Co-emulsified Alginate-Eudragit Nanoparticles: Potential Carriers for Localized and Time-defined Release of Tenofovir in the Female Genital Tract.

This research aimed to explore the possibilities of Eudragit S100 (ES100) and sodium alginate as carriers for tenofovir disoproxil fumarate (TDF) in the female genital tract. Alginate and alginate-ES100 nanoparticles were prepared using the ionic gelation and emulsion/gelation complexation method, respectively. The nanocarriers were tested using morphological, physicochemical, in vitro drug release, and cytotoxicity analyses. In SEM and TEM images, the presence of spherical and uniformly distributed nanoparticles was revealed. The FTIR spectrum showed that alginate and calcium chloride interacted due to ionic bonds linking divalent calcium ions and the -COO- of alginate groups. Alginate and ES100 interacted via the ester C=O amide stretching. The results obtained from XRD and DSC, on the other hand, revealed a favorable interaction between sodium alginate and ES100 polymers, as evidenced by the crystallization peaks observed. Under experimental design analysis and optimization, overall size distribution profiles ranged from 134.9 to 228.0 nm, while zeta potential results showed stable nanoparticles (-17.8 to -38.4 MV). The optimal formulation exhibited a maximum cumulative in vitro release of 72% (pH 4.2) up to 96 h. The cytotoxicity tests revealed the safety of TDF-loaded nanoparticles on vaginal epithelial cells at concentrations of 0.025 mg/mL, 0.5 mg/mL, and 1 mg/mL for 72 h. These results indicated that alginate-ES100 nanoparticles have the potential to preserve and sustain the release of the TDF drug in the FGT. The future goal is to develop a low-dose non-toxic microbicide that can be administered long term in the vagina to cater to both pregnant and non-pregnant HIV patients.

A 3D-Printed Biomaterial Scaffold Reinforced with Inorganic Fillers for Bone Tissue Engineering: In Vitro Assessment and In Vivo Animal Studies.

This research aimed to substantiate the potential practicality of utilizing a matrix-like platform, a novel 3D-printed biomaterial scaffold, to enhance and guide host cells' growth for bone tissue regeneration. The 3D biomaterial scaffold was successfully printed using a 3D Bioplotter® (EnvisionTEC, GmBH) and characterized. Osteoblast-like MG63 cells were utilized to culture the novel printed scaffold over a period of 1, 3, and 7 days. Cell adhesion and surface morphology were examined using scanning electron microscopy (SEM) and optical microscopy, while cell viability was determined using MTS assay and cell proliferation was evaluated using a Leica microsystem (Leica MZ10 F). The 3D-printed biomaterial scaffold exhibited essential biomineral trace elements that are significant for biological bone (e.g., Ca-P) and were confirmed through energy-dispersive X-ray (EDX) analysis. The microscopy analyses revealed that the osteoblast-like MG63 cells were attached to the printed scaffold surface. The viability of cultured cells on the control and printed scaffold increased over time (p < 0.05); however, on respective days (1, 3, and 7 days), the viability of cultured cells between the two groups was not significantly different (p > 0.05). The protein (human BMP-7, also known as growth factor) was successfully attached to the surface of the 3D-printed biomaterial scaffold as an initiator of osteogenesis in the site of the induced bone defect. An in vivo study was conducted to substantiate if the novel printed scaffold properties were engineered adequately to mimic the bone regeneration cascade using an induced rabbit critical-sized nasal bone defect. The novel printed scaffold provided a potential pro-regenerative platform, rich in mechanical, topographical, and biological cues to guide and activate host cells toward functional regeneration. The histological studies revealed that there was progress in new bone formation, especially at week 8 of the study, in all induced bone defects. In conclusion, the protein (human BMP-7)-embedded scaffolds showed higher regenerative bone formation potential (week 8 complete) compared to the scaffolds without protein (e.g., growth factor; BMP-7) and the control (empty defect). At 8 weeks postimplantation, protein (BMP-7) significantly promoted osteogenesis as compared to other groups. The scaffold underwent gradual degradation and replacement by new bones at 8 weeks in most defects.

In Vitro Prototyping of a Nano-Organogel for Thermo-Sonic Intra-Cervical Delivery of 5-Fluorouracil-Loaded Solid Lipid Nanoparticles for Cervical Cancer.

