Theranostic Mesoporous Silica Nanoparticles Loaded With a Curcumin-Naphthoquinone Conjugate for Potential Cancer Intervention.

A novel theranostic molecule, derived from curcumin (Cur) and naphthoquinone (NQ), allowing for cancer targeting, detection and treatment was previously described and termed CurNQ. To allow for enhanced theranostic capabilities, advanced drug delivery techniques are required. To this end, mesoporous silica nanoparticles (MSN) were synthesized and CurNQ was loaded into its pores to form the novel nanosystem MSN_CurNQ. The formation of the nanosystem aimed to augment the drug delivery of CurNQ through the EPR effect and sustained release. Moreover, the loading of CurNQ into its pores, formed a fluorescent nanoparticle that can be tracked, detected and visualized. Herein, the synthesis of a novel nanosystem is described and its theranostic potential are explored in vitro. MSN with an average size of 108 d.nm, a zeta potential of -42 mV and a PDI of 0.150 were synthesized and were impregnated with CurNQ to form the novel nanosystem MSN_CurNQ. MSN_CurNQ was demonstrated to have pH-responsivity whereby after 96 h, at pH 7.4, 31.5% of CurNQ was released from the MSN compared to 57% release at pH 6.8, corresponding to an increase of 25.5% in release with a 0.6 pH drop. The innate fluorescence was then characterized through confocal and fluorescence microscopy. Microscopy images illustrated the distinct, high intensity innate fluorescence with a high background to target ratio, thus confirming detection capabilities and potentially extending MSN_CurNQ's application to molecular imaging purposes. Moreover, the chemotherapeutic potential of MSN_CurNQ was demonstrated as cell viability was reduced to below 50% in OVCAR-5, CACO-2, CHLA, and MCF-7 cell lines. Furthermore, MSN_CurNQ displayed tumor specific toxicity whereby the cell viability was reduced to a far greater extent in the cancer cell lines compared to a healthy fibroblast cell line (p = 0.000). Indeed, the novel MSN_CurNQ nanosystem has potential for applications in cancer targeting, detection and treatment.

Synthesis and Properties of CurNQ for the Theranostic Application in Ovarian Cancer Intervention.

Synthesis of a novel theranostic molecule for targeted cancer intervention. A reaction between curcumin and lawsone was carried out to yield the novel curcumin naphthoquinone (CurNQ) molecule (2,2'-((((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl) bis(2-methoxy-4,1-phenylene))bis(oxy))bis(naphthalene-1,4-dione). CurNQ's structure was elucidated and was fully characterized. CurNQ was demonstrated to have pH specific solubility, its saturation solubility increased from 11.15 µM at pH 7.4 to 20.7 µM at pH 6.8. This pH responsivity allows for cancer targeting (Warburg effect). Moreover, CurNQ displayed intrinsic fluorescence, thus enabling imaging and detection applications. In vitro cytotoxicity assays demonstrated the chemotherapeutic properties of CurNQ as CurNQ reduced cell viability to below 50% in OVCAR-5 and SKOV3 ovarian cancer cell lines. CurNQ is a novel theranostic molecule for potential targeted cancer detection and treatment.

Oroactive dental biomaterials and their use in endodontic therapy.

Dental biomaterials have revolutionized modern therapies. Untreated dental caries remains the major etiological factor for endodontic treatment, and together with a decreasing rate of tooth loss escalates the importance of continuously improving the materials used for endodontic therapies. Endodontic biomaterials are used for vital pulp therapies, irrigation, intracanal medicaments, obturation and regenerative procedures. These materials offer several functions including: antimicrobial activity, mechanical reinforcement, aesthetics, and therapeutic effects. Vital pulp therapies have seen an improvement in clinical results with an incremental approach to build on the strengths of past materials such as calcium hydroxide and calcium silicates. While sodium hypochlorite remains the gold standard for canal irrigation, numerous nanoparticle formulations have been developed to promote sustained antimicrobial action. Gutta-percha based bulk fillers remain the most common materials for root filling. However, while multiple studies focus on the development of novel formulations containing drugs, glass derivatives or ionic-, polymeric-, or drug- loaded nanoparticles, a lack of reliable and long-term clinical evidence obligates further study as experienced clinicians prefer to use what has worked for decades. This review delves in to the biochemistry of the materials to scrutinize their shortcomings, and where opportunity lies to further enhance their efficacy in endodontic practice. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 108B:201-212, 2020.

Synthesis, Characterisation and In Vitro Permeation, Dissolution and Cytotoxic Evaluation of Ruthenium(II)-Liganded Sulpiride and Amino Alcohol.

