PSMA-Targeted 2-Deoxyglucose-Based Dendrimer Nanomedicine for the Treatment of Prostate Cancer.

Prostate cancer (PC) is the fifth leading cause of cancer-related deaths among men worldwide. Prostate-specific membrane antigen (PSMA), a molecular target of PC, is clinically used for the treatment and diagnosis of PC using radioligand approaches. However, no PSMA-based chemotherapies have yet been approved by the FDA. Here, we present a novel therapeutic approach using PSMA-targeted 2-deoxyglucose-dendrimer (PSMA-2DG-D) for targeted delivery of a potent tyrosine kinase inhibitor, cabozantinib (Cabo), selectively to PC cells. PSMA-2DG-D demonstrates intracellular localization in PSMA (+) PC cells through PSMA-mediated internalization. This PSMA-specific targeting translates to enhanced efficacy of Cabo compared to the free drug when conjugated to PSMA-2DG-D. Furthermore, systemically administered fluorescently labeled PSMA-2DG-D-Cy5 specifically targets PSMA (+) tumors with minimal off-target accumulation in the PC3-PIP tumor xenograft mouse model. This demonstrates that the PSMA-2DG-D platform is a promising new delivery system for potent chemotherapeutics, where systemic side effects are a significant concern.

Multifunctional Gold Nanoparticle-Conjugated Cellulose Nanoonions Alleviate Aß42 Fibrillation-Induced Toxicity via Regulation of Oxidative Stress and Ion Homeostasis.

Inhibition of hen egg white lysozyme (HEWL) and Aß42 fibrillation have been established as the main models for the treatment of systemic lysozyme amyloidosis and Alzheimer's disease (AD), respectively. Several antiamyloidogenic nanomaterials have been developed over the period; however, their intracellular mechanism of action is still not well understood. In this context, plant-based, gold-conjugated, injectable, hydrophilic cellulose nanoonions (CNOs), viz., DH-CNO (∼60 ± 5 nm) and LC-CNO (∼55 ± 12 nm), were developed from their respective hydrophobic cellulose nanocrystals (DH-CNC and LC-CNC) using a single-step chemical template-mediated process. This unique nanocellulose architecture was chemically and morphologically characterized by various spectroscopic and microscopic techniques. Further, the different biophysical studies documented marked the inhibition/disintegration potential of gold-conjugated LC-CNO against HEWL and Aß42 peptide aggregation. It was further observed that inhibition of protein fibrillation could be achieved within ∼10 min when the same materials were used under photoirradiation conditions. In vitro protein aggregation studies using HEK293 cells suggested that gold-conjugated LC-CNO could effectively reduce the cellular toxicity via regulation of oxidative stress and ion homeostasis. The outcome of the present study will help in designing cellulose-based novel functional nanochaperones against various neurodegenerative diseases.

Discovery of 2-deoxy glucose surfaced mixed layer dendrimer: a smart neuron targeted systemic drug delivery system for brain diseases.

The availability of non-invasive drug delivery systems capable of efficiently transporting bioactive molecules across the blood-brain barrier to specific cells at the injury site in the brain is currently limited. Delivering drugs to neurons presents an even more formidable challenge due to their lower numbers and less phagocytic nature compared to other brain cells. Additionally, the diverse types of neurons, each performing specific functions, necessitate precise targeting of those implicated in the disease. Moreover, the complex synthetic design of drug delivery systems often hinders their clinical translation. The production of nanomaterials at an industrial scale with high reproducibility and purity is particularly challenging. However, overcoming this challenge is possible by designing nanomaterials through a straightforward, facile, and easily reproducible synthetic process. Methods: In this study, we have developed a third-generation 2-deoxy-glucose functionalized mixed layer dendrimer (2DG-D) utilizing biocompatible and cost-effective materials via a highly facile convergent approach, employing copper-catalyzed click chemistry. We further evaluated the systemic neuronal targeting and biodistribution of 2DG-D, and brain delivery of a neuroprotective agent pioglitazone (Pio) in a pediatric traumatic brain injury (TBI) model. Results: The 2DG-D exhibits favorable characteristics including high water solubility, biocompatibility, biological stability, nanoscale size, and a substantial number of end groups suitable for drug conjugation. Upon systemic administration in a pediatric mouse model of traumatic brain injury (TBI), the 2DG-D localizes in neurons at the injured brain site, clears rapidly from off-target locations, effectively delivers Pio, ameliorates neuroinflammation, and improves behavioral outcomes. Conclusions: The promising in vivo results coupled with a convenient synthetic approach for the construction of 2DG-D makes it a potential nanoplatform for addressing brain diseases.

