Design and Development of Hybrid Hydrogels for Biomedical Applications: Recent Trends in Anticancer Drug Delivery and Tissue Engineering.

The applications of hydrogels in biomedical field has been since multiple decades. Discoveries in biology and chemistry render this platform endowed with much engineering potentials and growing continuously. Novel approaches in constructing these materials have led to the production of complex hybrid hydrogels systems that can incorporate both natural and synthetic polymers and other functional moieties for mediated cell response, tunable release kinetic profiles, thus they are used and research for diverse biomedical applications. Recent advancement in this field has established promising techniques for the development of biorelevant materials for construction of hybrid hydrogels with potential applications in the delivery of cancer therapeutics, drug discovery, and re-generative medicines. In this review, recent trends in advanced hybrid hydrogels systems incorporating nano/microstructures, their synthesis, and their potential applications in tissue engineering and anticancer drug delivery has been discussed. Examples of some new approaches including click reactions implementation, 3D printing, and photopatterning for the development of these materials has been briefly discussed. In addition, the application of biomolecules and motifs for desired outcomes, and tailoring of their transport and kinetic behavior for achieving desired outcomes in hybrid nanogels has also been reviewed.

Targeting Tumor Immunosuppressive Microenvironment for the Prevention of Hepatic Cancer: Applications of Traditional Chinese Medicines in Targeted Delivery.

Traditional Chinese Medicine (TCM) is one of the ancient and most accepted alternative medicinal systems in the world for the treatment of health ailments. World Health Organization recognizes TCM as one of the primary healthcare practices followed across the globe. TCM utilizes a holistic approach for the diagnosis and treatment of cancers. The tumor microenvironment (TME) surrounds cancer cells and plays pivotal roles in tumor development, growth, progression, and therapy resistance. TME is a hypoxic and acidic environment that includes immune cells, pericytes, fibroblasts, endothelial cells, various cytokines, growth factors, and extracellular matrix components. Targeting TME using targeted drug delivery and nanoparticles is an attractive strategy for the treatment of solid tumors and recently has received significant research attention under precise medicine concept. TME plays a pivotal role in the overall survival and metastasis of a tumor by stimulating cell proliferation, preventing the tumor clearance by the immune cells, enhancing the oncogenic potential of the cancer cells, and promoting tumor invasion. Hepatocellular Carcinoma (HCC) is one of the major causes of cancer-associated deaths affecting millions of individuals worldwide each year. TCM herbs contain several bioactive phytoconstituents with a broad range of biological, physiological, and immunological effects on the system. Several TCM herbs and their monomers have shown inhibitory effects in HCC by controlling the TME. This study reviews the fundamentals and applications of targeting strategies for immunosuppressing TME to treat cancers. This study focuses on TME targeting strategies using TCM herbs and the molecular mechanisms of several TCM herbs and their monomers on controlling TME.

Surface Engineered Metal-Organic Frameworks (MOFs) Based Novel Hybrid Systems for Effective Wound Healing: A Review of Recent Developments.

Wounds present serious medical complications and their healing requires strategies that promote angiogenesis, deposition of collagen as well as re-epithelialization of wounds. Currently used conventional wound healing strategies have become less effective due to various issues associated with them. Thus, novel strategies are needed to be developed for early and effective healing of wounds. Metal-organic frameworks (MOFs), formed by linking of metal ions through organic bridging ligands, are highly tunable hybrid materials and have attracted more considerable scientific attention due to their charming and prominent properties, such as abundant pore structures and multiple functionalities. Surface engineering of MOFs with unique ligands can overcome issues associated with conventional wound healing methods, thus resulting in early and effective wound healing. This review has been undertaken to elaborate wound healing, and the use of surface engineered MOFs for effective and rapid wound healing. The process of wound healing will be discussed followed by a detailed review of recent literature for summarizing applications of surface engineered MOFs for wound healing. MOFs wound healing will be discussed in terms of their use as antibacterial agents, therapeutic delivery vehicles, and dressing systems in wound healing.