Sulpiride (SPR) is a selective antagonist of central dopamine receptors but has limited clinical use due to its poor pharmacokinetics. The aim of this study was to investigate how metal ligation to SPR may improve its solubility, intestinal permeability and prolong its half-life. The synthesis and characterisation of ternary metal complexes [Ru(p -cymene)(L)(SPR)]PF6 (L1 = (R)-(+)-2-amino-3-phenyl-1-propanol, L2 = ethanolamine, L3 = (S)-(+)-2-amino-1-propanol, L4 = 3-amino-1-propanol, L5 = (S)-(+)-2-pyrrolidinemethanol) are described in this work. The stability constant of the [Ru(p -cymene)(SPR)] complex was determined using Job's method. The obtained value revealed higher stability of the metal complex in the physiological pH than in an acidic environment such as the stomach. The ternary metal complexes were characterised by elemental analysis, Fourier transform infrared spectroscopy (FT-IR), 1H and 13C nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), thermal analyses, Ultraviolet-Visible (UV-Vis). Solubility studies showed higher aqueous solubility for complexed SPR than the free drug. Dissolution profiles of SPR from the metal complexes exhibited slower dissolution rate of the drug. Permeation studies through the pig's intestine revealed enhanced membrane permeation of the complexed drug. In vitro methyl thiazolyl tetrazolium (MTT) assay showed no noticeable toxic effects of the ternary metal complexes on Caco-2 cell line.

In situ thermo-co-electroresponsive mucogel for controlled release of bioactive agent.

The purpose of this work was to develop an in situ thermosensitive electro-responsive mucoadhesive gel loaded with bioactive agent (nanocomposite) meant for nose to brain delivery in a controllable manner when electric stimulation is applied. Nanocomposite was developed using a combinatorial blending of chitosan, hydroxypropylmethylcellulose, pluronic F127 and polyaniline which was then loaded with BCNU-Nano-co-Plex (the bioactive agent). The nanocomposite was a liquid at room temperature but formed an in situ mucogel at a temperature of 27.5 ±â€¯0.5 °C. Furthermore, the nanocomposite possessed a redox element which makes it responsive to electrical stimulation (ES). The stimuli responsiveness enabled the formulation to release the bioactive agent when electrical potential was applied and demonstrated a desired 10.28% release of nanoparticles per application cycle. The results further revealed pore formation within the formulation which accommodated the loaded nanoparticles. The release profile also demonstrated a pulsatile release of the bioactive material when subjected to ES. This formulation may therefore be useful as a nose to brain drug delivery system that can be modulated to deliver bioactive agents to the brain via electro-actuation in an "on-off" drug release kinetics by means of an external ES for a controlled nose-to-brain delivery.

Functionalizing bioinks for 3D bioprinting applications.

3D bioprinting has emerged as the intersection between chemistry, biology and technology. Through its integration of cells, biocompatible materials and robotic-controlled dispensing systems, the process enables the production of structures that are biomimetic and functional, thus revolutionizing the concept of tissue engineering. One of the biggest limitations of 3D bioprinting for tissue engineering is the lack of printable materials (bioinks) with all-inclusive properties desirable for the construction of engineered 'bio-physico-functional' tissues and organs. Thus, bioinks are required to be functionalized or altered to produce the most desirable bioarchetypes. Functionalization methods vary across chemical, mechanical, physical and biological methods, and common methods include blending of materials, coatings, crosslinking and exploiting functional groups. In this short review, a description and critical comparison of reported functionalization methods, focusing on their effects and contributions toward bioinks, have been presented.

Chemotherapeutic Efficacy of Implantable Antineoplastic-Treatment Protocols in an Optimal Mouse Model for Human Ovarian Carcinoma Cell Targeting.