Solid lipid nanoparticles (SLNs) are used extensively to achieve site-specific drug delivery with improved bioavailability and reduced toxicity. This work focused on a new approach to provide site-specific stimuli-responsive delivery of SLNs loaded within thermo-sonic nano-organogel (TNO) variants to deliver the model chemotherapeutic agent 5-FU in treating cervical cancer. Pharmaceutically stable nanospherical SLNs comprising poly-L-lactic acid (PLA), palmitic acid (PA), and polyvinyl alcohol (PVA) were prepared and incorporated into TNO variants augmented by external thermal and ultrasound stimuli for release of 5-FU in the cervix. Results revealed that rate-modulated 5-FU release was achieved from SLNs (particle size =450.9 nm; PDI =0.541; zeta potential =-23.2 mV; %DL =33%) within an organogel upon exposure to either a single (thermo-) and/or both (thermo-sonic) stimuli. 5FU was released from all TNO variants with an initial burst on day 1 followed by sustained release over 14 days. TNO 1 provided desirable release over 15 days (44.29% vs. 67.13% under single (T) or combined (TU) stimuli, respectively). Release rates were primarily influenced by the SLN:TO ratio in tandem with biodegradation and hydrodynamic influx. Biodegradation by day 7 revealed that variant TNO 1 (1:5) released 5FU (46.8%) analogous to its initial mass than the other TNO variants (i.e., ratios of 2:5 and 3:5). FT-IR spectra revealed assimilation of the system components and corroborative with the DSC and XRD analysis (i.e., in ratios of PA:PLA 1:1 and 2:1). In conclusion, the TNO variants produced may be used as a potential stimuli-responsive platform for the site-specific delivery of chemotherapeutic agents such as 5-FU to treat cervical cancer.

Novel ferrocenylbisphosphonate hybrid compounds: Synthesis, characterization and potent activity against cancer cell lines.

The toxicity of existing anticancer agents on healthy cells and the emergence of multidrug-resistance cancer cells have led to the search for less toxic anticancer agents with different mechanisms of action. In this study, a novel class of ferrocenylbisphosphonate hybrid compounds (H1-H8) were designed and characterized using NMR, IR and HRMS. The in vitro anticancer activity of the hybrid compounds on HeLa (cervix adenocarcinoma) and A549 (non-small cell lung cancer cell lines) was evaluated. The structure-activity relationship of the hybrid molecules was also studied. The lead compound, tetraethyl (3-(4-oxo-4-ferrocenylbutanamido) propane-1-1-diylbis(phosphonate) (H6) exhibited higher cytotoxicity on A549 (IC50 = 28.15 µM) than cisplatin (IC50 = 58.28 µM), while its activity on HeLa cells (IC50 = 14.69 µM) was equivalent to that of cisplatin 15.10 µM (HeLa cells). H6 (IC50 = 95.58 µM) was also five times less toxic than cisplatin (IC50 = 20.86 µM) on fibroblast NIH3T3 suggesting that H6 can be a future replacement for cisplatin due to its non-toxicity to healthy cells. Interestingly, some ferrocene and bisphosphonate parent compounds exhibited promising anticancer activity with 4-ferrocenyl-4-oxobutanoic acid (FI) exhibiting higher cytotoxic activity (IC50 = 1.73 µM) than paclitaxel (IC50 = 3.5 µM) on A549 cell lines. F1 also exhibited lower cytotoxicity than paclitaxel and cisplatin on the normal murine fibroblast cell line (NIH3T3). The molecular docking studies showed H6 strong binding affinity for the STAT3 signaling pathway in A549 cell line, and the MAdCAM-1 and cellular tumor antigen p53 proteins in HeLa cell lines.

In Vivo Evaluation of Praziquantel-Loaded Solid Lipid Nanoparticles against S. mansoni Infection in Preclinical Murine Models.

This study aimed to develop and assess the long-term stability of drug-loaded solid lipid nanoparticles (SLNs). The SLNs were designed to extend the release profile, overcome the problems of bioavailability and solubility, investigate toxicity, and improve the antischistosomal efficacy of praziquantel. The aim was pursued using solvent injection co-homogenization techniques to fabricate SLNs in which Compritol ATO 888 and lecithin were used as lipids, and Pluronic F127 (PF127) was used as a stabilizer. The long-term stability effect of the PF127 as a stabilizer on the SLNs was evaluated. Dynamic light scattering (DLS) was used to determine the particle size, stability, and polydispersity. The morphology of the SLNs was examined through the use of transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The chemical properties, as well as the mechanical, thermal, and crystal behaviours of SLNs were evaluated using FTIR, ElastoSens Bio2, XRPD, DSC, and TGA, respectively. SLNs with PF127 depicted an encapsulation efficiency of 71.63% and a drug loading capacity of 11.46%. The in vitro drug release study for SLNs with PF127 showed a cumulative release of 48.08% for the PZQ within 24 h, with a similar release profile for SLNs' suspension after 120 days. DLS, ELS, and optical characterization and stability profiling data indicate that the addition of PF127 as the surfactants provided long-term stability for SLNs. In vitro cell viability and in vivo toxicity evaluation signify the safety of SLNs stabilized with PF127. In conclusion, the parasitological data showed that in S. mansoni-infected mice, a single (250 mg/kg) oral dosage of CLPF-SLNs greatly improved PZQ antischistosomal efficacy both two and four weeks post-infection. Thus, the fabricated CLPF-SLNs demonstrated significant efficiency inthe delivery of PZQ, and hence are a promising therapeutic strategy against schistosomiasis.

