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The heterogeneity of tumors and the lack of effective therapies have resulted in triple-negative breast cancer (TNBC) exhibiting the least favorable outcomes among breast cancer subtypes. TNBC is characterized by its aggressive nature, often leading to high rates of relapse, metastasis, and mortality. Niclosamide (Nic), an Food and Drug Administration-approved anthelmintic drug, has been repurposed for cancer treatment; however, its application for TNBC is hindered by significant challenges, including strong hydrophobicity, poor aqueous solubility, and low bioavailability. This study aimed to develop Nic nanoparticles (Nic NPs) using biodegradable and biocompatible polyanhydride copolymers to enhance Nic's bioavailability and therapeutic efficacy. Nic NPs effectively inhibited migration, proliferation, and clonogenicity in both murine and human TNBC cells, inducing apoptosis and suppressing STAT3 signaling. For the first time, we utilized Raman spectroscopy and Seahorse extracellular flux assays to demonstrate the metabolic responses of TNBC cells to Nic NPs, revealing significant metabolic alterations, including the inhibition of mitochondrial respiration and glycolysis. Additionally, this study is the first to explore the combination therapy of repurposed Nic with the approved chemotherapeutic agent paclitaxel in the 4T1 TNBC immunocompetent mouse model. The combination of Nic NPs and paclitaxel significantly reduced tumor growth without adversely affecting the body weight of tumor-bearing mice. In summary, these findings suggest that Nic NPs could serve as a promising component in combination therapies for the effective treatment of TNBC.

The tumor stroma, or the microenvironment surrounding solid tumors, can significantly impact the effectiveness of cancer therapies. The tumor microenvironment is characterized by high interstitial pressure, a consequence of leaky vasculature, and dense stroma created by excessive deposition of various macromolecules such as collagen, fibronectin, and hyaluronic acid (HA). In addition, non-cancerous cells such as cancer-associated fibroblasts (CAFs) and the extracellular matrix (ECM) itself can promote tumor growth. In recent years, there has been increased interest in combining standard cancer treatments with stromal-targeting strategies or stromal modulators to improve therapeutic outcomes. Furthermore, the use of nanomedicine, which can improve the delivery and retention of drugs in the tumor, has been proposed to target the stroma. This review focuses on how different stromal components contribute to tumor progression and impede chemotherapeutic delivery. Additionally, this review highlights recent advancements in nanomedicine-based stromal modulation and discusses potential future directions for developing more effective stroma-targeted cancer therapies.

To date, there is no cure for Parkinson's disease (PD). There is a pressing need for anti-neurodegenerative therapeutics that can slow or halt PD progression by targeting underlying disease mechanisms. Specifically, preventing the build-up of alpha-synuclein (αSyn) and its aggregated and mutated forms is a key therapeutic target. In this study, an adeno-associated viral vector loaded with the A53T gene mutation was used to induce rapid αSyn-associated PD pathogenesis in C57BL/6 mice. We tested the ability of a novel therapeutic, a single chain fragment variable (scFv) antibody with specificity only for pathologic forms of αSyn, to protect against αSyn-induced neurodegeneration, after unilateral viral vector injection in the substantia nigra. Additionally, polyanhydride nanoparticles, which provide sustained release of therapeutics with dose-sparing properties, were used as a delivery platform for the scFv. Through bi-weekly behavioral assessments and across multiple post-mortem immunochemical analyses, we found that the scFv-based therapies allowed the mice to recover motor activity and reduce overall αSyn expression in the substantia nigra. In summary, these novel scFv-based therapies, which are specific exclusively for pathological aggregates of αSyn, show early promise in blocking PD progression in a surrogate mouse PD model.

Our earlier reports established that zinc oxide nanoflowers (ZONF) show significant pro-angiogenic properties, where reactive oxygen species, nitric oxide and MAPK-AKT-eNOS cell signaling axis play an essential task. Considering the significance of angiogenesis in healthcare, our research group has recently demonstrated the in vivo therapeutic application of ZONF (10 mg/kg b.w.) for treating peripheral artery disease. Moreover, based on the angio-neural crosstalk between vascular and neuronal systems, we have further demonstrated the neuritogenic and neuroprotective characteristics of pro-angiogenic nanoflowers (10 mg/kg b.w.) for the treatment of cerebral ischemia. However, it is crucial for a therapeutic material to be non-toxic for its practical clinical applications and therefore assessment of its in vivo toxicity and adverse effect is highly important. Herein, for the first time, we investigate a detailed nanotoxicology of therapeutically active ZONF in Swiss albino mice to evaluate their safety profile and comprehend their aspects for future clinical applications. The maximum tolerated dose (MTD) of ZONF was found to be 512.5 mg/kg b.w. which was employed for acute exposure (2 weeks), showing slight toxicity. However, sub-chronic (4 weeks) and long term chronic (8-12 weeks) studies of nanoflowers exhibited their non-toxic nature particularly at lower therapeutic doses (1-10 mg/kg b.w.). Additionally, in depth genotoxicity study revealed that lower therapeutic dose of ZONF (10 mg/kg b.w.) did not exhibit significant toxicity even in genetic level. Overall, the present nanotoxicology of ZONF suggests their high biocompatible nature at therapeutic dose, offering the basis of their future clinical applications in ischemic and other vascular diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Mesenchymal stem cells (MSCs) have been studied for their potential in facilitating tumor-targeted delivery of chemotherapeutics due to their tumor-homing characteristics. We hypothesized that targeting effectiveness of MSCs can be further enhanced by incorporating tumor-targeting ligands on MSC surfaces that will allow for enhanced arrest and binding within the tumor tissue. We utilized a unique strategy of modifying MSCs with synthetic antigen receptors (SARs), targeting specific antigens overexpressed on cancer cells. MSCs were surface-functionalized by first incorporating recombinant protein G (PG) on the surface, followed by binding of the targeting antibody to the PG handle. We functionalized MSCs with antibodies targeting a tyrosine kinase transmembrane receptor protein, epidermal growth factor receptor (EGFR), overexpressed in non-small-cell lung cancer (NSCLC). The efficacy of MSCs functionalized with anti-EGFR antibodies (cetuximab and D8) was determined in murine models of NSCLC. Cetuximab-functionalized MSCs demonstrated improved binding to EGFR protein and to EGFR overexpressing A549 lung adenocarcinoma cells. Further, cetuximab-functionalized MSCs loaded with paclitaxel nanoparticles were efficient in slowing orthotopic A549 tumor growth and improving the overall survival relative to that of other controls. Biodistribution studies revealed a six-fold higher retention of EGFR-targeted MSCs than non-targeted MSCs. Based on these results, we conclude that targeting ligand functionalization could be used to enhance the concentration of therapeutic MSC constructs at the tumor tissue and to achieve improved antitumor response.