Recent Advances in Biomaterials for the Treatment of Bone Defects.

Bone defects or fractures generally heal in the absence of major interventions due to the high regenerative capacity of bone tissue. However, in situations of severe/large bone defects, these orchestrated regeneration mechanisms are impaired. With advances in modern medicine, natural and synthetic bio-scaffolds from bioceramics and polymers that support bone growth have emerged and gained intense research interest. In particular, scaffolds that recapitulate the molecular cues of extracellular signals, particularly growth factors, offer potential as therapeutic bone biomaterials. The current challenges for these therapies include the ability to engineer materials that mimic the biological and mechanical properties of the real bone tissue matrix, whilst simultaneously supporting bone vascularization. In this review, we discuss the very recent innovative strategies in bone biomaterial technology, including those of endogenous biomaterials and cell/drug delivery systems that promote bone regeneration. We present our understanding of their current value and efficacy, and the future perspectives for bone regenerative medicine.

Role of Treg/Th17 Imbalance, Microbiota and miRNAs in Pancreatic Cancer: Therapeutic Options.

Pancreatic cancer is one of the most lethal kinds of cancer; numerous patients die from it every year all over the word. Fewer than 5% of people with pancreatic cancer survive death and recover. Recent evidence suggests that inflammation parameters, such as Th17 cells and Tregs, affect the progression and even the diagnosis and treatment of pancreatic cancer. In the inflammation process, T lymphocytes play an essential role in inflammation intensity, and related cytokines modulate immune responses in the tumor microenvironment. Their function is to establish a balance between destructive inflammation and defense against tumor cells via immune system, and Treg/Th17 imbalance is a common problem in this cancer. The role of microbiota in the development of some cancers is clear; microbiota may also be involved in the pancreatic cancer development. All risk factors for pancreatic cancer, such as chronic pancreatitis-related to microbiota, influence the acute or chronic immune response. Some evidence has been presented regarding the role of the immune response in carcinogenesis. In addition, miRNAs are very important in suppressing and stimulating the growth of cancer cells, and a variety of them have been identified. Some miRNAs are abnormally expressed in many cancers and have main roles as post-transcriptional regulators. They show oncogenic or tumor-suppressive functions by binding to marked mRNAs. In this review, we highlight recent findings regarding the role of Treg/Th17 imbalance, microbiota functions, and miRNAs performance in pancreatic cancer. We also present the evidence regarding therapeutic options.

The roles of tumor-associated macrophages in tumor angiogenesis and metastasis.

Tumor associated macrophages (TAMs) are the most frequent immune cells within tumor microenvironment (TME). There is growing evidence that TAMs are involved in tumor progression via multiple mechanisms. TAMs create an immunosuppressive TME by producing growth factors, chemokines, and cytokines which modulate recruitment of immune cells and inhibit anti-tumor responses. They also serve as angiogenesis promoting cells by production of pro-angiogenic factors and matrix metalloproteinases (MMPs) and vascular constructing which guarantee supplying oxygen and nutrients to solid tumor cells. Furthermore, TAMs play important functions in tumor metastasis through contributing to invasion, extravasation, survival, intravasation, and colonization of tumor cells. In this review, we summarized macrophage classification, TAMs polarization, and mechanisms underlying TAM-promoting angiogenesis and metastasis.

Recent advances in oncolytic virus-based cancer therapy.

Administration of oncolytic viruses (OVs) is an emerging anticancer strategy that exploits the lytic nature of viral replication to enhance the killing of malignant cells. OVs can be used as tools to directly induce cancer cell death and to trigger local and/or systemic immune responses to metastatic cancer in vivo. The effectiveness of OV therapy was initially highlighted by the clinical use of the genetically modified herpes virus, talimogene laherparepvec, for melanoma therapy. A number of OVs are now being evaluated as potential treatments for cancer in clinical trials. In spite of being engineered to specifically target tumor cells, the safety and off-target effects of OV therapy are a concern. The potential safety concerns of OVs are highlighted by current clinical trial criteria, which exclude individuals harbouring other viral infections and people who are immunocompromised. Despite the potential for adverse effects, clinical trials to date revealed relatively minimal adverse immune-related effects, such as fever. With advances in our understanding of virus replication cycles, several novel OVs have emerged. Reverse genetic systems have facilitated the insertion of anticancer genes into a range of OVs to further enhance their tumor-killing capacity. In this review, we highlight the recent advances in OV therapy for a range of human cancers in in vitro and in in vivo animal studies. We further discuss the future of OVs as a therapeutic strategy for a range of life-threatening cancers.