Erythrocyte Membrane Cloaked Cytokine Functionalized Gold Nanoparticles Create Localized Controlled Inflammation for Rapid In Vitro Wound Healing.

Due to impaired wound healing, millions of acute and chronic wound cases with increased morbidity have been recorded in the developed countries. The primary reason has been attributed to uncontrolled inflammation at the wound site, which makes healing impossible for years. The use of red blood cell (RBC) ghosts or erythrocyte membranes for different theranostic applications has gained significant attention in recent years due to their biocompatibility and biomimicking properties. Our study builds upon this concept by presenting a new approach for creating an improved and controlled inflammatory response by employing RBC ghost encapsulated tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) modified AuNPs (gold nanoparticles) for accelerating the wound healing at early postinjury stage (∼48 h). The results suggested that the developed GTNFα-IL6@AuNPs created a controlled and time dependent TNF-α response and showed increased reactive oxygen species generation at ∼12 h. Further, proper M1/M2 functional transition of macrophages was observed in macrophages at different time intervals. The expression results suggested that the levels of wound healing biomarkers like transforming growth factor-ß (1.8-fold) and collagen (2.4-fold) increased while matrix metalloproteinase (3-8-fold) levels declined at later stages, which possibly increased the cell migration rate of NP treated cells to ∼90%. Hence, we are here reducing the timeline of the inflammatory phase of wound healing by actually creating a controlled inflammatory response at an early postinjury stage and further assisting in regaining the ability of cells for wound remodelation and repair. We intend that this new approach has the potential to improve the current treatment strategies for wound healing and skin repair under both in vitro and in vivo conditions.

Physio-Biochemical Integrators and Transcriptome Analysis Reveal Nano-Elicitation Associated Response during Dendrocalamus asper (Schult. and Schult. F.) Backer ex K. Heyne Micropropagation.

Bamboos are perennial, arborescent, monocarpic and industrially important non-timber plants. They are important for various purposes, such as carbon sequestration, biodiversity support, construction, and food and fiber production. However, traditional vegetative propagation is insufficient for bamboo multiplication. Moreover, little is known about the mechanism of gold nanoparticles (AuNPs) in vitro proliferation and regulation of physiological and biochemical properties. In this study, we investigated the impacts of citrate and cetyltrimethylammonium bromide (CTAB) coated AuNPs on in vitro proliferation, photosynthetic pigment content and antioxidant potential of Dendrocalamus asper (Schult. and Schult. F.) Backer ex K. Heyne. Various morpho-physiological and biochemical parameters were differentially affected along the citrate- and CTAB-coated AuNPs concentration gradients (200-600 µM). In vitro shoot proliferation, photosynthetic pigment content and antioxidant activities were higher in D. asper grown on Murashige and Skoog medium supplemented with 2 mg·L-1 benzyladenine and 400 µM citrate-coated AuNPs than in those grown on Murashige and Skoog medium supplemented with 600 µM CTAB- coated AuNPs. Identification of genes regulating in vitro D. asper proliferation will help understand the molecular regulation of AuNPs-mediated elicitation for modulating various physiological and biochemical activities during micropropagation. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analyses identified differentially expressed genes associated with in vitro modulation of AuNPs-regulated biological processes and molecular functions. The findings of this study provide new insight into AuNPs-mediated elicitation of in vitro mass scale bamboo propagation.

Nanogel-based Transdermal Drug Delivery System: A Therapeutic Strategy with Under Discussed Potential.

The application of nanoparticles in medication delivery has revolutionized the field of therapeutic biology. To improve medical efficacy, currently, drug nanocarriers are employed to control the release and stability, expand its circulation time, or protect it from cell clearance or premature breakdown. A crosslinked polymeric framework is used to crosslink the hydrogel nanoparticle dispersions for safer and stable delivery on target sites. Nanogels have developed in the last two decades as potential biomaterials with a wide variety of applications. Later attributes of nanogels are mainly due to large surface areas, retention of molecules, size flexibility, and water-based formulations that have made them popular as drug delivery vehicles, as seen by several in vivo uses. The gel matrix containing the nanoparticle drug demonstrated a considerable increase in drug penetration in transdermal drug and topical delivery methods. This review aims to understand why and how nanogels are considered so innovative as a drug delivery method. It also examines their preparation methods and applications in the pharmaceutical and biomedical fields and discusses the benefits of nanogels, including swelling capacity and stimulus stimuli sensitivity. Nanogels, on the other hand, have recently been investigated for applications outside the field of biomedicine. Since there are many possible uses for nanogels, we have comprehensively reviewed the current state of the art for all feasible nanogel applications and manufacturing methods.