Mesenchymal stem cells (MSCs) are multipotent cells and are considered a potential source for tissue and organ repair due to their self-renewal, proliferation, and differentiation abilities. However, in most cases, MSCs are needed to be stimulated with external growth factors to promote their proliferation and differentiation. Over the past decade, it has been demonstrated that nanomaterials could facilitate MSC proliferation and differentiation, and excellent efforts are carried out to investigate their possible modulating pattern and mechanisms for MSC differentiation. Europium hydroxide (Eu III (OH) 3 ) nanorods (EHN) are well-researched for their biomimicking properties and act as a substitute for growth factors that induce cell proliferation, migration, and differentiation. In the current study, the human MSCs were chosen as an in vitro model for evaluating the role of EHN in modulating the differentiation process of MSCs into neuronal and glial lineages. The characterization of MSCs and differentiated neuronal cells observed by flow cytometry, confocal, and gene marker expression studies supported our hypothesis that the EHNs are pro-angiogenic and pro-neurogenic. Finally, altogether our results suggest that EHNs have the potential to play an essential part in developing novel treatment strategies for neurodegenerative diseases and spinal cord injuries based on the nanomedicine approach., (© 2023 IOP Publishing Ltd.)

Engineered mesenchymal stem cells (MSCs) have been investigated extensively for gene delivery and, more recently, for targeted small molecule delivery. While preclinical studies demonstrate the potential of MSCs for targeted delivery, clinical studies suggest that tumor homing of native MSCs may be inefficient. We report here a surprising finding that loading MSCs with the anticancer drug paclitaxel (PTX) by nanoengineering results in significantly improved tumor homing compared to naïve MSCs. Loading PTX in MSCs results in increased levels of mitochondrial reactive oxygen species (ROS). In response to this oxidative stress, MSCs upregulate two important set of proteins. First were critical antioxidant proteins, most importantly nuclear factor erythroid 2-like 2 (Nrf2), the master regulator of antioxidant responses; upregulation of antioxidant proteins may explain how MSCs protect themselves from drug-induced oxidative stress. The second was CXCR4, a direct target of Nrf2 and a key mediator of tumor homing; upregulation of CXCR4 suggested a mechanism that may underlie the improved tumor homing of nanoengineered MSCs. In addition to demonstrating the potential mechanism of improved tumor targeting of nanoengineered MSCs, our studies reveal that MSCs utilize a novel mechanism of resistance against drug-induced oxidative stress and cell death, explaining how MSCs can deliver therapeutic concentrations of cytotoxic payload while maintaining their viability., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Nanotechnology has immensely advanced the field of cancer diagnostics and treatment by introducing potential delivery vehicles as carriers for drugs or therapeutic agents. In due course, mesoporous silica nanoparticles (MSNs) have emerged as excellent vehicles for delivering drugs, biomolecules, and biomaterials, attributed to their solid framework and porosity providing a higher surface area for decorating with various functional ligands. Recently, the metal tin (Sn) has gained huge importance in cancer research owing to its excellent cytotoxicity and ability to kill cancer cells. In the present work, we synthesized MSNs, conjugated them with organotin compounds, and characterized them using various physicochemical techniques. Subsequently, the biological evaluation of MSN (S1), MSN-MP (S2) and tin-conjugated MSNs (S3: MSN-MP-SnPh 3 ) (MP = 3-mercaptopropyltriethoxysilane) revealed that these nanoconjugates induced cytotoxicity, necrosis, and apoptosis in MCF-7 cells. Moreover, these nanoconjugates exhibited anti-angiogenic properties as demonstrated in the chick embryo model. The increase of reactive oxygen species (ROS) was found as a one of the plausible mechanisms underlying cancer cell cytotoxicity induced by these nanoconjugates, encouraging their application for the treatment of cancer. The tin-conjugated MSNs demonstrated less toxicity to normal cells compared to cancer cells. Furthermore, the genotoxicity studies revealed the clastogenic and aneugenic effects of these nanoconjugates in CHO cells mostly at high concentrations. These interesting observations are behind the idea of developing tin-conjugated MSNs as prospective candidates for anticancer therapy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Critical limb ischemia (CLI) is a severe type of peripheral artery disease (PAD) which occurs due to an inadequate supply of blood to the limb extremities. Patients with CLI often suffer from extreme cramping pain, impaired wound healing, immobility, cardiovascular complications, amputation of the affected limb and even death. The conventional therapy for treating CLI includes surgical revascularization as well as restoration of angiogenesis using growth factor therapy. However, surgical revascularization is only suitable for a small percentage of CLI patients and is associated with a high perioperative mortality rate. The use of growth factors is also limited in terms of their poor therapeutic angiogenic potential, as observed in earlier clinical studies which could be attributed to their poor bio-availability and non-specificity issues. Therefore, to overcome the aforesaid disadvantages of conventional strategies there is an urgent need for the advancement of new alternative therapeutic biomaterials to treat CLI. In the past few decades, various research groups, including ours, have been involved in developing different pro-angiogenic nanomaterials. Among these, zinc oxide nanoflowers (ZONFs), established in our laboratory, are considered one of the more potent nanoparticles for inducing therapeutic angiogenesis. In our earlier studies we showed that ZONFs promote angiogenesis by inducing the formation of reactive oxygen species and nitric oxide (NO) as well as activating Akt/MAPK/eNOS cell signaling pathways in endothelial cells. Recently, we have also reported the therapeutic potential of ZONFs to treat cerebral ischemia through their neuritogenic and neuroprotective properties, exploiting angio-neural cross-talk. Considering the excellent pro-angiogenic properties of ZONFs and the importance of revascularization for the treatment of CLI, in the present study we comprehensively explore the therapeutic potential of ZONFs in a rat hind limb ischemia model (established by ligating the hind limb femoral artery), an animal model that mimics CLI in humans. The behavioral studies, laser Doppler perfusion imaging, histopathology and immunofluorescence as well as estimation of serum NO level showed that the administration of ZONFs could ameliorate ischemia in rats at a faster rate by promoting therapeutic angiogenesis to the ischemic sites. Altogether, the present study offers an alternative nanomedicine approach employing ZONFs for the treatment of PADs., (© 2021 IOP Publishing Ltd.)