Regorafenib suppresses colon tumorigenesis and the generation of drug resistant cancer stem-like cells via modulation of miR-34a associated signaling.

BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent malignancies in the world and developed drug resistance has represented one of the most challenging tasks for management. The current therapeutic regimens may select and enrich cancer stem-like cells (CSCs) resulting in the increased resistance against treatment, metastatic potential and mortality. Regorafenib is a multi-kinase inhibitor, an FDA-approved last-of-line treatment for patients with chemo-refractory metastatic CRC. However, regorafenib's potential effects on CSCs have not been fully elucidated. METHODS: Here, we developed two 5-FU resistant CRC cell lines, HCT-116R and DLD-1R and showed the increased CSCs characteristics such as increased side-population cells, tumor sphere formation and expression of stemness markers. These cell lines and CSCs properties were used for evaluating the potential of regorafenib in suppressing CSCs. RESULTS: We showed that regorafenib treatment decreased the stemness phenotypes including tumor sphere formation, and side-population, of both HCT-116R and DLD-1R cells. Additionally, regorafenib suppressed the cell viability in both cell lines synergistically with 5-FU. In vivo, the combination of regorafenib and 5-FU significantly suppressed the tumorigenesis and stemness markers of 5-FU resistant DLD-1R. Mechanistically, regorafenib-mediated effects were associated with the induction of tumor suppressor miR-34a and suppression of WNT/ß-catenin signaling. Our findings demonstrated that regorafenib treatment was associated with the increased level of miR-34a, resulting in reversing drug resistance and cancer-initiating cell phenotypes by degrading WNT/ß-catenin in CRC. CONCLUSION: Regorafenib might be a potential drug for colon cancer stem-like cells and it should be investigated in future clinical trials.

Depletion of HDAC1, 7 and 8 by Histone Deacetylase Inhibition Confers Elimination of Pancreatic Cancer Stem Cells in Combination with Gemcitabine.

Trichostatin A (TSA) possess histone deacetylase (HDAC) inhibitory potential, can reverse the deactivation of tumor suppressor genes and inhibit tumor cell proliferation. We evaluated the effect of TSA on HDAC expression, tumor cell proliferation, and cancer stem cells (CSCs) activities in pancreatic ductal adenocarnoma (PDAC) cells. The PDAC cell lines MiaPaCa-2 and PANC-1 were distinctly sensitive to TSA, with enhanced apoptosis, compared to SAHA. TSA or SAHA inhibited vimentin, HDACs 1, 7 and 8, upregulated E-cadherin mRNA and protein levels in the PDAC cells, and time-dependently downregulated Oct-4, Sox-2, and Nanog, as well as inhibited PDAC tumorsphere formation. TSA also induces accumulation of acetylated histones, while increasing histone 3 lysine 4 or 9 dimethylation levels in PDAC cells and enhancing the epigenetic activity of SAHA. The anti-CSCs effect of TSA was like that obtained by silencing HDAC-1 or 7 using siRNA, and enhances Gemcitabine activity. Our study highlights the molecular targetability of HDACs 1, 7, and 8, confirm their PDAC-CSCs maintaining role, and demonstrate that compared to SAHA, TSA modulates the epigenetically- mediated oncogenic activity of PDAC-CSCs, and potentiate Gemcitabine therapeutic activity, making a case for further exploration of TSA activity alone or in combination with Gemcitabine in PDAC therapy.