Facile synthesis of biogenic silica nanomaterial loaded transparent tragacanth gum hydrogels with improved physicochemical properties and inherent anti-bacterial activity.

In this report, biogenic, crystalline (∼60.5 ± 2%) bowknot structured silica nanoparticles (BSNPs) of length ∼ 274 ± 7 nm and width ∼ 36 ± 2 nm were isolated from invasive species viz. Lantana camara. These were then chemically modified using nitrogen containing moieties viz. APTES and CTAB. These modified BSNPs were then used as electrostatic cross-linking agents for the formation of tragacanth gum (TG) hydrogels. The cytocompatible CTAB@BSNP-TG hydrogels documented ∼10-12 fold enhancement in anti-bacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa when compared with TG hydrogels. Disruption of the bacterial membrane by ROS generation and protein leakage were responsible for anti-bacterial activity. A cell migration assay suggested that CTAB@BSNP-TG augmented the cell proliferation of NIH-3T3 cells compared to other TG hydrogels. The present study will pave the path for the development of organic-inorganic hybrid nanocomposite-based hydrogels for anti-bacterial and cell migration applications.

Protein-Cloaked Nanoparticles for Enhanced Cellular Association and Controlled Pathophysiology via Immunosurveillance Escape.

Weak interactions play an important role in soft corona (SC) formation and thus help in evaluating the biological fate of the nanoparticles (NPs). Preadsorption of specific proteins on the NP surface, leading to SC formation, has been found to help NPs in evading immunosurveillance. However, the role of different preadsorbed biomolecules in determining the NP pathophysiology and cellular association, upon their re-exposure to in vivo conditions, still remains elusive. Here, differently charged gold NPs were precoated with two different blood components, viz. red blood cells and human serum albumin protein, and these were then re-exposed to human serum. Cloaking NPs with protein improved the NP colloidal stability and other physico-chemical properties along with increased cellular association. Detailed proteomic analysis suggested that protein-camouflaged NPs showed a decrease in immune-responsive proteins compared to their bare counterparts. Further, it was also observed that the secondary protein signature on the NP surface was governed by primary protein coating; however, the event was more or less NP charge-independent. This study will pave the path for future strategies to make NPs invincible to the immunosurveillance system of the body.

The curious cases of nanoparticle induced amyloidosis during protein corona formation and anti-amyloidogenic nanomaterials: Paradox or prejudice?

Protein corona (PC) formation remains a major hurdle in the successful delivery of nanomedicines to the target sites. Interacting proteins have been reported to undergo structural changes on the nanoparticle (NP) surface which invariably impacts their biological activities. Such structural changes are the result of opening of more binding sites of proteins to adsorb on the NP surface. The process of conversion of α-helix proteins to their ß-sheet enriched counterpart is termed as amyloidosis and in case of PC formation, NPs apparently play the crucial role of being the nucleation centres where this process takes place. Conversely, increasing numbers of artificial nano-chaperones are being used to treat the protein misfolding disorders. Anti-amyloidogenic nanomaterials (NM) have been gaining utmost importance in inhibiting Aß42 (hallmark peptide for Alzheimer's disease) and Hen egg white lysozyme (HEWL, model protein for systemic amyloidosis) aggregation. Interestingly, in this process, NPs inhibit protein ß-sheet enrichment. These two seemingly opposite roles of NPs, propelling confirmatory change onto the smorgasbord of adsorbed native proteins and the ability of NPs in inhibiting amyloidosis creates a paradox, which has not been discussed earlier. Here, we highlight the key points from both the facets of the NP behaviour with respect to their physicochemical properties and the nature of proteins they adsorb onto them to unravel the mystery. BRIEF: Protein corona formation remains a major hurdle in achieving the desired efficacy of nanomedicine. Proteins when interact with nanoparticle (NP) surface, undergo both structural and biological changes. Again, NPs are known to exhibit anti-amyloidogenic behaviour where these play the crucial role of preventing any change in their native structure. Such seemingly different roles of NPs need sincere inquisition.

Molecular recognition based rapid diagnosis of immunoglobulins via proteomic profiling of protein-nanoparticle complexes.

Protein-nanoparticle (NP) interaction, which inevitably form protein corona (PC), has been the subject of much debate about its role in modern biomedical research. In this regard, PC associated with two different NPs viz., magneto-fluorescent (MF) and chitosan coated MF (CMF) NPs were thoroughly investigated, to analyze the effect of polymer coating on protein adsorption. Bradford assay, along with the spectroscopic and microscopic studies suggested increase in adsorbed protein quantity, though the results varied significantly on moving from bare to polymeric coating and in vitro to ex vivo conditions. Interestingly, polymer coated NPs showed increased protein adsorption and induce minimal changes in protein structural integrity under the same conditions. We predict that the changes in secondary structure of primary corona determine the overall signature of surface binding proteins in PC. Our findings suggested that rapid diagnosis of immunoglobulins is possible using the concept of protein corona formation ex vivo.