Heterogeneity in tumor expression as well as expression in normal tissues of various targets limit the usefulness of current ligand-based active targeting approaches. Incorporation of synthetic receptors, which can be recognized by delivery systems engineered to present specific functional groups on the surface, is a novel approach to improve tumor targeting. Alternatively, introduction of synthetic functionalities on cellular carriers can also enhance tumor targeting. We review various strategies that have been utilized for the introduction of synthetic targets in tumor tissues. The introduction of synthetic functional groups in the tumor through improved strategies is anticipated to result in improved target specificity and reduced heterogeneity in target expression.

Nano-engineered mesenchymal stem cells (nano-MSCs) are promising targeted drug delivery platforms for treating solid tumors. MSCs engineered with paclitaxel (PTX) loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) are efficacious in treating lung and ovarian tumors in mouse models. The quantitative description of pharmacokinetics (PK) and pharmacodynamics (PD) of nano-MSCs is crucial for optimizing their therapeutic efficacy and clinical translatability. However, successful translation of nano-MSCs is challenging due to their complex composition and physiological mechanisms regulating their pharmacokinetic-pharmacodynamic relationship (PK-PD). Therefore, in this study, a mechanism-based preclinical PK-PD model was developed to characterize the PK-PD relationship of nano-MSCs in orthotopic A549 human lung tumors in SCID Beige mice. The developed model leveraged literature information on diffusivity and permeability of PTX and PLGA NPs, PTX release from PLGA NPs, exocytosis of NPs from MSCs as well as PK and PD profiles of nano-MSCs from previous in vitro and in vivo studies. The developed PK-PD model closely captured the reported tumor growth in animals receiving no treatment, PTX solution, PTX-PLGA NPs and nano-MSCs. Model simulations suggest that increasing the dosage of nano-MSCs and/or reducing the rate of PTX-PLGA NPs exocytosis from MSCs could result in improved anti-tumor efficacy in preclinical settings.