The present study aimed to design and develop a nanocomposite drug delivery system employing an antineoplastic-loaded antibody functionalized nanomicelle encapsulated within a Chitosan⁻Poly(vinylpyrrolidone)⁻Poly(N-isopropylacrylamide) (C⁻P⁻N) hydrogel to form an in situ forming implant (ISFI), responsive to temperature and pH for cancer cell-targeting following intraperitoneal implantation. The optimum nanomicelle formulation was surface-functionalized with anti-MUC 16 (antibody) for the targeted delivery of methotrexate to human ovarian carcinoma (NIH:OVCAR-5) cells in Athymic nude mice that expressed MUC16, as a preferential form of intraperitoneal ovarian cancer (OC) chemotherapy. The cross-linked interpenetrating C⁻P⁻N hydrogel was synthesized for the preparation of an in situ-forming implant (ISFI). Subsequently, the ISFI was fabricated by encapsulating a nanocomposite comprising of anti-MUC16 (antibody) functionalized methotrexate (MTX)-loaded poly(N-isopropylacrylamide)-b-poly(aspartic acid) (PNIPAAm-b-PASP) nanomicelles (AF(MTX)NM's) within the cross-linked C⁻P⁻N hydrogel. This strategy enabled specificity and increased the residence time of the nanomicelles at tumor sites over a period exceeding one month, enhancing uptake of drugs and preventing recurrence and chemo-resistance. Chemotherapeutic efficacy was tested on the optimal ovarian tumor-bearing Athymic nude mouse model and the results demonstrated tumor regression including reduction in mouse weight and tumor size, as well as a significant (p < 0.05) reduction in mucin 16 levels in plasma and ascitic fluid, and improved survival of mice after treatment with the experimental anti-MUC16/CA125 antibody-bound nanotherapeutic implant drug delivery system (ISFI) (p < 0.05). The study also concluded that ISFI could potentially be considered an important immuno-chemotherapeutic agent that could be employed in human clinical trials of advanced, and/or recurring, metastatic epithelial ovarian cancer (EOC). The development of this ISFI may circumvent the treatment flaws experienced with conventional systemic therapies, effectively manage recurrent disease and ultimately prolong disease-free intervals in ovarian cancer patients.

Nanotechnology and Glycosaminoglycans: Paving the Way Forward for Ovarian Cancer Intervention.

Ovarian cancer (OC) has gained a great deal of attention due to its aggressive proliferative capabilities, high death rates and poor treatment outcomes, rendering the disease the ultimate lethal gynaecological cancer. Nanotechnology provides a promising avenue to combat this malignancy by the niche fabrication of optimally-structured nanomedicines that ensure potent delivery of chemotherapeutics to OC, employing nanocarriers to act as "intelligent" drug delivery vehicles, functionalized with active targeting approaches for precision delivery of chemotherapeutics to overexpressed biomarkers on cancer cells. Recently, much focus has been implemented to optimize these active targeting mechanisms for treatment/diagnostic purposes employing nanocarriers. This two-part article aims to review the latest advances in active target-based OC interventions, where the impact of the newest antibody, aptamer and folate functionalization on OC detection and treatment is discussed in contrast to the limitations of this targeting mechanism. Furthermore, we discuss the latest advances in nanocarrier based drug delivery in OC, highlighting their commercial/clinical viability of these systems beyond the realms of research. Lastly, in the second section of this review, we comprehensively discussed a focus shift in OC targeting from the well-studied OC cells to the vastly neglected extracellular matrix and motivate the potential for glycosaminoglycans (GAGs) as a more focused extracellular molecular target.

Hypothesis: apo-lactoferrin-Galantamine Proteo-alkaloid Conjugate for Alzheimer's disease Intervention.

Alzheimer's disease (AD) is known to be caused by the accumulation of deformed beta amyloid and hyperphosphorylated tau proteins resulting into formation and aggregation of senile plaques and neurofibrillary tangles in the brain. Additionally, AD is associated with the accumulation of iron or metal ions in the brain which causes oxidative stress. Galantamine (Gal) is one of the therapeutic agents that has been approved for the treatment of AD, but still saddled with numerous side effects and could not address the issue of iron accumulation in the brain. The use of metal chelators to address the iron accumulation has not been successful due to toxicity and inability to address the aggregation of the plaques. We therefore hypothesize a combinatorial antioxidant-metal-chelator approach by formulating a single dosage form that has the ability to prevent the formation of free radicals, plaques and accumulation of iron in the brain. This can be achieved by conjugating Gal with apo-lactoferrin (ApoLf), a natural compound that has high binding affinity for iron, to form an apo-lactoferrin-galantamine proteo-alkaloid conjugate (ApoLf-Gal) as a single dosage form for AD management. The conjugation is achieved through self-assembly of ApoLf which results in encapsulation of Gal. ApoLf changes its conformational structure in the presence of iron; therefore, ApoLf-Gal is proposed to deliver Gal and pick up excess iron when in contact with iron. This strategy has the potential to proffer a dual neuroprotection and neurotherapeutic interventions for the management of AD.

Alternative fluorophores designed for advanced molecular imaging.

Fluorescent molecular imaging has advanced drastically over the past decade. With the development of high-resolution microscopy techniques and the ability to visualize intracellular molecular events, there is a growing need for new fluorophores to accompany these fast-developing techniques. Therefore, there has been substantial development of alternative fluorophores for single-molecule detection and molecular imaging. These rationally designed fluorophores have infinite possibilities and novel fluorophores are constantly being produced for different applications. This review focuses on the recent developments in novel fluorophores designed for molecular imaging and single-molecule detection. Here, single-molecule imaging, smart fluorescent probes, two-photon microscopy, Förster resonance energy transfer (FRET) and super-resolution microscopy are discussed in detail.