Molecule(s) of Interest: I. Ionic Liquids-Gateway to Newer Nanotechnology Applications: Advanced Nanobiotechnical Uses', Current Status, Emerging Trends, Challenges, and Prospects.

Ionic liquids are a potent class of organic compounds exhibiting unique physico-chemical properties and structural compositions that are different from the classical dipolar organic liquids. These molecules have found diverse applications in different chemical, biochemical, biophysical fields, and a number of industrial usages. The ionic liquids-based products and procedural applications are being developed for a number of newer industrial purposes, and academic uses in nanotechnology related procedures, processes, and products, especially in nanobiotechnology and nanomedicine. The current article overviews their uses in different fields, including applications, functions, and as parts of products and processes at primary and advanced levels. The application and product examples, and prospects in various fields of nanotechnology, domains of nanosystem syntheses, nano-scale product development, the process of membrane filtering, biofilm formation, and bio-separations are prominently discussed. The applications in carbon nanotubes; quantum dots; and drug, gene, and other payload delivery vehicle developments in the nanobiotechnology field are also covered. The broader scopes of applications of ionic liquids, future developmental possibilities in chemistry and different bio-aspects, promises in the newer genres of nanobiotechnology products, certain bioprocesses controls, and toxicity, together with emerging trends, challenges, and prospects are also elaborated.

Synthesis and Cytotoxic Activity of 1,2,4-Triazolo-Linked Bis-Indolyl Conjugates as Dual Inhibitors of Tankyrase and PI3K.

A series of new 1,2,4-triazolo-linked bis-indolyl conjugates (15a-r) were prepared by multistep synthesis and evaluated for their cytotoxic activity against various human cancer cell lines. It was observed that they were more susceptible to colon and breast cancer cells. Conjugates 15o (IC50 = 2.04 µM) and 15r (IC50 = 0.85 µM) illustrated promising cytotoxicity compared to 5-fluorouracil (5-FU, IC50 = 5.31 µM) against the HT-29 cell line. Interestingly, 15o and 15r induced cell cycle arrest at the G0/G1 phase and disrupted the mitochondrial membrane potential. Moreover, these conjugates led to apoptosis in HT-29 at 2 µM and 1 µM, respectively, and also enhanced the total ROS production as well as the mitochondrial-generated ROS. Immunofluorescence and Western blot assays revealed that these conjugates reduced the expression levels of the PI3K-P85, ß-catenin, TAB-182, ß-actin, AXIN-2, and NF-κB markers that are involved in the ß-catenin pathway of colorectal cancer. The results of the in silico docking studies of 15r and 15o further support their dual inhibitory behaviour against PI3K and tankyrase. Interestingly, the conjugates have adequate ADME-toxicity parameters based on the calculated results of the molecular dynamic simulations, as we found that these inhibitors (15r) influenced the conformational flexibility of the 4OA7 and 3L54 proteins.

In Situ Forming Chitosan-Alginate Interpolymer Complex Bioplatform for Wound Healing and Regeneration.

Cytocompatibility, biocompatibility, and biodegradability are amongst the most desirable qualities of wound dressings and can be tuned during the bioplatform fabrication steps to enhance wound healing capabilities. A three-stepped approach (partial-crosslinking, freeze-drying, and pulverisation) was employed in fabricating a particulate, partially crosslinked (PC), and transferulic acid (TFA)-loaded chitosan-alginate (CS-Alg) interpolymer complex (IPC) with enhanced wound healing capabilities. The PC TFA-CS-Alg IPC bioplatform displayed fluid uptake of 3102% in 24 h and a stepwise degradation up to 53.5% in 14 days. The PC TFA-CS-Alg bioplatform was used as a bioactive delivery system with an encapsulation efficiency of 65.6%, bioactive loading of 9.4%, burst release of 58.27%, and a steady release of 1.91% per day. PC TFA-CS-Alg displayed a shift in cytocompatibility from slightly cytotoxic (60-90% cell viability) to nontoxic (> 90% cell viability) over a 72-h period in NIH-3T3 cells. The wound closure and histological evaluations of the lesions indicated better wound healing performance in lesions treated with PC TFA-CS-Alg and PC CS-Alg compared to those treated with the commercial product and the control. Application of the particulate bioplatform on the wound via sprinkles, the in situ hydrogel formation under fluid exposure, and the accelerated wound healing performances of the bioplatforms make it a good candidate for bioactive delivery system and skin tissue regeneration.