Cadmium (Cd) is a common heavy metal that causes major environmental pollution with adverse effects on human health and well-being. Exposure to Cd is known to exhibit detrimental consequences on all the vital organ systems of the body, especially the vascular system. Certain approaches using anti-oxidants and chelating agents have been demonstrated previously to mitigate Cd-induced toxicity. However, these approaches are associated with their own limitations. In this context, there is a critical need for the development of alternative treatment strategies to address the conditions associated with Cd-poisoning. One such novel approach is the application of nanomedicine which is well-known to resolve several health complications by improving disease therapy. Recently, our group demonstrated the role of europium hydroxide nanorods (EHN) in promoting vascular growth using in vitro and in vivo assay systems. Therefore, in the present study, we have evaluated the effect of EHN on health of endothelial cells (EA.hy926) and fibroblasts (NIH 3T3) intoxicated by Cd. The results revealed that EHN significantly improved the viability of EA.hy926 and NIH 3T3 cells, reduced apoptotic cell population, increased nitric oxide (NO) production and promoted blood vasculature development in the chick embryo model, which were hampered due to Cd insult. Molecular studies demonstrated the reduced expression of tumor suppressor (p53) and elevated anti-apoptotic protein (Bcl-xL) levels along with enhanced NO production through endothelial nitric oxide synthase (eNOS) activation as the plausible mechanisms underlying protective role of EHN against Cd-induced vascular toxicity. Considering the above observations, we strongly believe that EHN could be a potential nanomedicine approach for overcoming Cd-induced toxicity by improving vascular health and functioning., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Nanocarriers have been extensively utilized for the systemic targeting of various solid tumors and their metastases. However, current drug delivery systems, in general, suffer from a lack of selectivity for tumor cells. Here, we develop a novel two-step targeting strategy that relies on the selective accumulation of targetable synthetic receptors (i.e., azide moieties) in tumor tissues, followed by delivery of drug-loaded nanoparticles having a high binding affinity for these receptors. Mesenchymal stem cells (MSCs) were used as vehicles for the tumor-specific accumulation of azide moieties, while dibenzyl cyclooctyne (DBCO) was used as the targeting ligand. Biodistribution and antitumor efficacy studies were performed in both orthotopic metastatic and patient-derived xenograft (PDX) tumor models of ovarian cancer. Our studies show that nanoparticles are retained in tumors at a significantly higher concentration in mice that received azide-labeled MSCs (MSC-Az). Furthermore, we observed significantly reduced tumor growth ( p < 0.05) and improved survival in mice receiving MSC-Az along with paclitaxel-loaded DBCO-functionalized nanoparticles compared to controls. These studies demonstrate the feasibility of a two-step targeting strategy for efficient delivery of concentrated chemotherapy for treating solid tumors.

In spite of radical advances in nanobiotechnology, the clinical translation of nanoparticle (NP)-based agents is still a major challenge due to various physiological factors that influence their interactions with biological systems. Recent decade witnessed meticulous investigation on protein corona (PC) that is the first surrounds NPs once administered into the body. Formation of PC around NP surface exhibits resilient effects on their circulation, distribution, therapeutic activity, toxicity and other factors. Although enormous literature is available on the role of PC in altering pharmacokinetics and pharmacodynamics of NPs, understanding on its analytical characterization methods still remains shallow. Therefore, the current review summarizes the impact of PC on biological fate of NPs and stressing on analytical methods employed for studying the NP-PC.

Neuritogenesis, a complex process of the sprouting of neurites, plays a vital role in the structural and functional restoration of cerebral ischemia-injured neuronal tissue. Practically, there is no effective long-term treatment strategy for cerebral ischemia in clinical practice to date due to several limitations of conventional therapies, facilitating the urgency to develop new alternative therapeutic approaches. Herein, for the first time we report that pro-angiogenic nanomaterials, zinc oxide nanoflowers (ZONF), exhibit neuritogenic activity by elevating mRNA expression of different neurotrophins, following PI3K/Akt-MAPK/ERK signaling pathways. Further, ZONF administration to global cerebral ischemia-induced Fischer rats shows improved neurobehavior and enhanced synaptic plasticity of neurons via upregulation of Neurabin-2 and NT-3, revealing their neuroprotective activity. Altogether, this study offers the basis for exploitation of angio-neural cross talk of other pro-angiogenic nano/biomaterials for future advancement of alternative treatment strategies for cerebral ischemia, where neuritogenesis and neural repair are highly critical.

Angiogenesis is a crucial biological process of development of blood vessels from pre-existing vasculature, which helps in several physiological functions including embryonic development, hair growth, ovulation, menstruation, tissue repair, and regeneration. Contrastingly, it is also imperative in various pathological conditions like cardiovascular/ischemic diseases, rheumatoid arthritis, cancers, ocular/retinal diseases, and others. These disease conditions are often treated by manipulating angiogenesis using different pro-angiogenic or antiangiogenic factors/molecules through either promoting or inhibiting this complex process, respectively. However, these conventional angiogenic treatment strategies fall short in attaining the desired therapeutic effect due to several limitations including low bioavailability, rapid clearance, high cost, nonspecificity, drug resistance and side effects. Therefore, it is high time for the advancement of different pro- and antiangiogenic materials that could overcome aforesaid limitations, followed by their effective use for the therapy of angiogenesis related diseases. Recently, nanotechnology has drastically advanced in various areas of biology and medicine including therapeutic angiogenesis. Globally, many research groups including ours explored various inorganic metal nanomaterials that could efficiently manipulate the angiogenesis process either by augmenting or inhibiting it. The extensive investigation of the mechanisms underlying nanomaterials-mediated manipulation of angiogenesis is also well-documented. In the present review article, we intend to introduce the recent developments of inorganic nanomedicine manipulating angiogenesis with major focus on pro-angiogenic nanomaterials and their therapeutic applications along with associated challenges and future directions.

