and GP130 molecules in cancer cells using small interfering RNA (siRNA)-loaded alginate-conjugated trimethyl chitosan (ATMC) nanoparticles (NPs). The generated NPs had competent properties including the appropriate size, zeta potential, polydispersity index, morphology, high uptake of siRNA, high rate of capacity, high stability, and low toxicity. We evaluated the effects of siRNA loaded ATMC NPs on tumor hallmarks of three murine-derived cancer cell lines, including 4T1 (breast cancer), B16-F10 (melanoma), and CT26 (colon cancer). The results confirmed the tumor-suppressive effects of combinational targeting of S1PR1 and GP130. Moreover, combination therapy could potently suppress tumor growth as assessed by the chick chorioallantoic membrane assay. In this study, we targeted this positive feedback loop for the first time and applied this novel combination therapy, which provides a promising approach for cancer treatment. The development of a potent nanocarrier system with ATMC for this combination was also another aspect of this study, which should be further investigated in cancer animal models in further studies.

Nanomedicine for improvement of dendritic cell-based cancer immunotherapy.

Dendritic cell (DC)-based cancer immunotherapy has shown impressive outcomes, including the development of the first FDA-approved anti-cancer vaccine. However, the clinical application of DC-based cancer immunotherapy is associated with various challenges. Promising novel tools for the administration of cancer vaccines has emerged from recent developments in nanoscale biomaterials. One current strategy to enhance targeted drug delivery, while minimizing drug-related toxicities, is the use of nanoparticles (NPs). These can be utilized for antigen delivery into DCs, which have been shown to provide potent T cell-stimulating effects. Therefore, NP delivery represents one promising approach for creating an effective and stable immune response without toxic side effects. The current review surveys cancer immunotherapy with particular attention toward NP-based delivery methods that target DCs.

Codelivery of STAT3 siRNA and BV6 by carboxymethyl dextran trimethyl chitosan nanoparticles suppresses cancer cell progression.

High expression of inhibitor of apoptosis (IAP) molecules in cancer cells promotes cancer cell chemoresistance. Use of BV6, a well-known IAP inhibitor, along with inhibition of signal transducer and activator of transcription 3 (STAT3), which is an important factor in the survival of tumor cells, and NIK as a mediator of BV6 unpredicted side effects, can induce effective apoptosis in tumor cells. The present study has investigated the combination therapy of cancer cells using Carboxymethyl Dextran-conjugated trimethyl chitosan (TMC-CMD) nanoparticles (NPs) loaded with NIK/STAT3-specific siRNA and BV6 to synergistically induce apoptosis in the breast, colorectal and melanoma cancer cell lines. Our results showed that in addition to enhanced pro-apoptotic effects, this combination therapy reduced proliferation, cell migration, colony formation, and angiogenesis, along with expression of factors including IL-10 and HIF in tumor cells. The results indicate the potential of this combination therapy for further investigation in animal models of cancer.

Silencing of IL-6 and STAT3 by siRNA loaded hyaluronate-N,N,N-trimethyl chitosan nanoparticles potently reduces cancer cell progression.

The immunosuppressive nature of the tumor microenvironment is a critical problem that should be considered before the design of immunotherapies. Interleukin (IL)-6 and its related downstream molecules such as signal transducer and activator of transcription (STAT)3 play an important role in the cancer progression, which can be considered as potential therapeutic targets. In the present study, we generated the active-targeted hyaluronate (HA) recoated N, N, N-trimethyl chitosan (TMC) nanoparticles (NPs) to deliver IL-6- and STAT3-specific small interfering RNAs (siRNAs) to the CD44-expressing cancer cells. We utilized the interaction between HA and CD44 to increase the specificity and efficacy of cellular uptake in NPs. The results showed that the synthesized NPs had efficient physicochemical characteristics, high transfection efficiency, low toxicity, and controlled siRNA release. siRNA-loaded NPs significantly inhibited the IL-6/STAT3 expression, which was associated with blockade of proliferation, colony formation, migration, and angiogenesis in cancer cells. These findings imply the potential of HA-TMC NPs as potent vectors in gene therapy and their application for the silencing of IL-6 and STAT3, as a novel anti-cancer combination therapeutic strategy, for the first time.

Application of nanomedicine for crossing the blood-brain barrier: Theranostic opportunities in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease characterized with immunopathobiological events, including lymphocytic infiltration into the central nervous system (CNS), microglia activation, demyelination and axonal degeneration. Although several neuroprotective drugs have been designed for the treatment of MS, complete remission is yet matter of debate. Therefore, development of novel therapeutic approaches for MS is of a high priority in immunological research. Nanomedicine is a recently developed novel medical field, which is applicable in both diagnosis and treatment of several cancers and autoimmune diseases. Although there is a marked progress in neuroimaging through using nanoparticles, little is known regarding the therapeutic potential of nanomedicine in neurological disorders, particularly MS. Moreover, the majority of data is limited to the MS related animal models. In this review, we will discuss about the brain targeting potential of different nanoparticles as well as the role of nanomedicine in the diagnosis and treatment of MS and its animal model, experimental autoimmune encephalomyelitis.