Nanomaterials as potential and versatile platform for next generation tissue engineering applications.

Tissue engineering (TE) is an emerging field where alternate/artificial tissues or organ substitutes are implanted to mimic the functionality of damaged or injured tissues. Earlier efforts were made to develop natural, synthetic, or semisynthetic materials for skin equivalents to treat burns or skin wounds. Nowadays, many more tissues like bone, cardiac, cartilage, heart, liver, cornea, blood vessels, and so forth are being engineered using 3-D biomaterial constructs or scaffolds that could deliver active molecules such as peptides or growth factors. Nanomaterials (NMs) due to their unique mechanical, electrical, and optical properties possess significant opportunities in TE applications. Traditional TE scaffolds were based on hydrolytically degradable macroporous materials, whereas current approaches emphasize on controlling cell behaviors and tissue formation by nano-scale topography that closely mimics the natural extracellular matrix. This review article gives a comprehensive outlook of different organ specific NMs which are being used for diversified TE applications. Varieties of NMs are known to serve as biological alternatives to repair or replace a portion or whole of the nonfunctional or damaged tissue. NMs may promote greater amounts of specific interactions stimulated at the cellular level, ultimately leading to more efficient new tissue formation. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2433-2449, 2019.

Inhibition of Glycation-Induced Aggregation of Human Serum Albumin by Organic-Inorganic Hybrid Nanocomposites of Iron Oxide-Functionalized Nanocellulose.

Protein aggregation leads to the transformation of proteins from their soluble form to the insoluble amyloid fibrils and these aggregates get deposited in the specific body tissues, accounting for various diseases. To prevent such an aggregation, organic-inorganic hybrid nanocomposites of iron oxide nanoparticle (NP, ∼6.5-7.0 nm)-conjugated cellulose nanocrystals (CNCs) isolated from Syzygium cumini (SC) and Pinus roxburghii (PR) were chemically synthesized. Transmission electron microscopy (TEM) images of the nanocomposites suggested that the in situ-synthesized iron oxide NPs were bound to the CNC surface in a uniform and regular fashion. The ThT fluorescence assay together with 8-anilino-1-naphthalenesulfonic acid, Congo Red, and CD studies suggested that short fiber-based SC nanocomposites showed better inhibition as well as dissociation of human serum albumin aggregates. The TEM and fluorescence microscopy studies supported similar observations. Native polyacrylamide gel electrophoresis results documented dissociation of higher protein aggregates in the presence of the developed nanocomposite. Interestingly, the dissociated proteins retained their biological function by maintaining a high amount of α-helix content. The in vitro studies with HEK-293 cells suggested that the developed nanocomposite reduces aggregation-induced cytotoxicity by intracellular reactive oxygen species scavenging and maintaining the Ca2+ ion-channel. These results indicated that the hybrid organic-inorganic nanocomposite, with simultaneous sites for hydrophobic and hydrophilic interactions, tends to provide a larger surface area for nanocomposite-protein interactions, which ultimately disfavors the nucleation step for fibrillation for protein aggregates.

Synthetic Lethality: From Research to Precision Cancer Nanomedicine.

Cancer is an evolutionary disease with multiple genetic alterations, accumulated due to chromosomal instability and/or aneuploidy and it sometimes acquires drug-resistant phenotype also. Whole genome sequencing and mutational analysis helped in understanding the differences among persons for predisposition of a disease and its treatment non-responsiveness. Thus, molecular targeted therapies came into existence. Among them, the concept of synthetic lethality have enthralled great attention as it is a pragmatic approach towards exploiting cancer cell specific mutations to specifically kill cancer cells without affecting normal cells and thus enhancing anti-cancer drug therapeutic index. Thus, this approach helped in discovering new therapeutic molecules for development of precision medicine. Nanotechnology helped in delivering these molecules to the target site in an effective concentration thus reducing off target effects of drugs, dose and dosage frequency drugs. Researchers have tried to deliver siRNA targeting synthetic lethal partner for target cancer cell killing by incorporating it in nanoparticles and it has shown efficacy by preventing tumor progression. This review summarizes the brief introduction of synthetic lethality, and synthetic lethal gene interactions, with a major focus on its therapeutic anticancer potential with the application of nanotechnology for development of personalized medicine.