Mesenchymal stem cells (MSCs) have previously demonstrated considerable promise in regenerative medicine based on their ability to proliferate and differentiate into cells of different lineages. More recently, there has been a significant interest in using MSCs as cellular vehicles for targeted cancer therapy by exploiting their tumor homing properties. Initial studies focused on using genetically modified MSCs for targeted delivery of various proapoptotic, antiangiogenic, and therapeutic proteins to a wide variety of tumors. However, their use as drug delivery vehicles has been limited by poor drug load capacity. This review discusses various strategies for the nongenetic modification of MSCs that allows their use in tumor-targeted delivery of small molecule chemotherapeutic agents. SIGNIFICANCE STATEMENT: There has been considerable interest in exploiting the tumor homing potential of MSCs to develop them as a vehicle for the targeted delivery of cytotoxic agents to tumor tissue. The inherent tumor-tropic and drug-resistant properties make MSCs ideal carriers for toxic payload. While significant progress has been made in the area of the genetic modification of MSCs, studies focused on identification of molecular mechanisms that contribute to the tumor tropism along with optimization of the engineering conditions can further improve their effectiveness as drug delivery vehicles., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Chronic wounds have emerged as a major cause of mortality, especially in patients with diabetes and other pathologies. Statistics indicate that chronic wounds affect around 6.5 million patients annually, with wound care and management incurring huge economic costs. Growing incidence of chronic wounds and associated pathologies along with the limitations of current therapies have established a strong need for novel and innovative approaches to accelerate wound healing. Conventionally, chronic wounds are addressed using various FDA-approved silver-based formulations and other biomaterials. However, the toxicity associated with these conventional approaches, along with the increased frequency of chronic wound cases, makes the development of alternative therapies for effective wound healing necessary. Recently, researchers have investigated the design and development of nanoparticles, especially inorganic metal nanoparticles, as promising candidates for addressing various pathological conditions, including wound healing. Several research groups, including ours, have designed numerous metal nanoparticles (including silver, gold, zinc oxide, cerium oxide, terbium hydroxide, silica, titanium oxide, copper) and demonstrated their wound-healing properties using in vitro and in vivo models. The rise of nanotechnology-based platforms in wound healing is evidenced by the tremendous impact and number of publications observed in recent years, which has emphasized the robust potential of inorganic nanomedicine for addressing wounds. Therefore, the importance of these inorganic nanomaterial-based interventions for wound-healing applications needs to be emphasized to inform and encourage scientists and young researchers globally to engage with this expanding area of biology and medicine. In this review article, we mainly focus on highlighting the role of inorganic nanomaterials and nanomaterial-based approaches for wound healing and tissue regeneration, along with their mechanistic properties, clinical status, challenges, and future directions.

Cardiovascular diseases (CVDs) are one of the leading causes of global morbidity and mortality. Among these, the ischemic heart disease (IHD) or coronary artery disease (CAD) accounts for the major deaths due to CVDs. Several approaches followed to treat the ischemic heart diseases are limited due to various adverse effects and cost of treatment. Recently, nanotechnology has revolutionized the field of biomedical research by introducing various technologies to improve the health care, using a nanomedicine approach. In this context, our group has well-established the europium hydroxide nanorods (EHNs), which promote the formation of new blood vessels (angiogenesis) through reactive oxygen species (ROS) and nitric oxide (NO)-mediated signaling pathways. Further, these pro-angiogenic nanorods were also reported to exhibit a mild to nontoxic nature toward mammalian cells and mouse models. Henceforth, in the present study, myocardial ischemia (MI) was created in Wistar rats using isoproterenol (ISO), a well-established model for investigating MI. For the first time, the effect of the pro-angiogenic nanorods (EHNs) on the ischemic condition was validated using several assays, which revealed that the ischemia and cardiotoxicity induced by ISO were ameliorated by EHNs in both H9C2 rat cardiomyocytes ( in vitro ) and Wistar rats ( in vivo ). Considering the above results, we believe that EHN could be developed as alternative treatment strategies for myocardial ischemia therapy and other ischemic diseases where angiogenesis plays a significant role, in the near future.

Significance: Redox signaling plays a vital role in regulating various cellular signaling pathways and disease biology. Recently, nanomedicine (application of nanotechnology in biology and medicine) has been demonstrated to regulate angiogenesis through redox signaling. A complete understanding of redox signaling pathways influenced angiogenesis/antiangiogenesis triggered by therapeutic nanoparticles is extensively reviewed in this article. Recent Advances: In recent times, nanomedicines are regarded as the Trojan horses that could be employed for successful drug delivery, gene delivery, peptide delivery, disease diagnosis, and others, conquering barriers associated with conventional theranostic approaches., Critical Issues: Physiological angiogenesis is a tightly regulated process maintaining a balance between proangiogenic and antiangiogenic factors. The redox signaling is one of the main factors that contribute to this physiological balance. An aberrant redox signaling cascade can be caused by several exogenous and endogenous factors and leads to reduced or augmented angiogenesis that ultimately results in several disease conditions., Future Directions: Redox signaling-based nanomedicine approach has emerged as a new platform for angiogenesis-related disease therapy, where nanoparticles promote angiogenesis via controlled reactive oxygen species (ROS) production and antiangiogenesis by triggering excessive ROS formation. Recently, investigators have identified different efficient nano-candidates, which modulate angiogenesis by controlling intracellular redox molecules. Considering the importance of angiogenesis in health care a thorough understanding of nanomedicine-regulated redox signaling would inspire researchers to design and develop more novel nanomaterials that could be used as an alternative strategy for the treatment of various diseases, where angiogenesis plays a vital role.