Targeted nanotechnologies for cancer intervention: a patent review (2010-2016).

INTRODUCTION: In recent years, several active targeting nanostrategies have been patented for application in cancer theranostics. The versatility of nanostructures in terms of composition, manufacturability, functionalization, and matrix formation make them ideal for carrying large dose of bioactive contents, high density of targeting ligands on their surface, efficient delivery to the site of interest, and capable of forming multicomponent platforms. Areas covered: The patents were classified into polymeric and non-polymeric nanostructures and their applicability in addressing the targeting paradigm related to cancer intervention was explored. Specialized platforms such as nanoparticles, nanomicelles, nanocomposites, nanotubes, quantum dots, metal/silica particles, and dendrimers were cited as targeted nanostructures along with ligands such as antibody fragments, synthetic peptides, aptamers, small molecules, and folates. Here, we focused on patented targeted nanotechnological advances in recent years (2010-2016). Expert opinion: The formulation and performance prerequisites, available nanomaterial options, fabrication feasibility, and challenges and issues related with regulatory approval and patenting of cancer targeted nanocarriers are reviewed. Future research in this area should focus on clinically relevant bioactive combinations, better metastasis control, integration of imaging and theranostic techniques, predictive animal/pre-clinical models, maximal utilisation of extra- and intracellular tumor microenvironment for drug delivery, and exploring the metabolomic-, proteomic-, and genomic-based personalization of cancer nanomedicine.

Multi-target therapeutics for neuropsychiatric and neurodegenerative disorders.

Historically, neuropsychiatric and neurodegenerative disease treatments focused on the 'magic bullet' concept; however multi-targeted strategies are increasingly attractive gauging from the escalating research in this area. Because these diseases are typically co-morbid, multi-targeted drugs capable of interacting with multiple targets will expand treatment to the co-morbid disease condition. Despite their theoretical efficacy, there are significant impediments to clinical success (e.g., difficulty titrating individual aspects of the drug and inconclusive pathophysiological mechanisms). The new and revised diagnostic frameworks along with studies detailing the endophenotypic characteristics of the diseases promise to provide the foundation for the circumvention of these impediments. This review serves to evaluate the various marketed and nonmarketed multi-targeted drugs with particular emphasis on their design strategy.

"On-The-Spot" Arresting of Chondroitin Sulphate Proteoglycans: Implications for Ovarian Adenocarcinoma Recognition and Intervention.

Ovarian Cancer (OC) is one of the leading causes of cancer-associated death among women. The underlying biochemical cause of OC proliferation is usually attributed to the over-expression of Chondroitin Sulphate Proteoglycans (CSPGs) wherein the CS-E subgroup plays a major role in tumor cell proliferation by over-expressing vascular endothelial growth factor (VEGF). We hereby hypothesize that by targeting the OC extracellular matrix using a CS-E-specific antibody, GD3G7, we could provide spatial delivery of crosslinkers and anti-VEGF agents to firstly induce in vivo crosslinking and complexation (arresting) of CS-E into a "biogel mass" for efficient and effective detection, detachment and reduction of tumorous tissue, and secondly inhibit angiogenesis in OC. It is further proposed that the antibody-assisted targeted delivery of CS-E crosslinkers can bind to highly anionic CS-E to form a polyelectrolyte complex to inhibit the formation of ovarian tumor spheroids that are responsible for spheroid-induced mesothelial clearance and progression of OC. The hypothesis also describes the potential in vivo "On-The-Spot" CSPG crosslinkers such as sodium trimetaphosphate (physical crosslinker), 1,12-diaminododecane (chemical crosslinker), poly(ethylene glycol) diglycidyl ether (synthetic polymer), and chitosan (natural polyelectrolyte-forming agent). In conclusion, this hypothesis proposes in vivo spatial crosslinking of CSPGs as a potential theranostic intervention strategy for OC-a first in the field of cancer research.

3-Methyl-1-tosyl-1H-indole-2-carbaldehyde.

The title indole derivative, C(17)H(15)NO(3)S, crystallizes with two independent mol-ecules in the asymmetric unit. The benzene ring of the tosyl group is almost perpedicular to the indole ring in both mol-ecules, with inter-planar angles of 82.60 (5)° and 81.82 (6)°. The two mol-ecules are, as a consequence, able to form an almost centrosymmetric non-bonded dimer, in which the molecules are linked by pairs of C-H⋯π inter-actions. The crystal structure displays a three-dimensional network of C-H⋯O inter-actions. A π-π inter-action occurs between inversion-related indole rings with a centroid-centroid distance of 3.6774 (16) Šand an inter-planar angle of 1.53 (15)°. This inter-action leads to a stacking of mol-ecules along the a axis.