During the last decade, metal nanoparticles (MtNPs) have gained immense popularity due to their characteristic physicochemical properties, as well as containing antimicrobial, anti-cancer, catalyzing, optical, electronic and magnetic properties. Primarily, these MtNPs have been synthesized through different physical and chemical methods. However, these conventional methods have various drawbacks, such as high energy consumption, high cost and the involvement of toxic chemical substances. Microbial flora has provided an alternative platform for the biological synthesis of MtNPs in an eco-friendly and cost effective way. In this article we have focused on various microorganisms used for the synthesis of different MtNPs. We also have elaborated on the intracellular and extracellular mechanisms of MtNP synthesis in microorganisms, and have highlighted their advantages along with their challenges. Moreover, due to several advantages over chemically synthesized nanoparticles, the microbial MtNPs, with their exclusive and dynamic characteristics, can be used in different sectors like the agriculture, medicine, cosmetics and biotechnology industries in the near future.

Therapeutic agents harboring both wound healing and antibacterial activities have much demand in biomedical applications. Development of such candidates with clinically approved materials adds more advantages toward these applications. Recently, silver metal complex nanomaterials have been playing a major role in medical uses especially for antibacterial activity and wound healing. In this report, we designed and synthesized silver nitroprusside complex nanoparticles (abbreviated as AgNNPs) using sodium nitroprusside and silver nitrate (both are FDA approved precursors). The nanoparticles (AgNNPs) were thoroughly characterized by various physicochemical techniques such as XRD, FTIR, TGA, DLS, EDAX, Raman, ICP-OES, HRTEM, and FESEM. The cell viability assay in normal cells (EA.hy 926 cells, NIH 3T3) using MTT reagents and CEA assay (CEA: Chick embryo angiogenesis assay) in fertilized eggs demonstrate the biocompatibility of AgNNPs. These nanoparticles show effective antibacterial activity against both Gram positive and Gram negative bacteria through membrane and DNA damage. Additionally, AgNNPs accelerate the wound healing in C57BL6 mice by altering the macrophages from M1 to M2. Considering the results together, the current study may offer the development of new silver nanocomplex nanomaterials that shows synergistic effect on antibacterial activity and wound healing (2-in-1-system). To the best of our knowledge, this is the first report for the synthesis, characterization, and biomedical applications of silver nitroprusside nanoparticles.

The growth of new blood vessels from the pre-existing vasculature known as angiogenesis has a vital role in various physiological and pathological processes. In the present study, we demonstrate the pro-angiogenic properties of functional nanoconjugates of organosilane functionalized cerium oxide (CeO 2 ) nanoparticles (nanoceria). Aqueous dispersible CeO 2 and trivalent metal (samarium) ion-doped CeO 2 (SmCeO 2 ) nanoparticles conjugated with hydrophilic biocompatible and antifouling (6-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-hexyl)triethoxysilane moieties were prepared. These functional nanoconjugates were prepared via an in situ synthesis and functionalization procedure using an ammonia-induced ethylene glycol-assisted precipitation method. The prepared nanoconjugates were thoroughly characterized using various physico-chemical techniques such as transmission electron microscopy (TEM), X-ray diffraction (XRD) analysis, dynamic light scattering (DLS), Fourier-transform infrared (FTIR) spectroscopy, 13 C high-resolution solid-state nuclear magnetic resonance (NMR) spectroscopy, and X-ray photoelectron spectroscopy (XPS). The pro-angiogenic properties of the prepared nanoconjugates were evaluated by employing various angiogenesis assays (in vitro and in vivo). The results of the present study illustrate that the functional nanoconjugates of SmCeO 2 triggered endothelial cell proliferation and induced the growth of blood vessels in a chick embryo. The enhanced expression of pro-angiogenic markers (p38 MAPK/HIF-1α) by these functional nanoconjugates might be a plausible signaling mechanism underlying their pro-angiogenic properties. Considering all the observations, we believe that (6-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-hexyl)triethoxysilane conjugated SmCeO 2 nanoparticles could be developed as potential candidates for the treatment of cardiovascular, ischemic and ocular diseases where angiogenesis is the principal phenomenon.

The process of angiogenesis, involving generation of new blood vessels from the existing ones, is vital for the supply of oxygen and nutrients to various tissues of body system. Angiogenesis is directly associated with several physiological and pathological processes. It is well-established that impairment in angiogenesis process results in various fatal conditions. Recently, few research groups including ours demonstrated therapeutic angiogenesis through nanomedicine approach using metal oxide/hydroxide nanoparticles. However, there is still a thorough necessity for the development of novel, eco-friendly, pro-angiogenic nanomaterials. Hence, in the present study we demonstrate the in vitro and in vivo pro-angiogenic properties of terbium hydroxide nanorods (THNRs) synthesized using an advanced microwave irradiation method, along with the detailed molecular signaling cascade underlying THNRs induced angiogenesis. The in vivo wound healing and nonimmunogenicity of the THNRs have been validated in the mouse models. We thus strongly believe that the present study establishing the pro-angiogenic properties of THNRs will aid in the development of alternative treatment strategies for wound healing along with cardiovascular and ischemic diseases, where angiogenesis is the chief target.

Since the last decade, the metal composite nanostructures have evolved as promising candidates in regard to their wide applications in the fields of science and engineering. Recently, several investigators identified the titanium based nanomaterials as excellent agents for multifunctional environmental and biomedical applications. In this perspective, we have developed a series of zinc-doped (2 and 5%) titanium oxide-based nanomaterials using various reaction conditions and calcination temperatures (TZ1-TZ3: calcined at 500°C, TZ4-TZ6: calcined at 600°C and TZ7-TZ9: calcined at 700°C). The calcined materials (TZ1 to TZ9) were thoroughly analyzed by several physico-chemical characterization methods. The increase of the calcination temperature results in significant changes of the textural properties of the nanostructured materials. In addition, the increase of the calcination temperature leads to the formation of anatase/rutile mixtures with higher quantity of rutile. Furthermore, incorporation of zinc changes the morphology of the obtained nanoparticles. The materials were studied in the photodegradation of methylene blue observing that materials calcined at lower temperatures (TZ1-TZ3) have higher photocatalytic activity than those of the materials calcined at 600°C (TZ4-TZ6), rutile-based systems TZ7-TZ9 are not active. Based on the background literature of titanium and zinc based nanostructures in therapeutic angiogenesis, we have explored the pro-angiogenic properties of these materials using various in vitro and in vivo assays. The zinc-doped titanium dioxide nanostructures (TZ5 and TZ6) exhibited increased cell viability, proliferation, enhanced S-phase cell population, increased pro-angiogenic messengers (ROS: reactive oxygen species and NO: nitric oxide) production and promoted in vivo blood vessel formation in a plausible mechanistic p38/STAT3 dependent signaling cascade. Altogether, the results of the present study showcase these zinc doped-titanium oxide nanoparticles as promising candidates for environmental (water-remediation) and therapeutic angiogenic applications., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Electrospun polycaprolactone (PCL) tissue engineering scaffolds have been developed and used for a wide range of tissue engineering applications, where successful incorporation and conservation of the therapeutic activity of the embedded nanoparticles into scaffolds is critically needed for effective tissue engineering. Incorporation of pro-angiogenic nanomaterials to promote vascularization is a novel approach. Our group has well-demonstrated the potent pro-angiogenic properties of europium hydroxide nanorods (EHNs) using in vitro and in vivo systems. In the present study, electrospun PCL tissue engineering scaffolds containing EHNs were fabricated and characterized for various morphological and physico-chemical properties. Furthermore, biological studies showed enhanced cell growth and a greater density of endothelial cells grown on the scaffolds incorporated with EHNs (PCL-EHNs). The PCL-EHNs also exhibited good hemo-compatibility towards blood cells. Fluorescence microscopy and SEM observations showed good endothelial cell adhesion over these scaffolds. The PCL-EHNs demonstrated augmented growth of blood vessels in an in vivo chick embryo angiogenesis model. Furthermore, protein expression studies illustrated promoted angiogenesis of HUVECs on scaffolds in a VEGFR2/Akt mediated signaling cascade. Together, the above observations strongly suggest potent applications of EHN-incorporated PCL scaffolds in promoting angiogenesis/vascularization and their effective use in tissue engineering and vascular disease therapy.

Angiogenesis is a vital process that deals with the generation of new blood vessels from pre-existing vasculature and is well known to regulate various physiological as well as pathophysiological processes. We demonstrated that zinc oxide nanoflowers (ZONF) exhibited pro-angiogenic properties in endothelial cells through the production of intracellular reactive oxygen species (ROS), especially H 2 O 2 (hydrogen peroxide). The immense importance of angiogenesis in ischemic and cardiovascular diseases highlights an urgent need to comprehend the detailed molecular mechanisms underlying the ZONF induced angiogenesis process. However, the exact mechanism and signaling pathways behind nanoflowers mediated angiogenesis still remain unclear. In the present study, we report that ZONF induce angiogenesis through MAPK/Akt/eNOS mediated nitric oxide formation, which further acts in a cGMP dependent manner. We strongly believe that exploration of the molecular mechanism and signaling pathways of ZONF driven angiogenesis would be helpful for the advancement of alternative and efficient treatment strategies for ischemic and cardiovascular diseases using a nanomedicine approach.

Our group already demonstrated that europium hydroxide nanorods (EHNs) show none or mild toxicity in C57BL/6 mice even at high dose and exhibited excellent pro-angiogenic activity towards in vitro and in vivo models. In the present study, we evaluated the in vivo cytogenetic toxicity of intraperitoneally administered EHNs (12.5-250 mg/kg/b.w.) in male and female Swiss albino mice by analyzing chromosomal aberrations (CAs), mitotic index (MI), micronucleus (MN) from bone marrow and peripheral blood. Furthermore, we performed the cytogenetic toxicity study of EHNs towards Chinese hamster ovary (CHO) cells, in order to compare with the in vivo results. The results of CA assay of mice treated with EHNs (12.5-125 mg/kg/b.w.) showed no significant change in the formation of aberrant metaphases compared to the control group. Also, there was no significant difference in the number of dividing cells between the control group and EHNs-treated groups observed by MI study, suggesting the non-cytotoxicity of EHNs. Additionally, FACS study revealed that EHNs do not arrest cells at any phase of cell cycle in the mouse model. Furthermore, MN test of both bone marrow and peripheral blood showed no significant differences in the induction of MNs when compared with the control group. In vitro results from CHO cells also support our in vivo observations. Considering the role of angiogenesis by EHNs and the absence of its genotoxicity in mouse model, we strongly believe the future application of EHNs in treating various diseases, where angiogenesis plays an important role such as cardiovascular diseases, ischemic diseases and wound healing.

Angiogenesis, a process resulting in the formation of new capillaries from the pre-existing vasculature plays vital role for the development of therapeutic approaches for cancer, atherosclerosis, wound healing, and cardiovascular diseases. In this report, the synthesis, characterization, and angiogenic properties of graphene oxide (GO) and reduced graphene oxide (rGO) have been demonstrated, observed through several in vitro and in vivo angiogenesis assays. The results here demonstrate that the intracellular formation of reactive oxygen species and reactive nitrogen species as well as activation of phospho-eNOS and phospho-Akt might be the plausible mechanisms for GO and rGO induced angiogenesis. The results altogether suggest the possibilities for the development of alternative angiogenic therapeutic approach for the treatment of cardiovascular related diseases where angiogenesis plays a significant role., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Angiogenesis, a process involving the growth of new blood vessels from the pre-existing vasculature, plays a crucial role in various pathophysiological conditions. We have previously demonstrated that europium hydroxide [Eu(III)(OH)3] nanorods (EHNs) exhibit pro-angiogenic properties through the generation of reactive oxygen species (ROS) and mitogen activated protein kinase (MAPK) activation. Considering the enormous implication of angiogenesis in cardiovascular diseases (CVDs) and cancer, it is essential to understand in-depth molecular mechanisms and signaling pathways in order to develop the most efficient and effective alternative treatment strategy for CVDs. However, the exact underlying mechanism and cascade signaling pathways behind the pro-angiogenic properties exhibited by EHNs still remain unclear. Herein, we report for the first time that the hydrogen peroxide (H2O2), a redox signaling molecule, generated by these EHNs activates the endothelial nitric oxide synthase (eNOS) that promotes the nitric oxide (NO) production in a PI3K (phosphoinositide 3-kinase)/Akt dependent manner, eventually triggering angiogenesis. We intensely believe that the investigation and understanding of the in-depth molecular mechanism and signaling pathways of EHNs induced angiogenesis will help us in developing an effective alternative treatment strategy for cardiovascular related and ischemic diseases where angiogenesis plays an important role.

Background: We have previously reported that increased glucose levels were associated with higher serum nitric oxide (NO) levels in fructose-fed insulin resistant rats. However, the relationship between hyperglycemia and serum NO level was not clear. Therefore, the present study was designed to find the association between hyperglycemia and serum NO levels in Type 2 diabetic (T2DM) patients and T2DM with cardiovascular complication., Methods: Endothelial cells (HUVEC) were treated with of D-glucose (10-100mM), and NO levels and NOS gene expression was measured. Hyperglycaemia was induced in Sprague-Dawley rats, and serum NO levels were measured after 8 weeks. For clinical evaluation, five groups of patients were recruited: Control (CT, n=48), Type 2 diabetes (T2DM, n=26), T2DM with hypertension (DMHT, n=46), Coronary artery diseases (CAD, n=29) and T2DM with coronary artery diseases (DMCD, n=38). NO (nitrite + nitrate) levels were measured from human serum., Results: We found a significant (p<0.05) and dose-dependent increase in NO levels in HUVEC cells after 4 hours of high glucose exposure. eNOS and iNOS gene expression was increased in HUVEC cells after different concentrations and time periods of glucose treatment. We also observed significant (149.1 ± 25 μM, p<0.01) increase in serum NO levels in hyperglycaemic rats compared to control (76.6 ± 13.2 μM). Serum NO level was significantly higher in T2DM (111.8 μM (81.7-122.4), p<0.001) and DMCD patients ((129.4 μM (121.2-143.5), p <0.001) but not in CAD patients (76.4 μM (70.5-87)), as compared to control (68.2 μM (56.4-82.3)). We found significantly lower NO levels (83.5 μM (60.5-122.9)) in subjects suffering from diabetes since more than 5 years, compared to subjects (115.3 μM (75.2-127.1), p<0.001) with less than 5 years., Conclusion: In conclusion, high NO levels were observed in South Indian diabetic patients. Higher glucose levels in serum might be responsible for activation of endothelial cells to enhance NO levels.

We have designed and developed novel pro-angiogenic bio-synthesized gold nanoconjugates (b-Au-HP) that make new blood vessels, as observed by several in vitro and in vivo assays, suggesting their future potential applications in alternative treatment strategies for wound healing, cardiovascular diseases (CVD) and ischemic diseases using a nanomedicine approach.

Autophagy is one of the well-known pathways to accelerate the clearance of protein aggregates, which contributes to the therapy of neurodegenerative diseases. Although there are numerous reports that demonstrate the induction of autophagy with small molecules including rapamycin, trehalose and lithium, however, there are few reports mentioning the clearance of aggregate-prone proteins through autophagy induction by nanoparticles. In the present article, we have demonstrated that europium hydroxide [Eu(III)(OH)3] nanorods can reduce huntingtin protein aggregation (EGFP-tagged huntingtin protein with 74 polyQ repeats), responsible for neurodegenerative diseases. Again, we have found that these nanorods induce authentic autophagy flux in different cell lines (Neuro 2a, PC12 and HeLa cells) through the expression of higher levels of characteristic autophagy marker protein LC3-II and degradation of selective autophagy substrate/cargo receptor p62/SQSTM1. Furthermore, depression of protein aggregation clearance through the autophagy blockade has also been observed by using specific inhibitors (wortmannin and chloroquine), indicating that autophagy is involved in the degradation of huntingtin protein aggregation. Since [Eu(III)(OH)3] nanorods can enhance the degradation of huntingtin protein aggregation via autophagy induction, we strongly believe that these nanorods would be useful for the development of therapeutic treatment strategies for various neurodegenerative diseases in near future using nanomedicine approach., (Copyright © 2013 Elsevier Ltd. All rights reserved.)