Gellan-Xanthan Hydrogel Conduits with Intraluminal Electrospun Nanofibers as Physical, Chemical and Therapeutic Cues for Peripheral Nerve Repair.

Optimal levels of functional recovery in peripheral nerve injuries remain elusive due to the architectural complexity of the neuronal environment. Commercial nerve repair conduits lack essential guidance cues for the regenerating axons. In this study, the regenerative potential of a biosimulated nerve repair system providing three types of regenerative cues was evaluated in a 10 mm sciatic nerve-gap model over 4 weeks. A thermo-ionically crosslinked gellan-xanthan hydrogel conduit loaded with electrospun PHBV-magnesium oleate-N-acetyl-cysteine (PHBV-MgOl-NAC) nanofibers was assessed for mechanical properties, nerve growth factor (NGF) release kinetics and PC12 viability. In vivo functional recovery was based on walking track analysis, gastrocnemius muscle mass and histological analysis. As an intraluminal filler, PHBV-MgOl-NAC nanofibers improved matrix resilience, deformation and fracture of the hydrogel conduit. NGF release was sustained over 4 weeks, governed by Fickian diffusion and Case-II relaxational release for the hollow conduit and the nanofiber-loaded conduit, respectively. The intraluminal fibers supported PC12 proliferation by 49% compared to the control, preserved up to 43% muscle mass and gradually improved functional recovery. The combined elements of physical guidance (nanofibrous scaffolding), chemical cues (N-acetyl-cysteine and magnesium oleate) and therapeutic cues (NGF and diclofenac sodium) offers a promising strategy for the regeneration of severed peripheral nerves.

Fabrication and Characterisation of a Photo-Responsive, Injectable Nanosystem for Sustained Delivery of Macromolecules.

The demand for biodegradable sustained release carriers with minimally invasive and less frequent administration properties for therapeutic proteins and peptides has increased over the years. The purpose of achieving sustained minimally invasive and site-specific delivery of macromolecules led to the investigation of a photo-responsive delivery system. This research explored a biodegradable prolamin, zein, modified with an azo dye (DHAB) to synthesize photo-responsive azoprolamin (AZP) nanospheres loaded with Immunoglobulin G (IgG). AZP nanospheres were incorporated in a hyaluronic acid (HA) hydrogel to develop a novel injectable photo-responsive nanosystem (HA-NSP) as a potential approach for the treatment of chorio-retinal diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. AZP nanospheres were prepared via coacervation technique, dispersed in HA hydrogel and characterised via infrared spectroscopy (FTIR), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). Size and morphology were studied via scanning electron microscopy (SEM) and dynamic light scattering (DLS), UV spectroscopy for photo-responsiveness. Rheological properties and injectability were investigated, as well as cytotoxicity effect on HRPE cell lines. Particle size obtained was <200 nm and photo-responsiveness to UV = 365 nm by decreasing particle diameter to 94 nm was confirmed by DLS. Encapsulation efficiency of the optimised nanospheres was 85% and IgG was released over 32 days up to 60%. Injectability of HA-NSP was confirmed with maximum force 10 N required and shear-thinning behaviour observed in rheology studies. In vitro cell cytotoxicity effect of both NSPs and HA-NSP showed non-cytotoxicity with relative cell viability of ≥80%. A biocompatible, biodegradable injectable photo-responsive nanosystem for sustained release of macromolecular IgG was successfully developed.

Advanced Strategies for Tissue Engineering in Regenerative Medicine: A Biofabrication and Biopolymer Perspective.

Tissue engineering is known to encompass multiple aspects of science, medicine and engineering. The development of systems which are able to promote the growth of new cells and tissue components are vital in the treatment of severe tissue injury and damage. This can be done through a variety of different biofabrication strategies including the use of hydrogels, 3D bioprinted scaffolds and nanotechnology. The incorporation of stem cells into these systems and the advantage of this is also discussed. Biopolymers, those which have a natural original, have been particularly advantageous in tissue engineering systems as they are often found within the extracellular matrix of the human body. The utilization of biopolymers has become increasing popular as they are biocompatible, biodegradable and do not illicit an immune response when placed into the body. Tissue engineering systems for use with the eye are also discussed. This is of particular interest as the eye is known as an immune privileged site resulting in an extremely limited ability for natural cell regeneration.

Lipopolysaccharide Nanosystems for the Enhancement of Oral Bioavailability.

Nanosystems that incorporate both polymers and lipids have garnered attention as emerging nanotechnology approach for oral drug delivery. These hybrid systems leverage on the combined properties of polymeric and lipid-based nanocarriers while eliminating their inherent limitations. In view of the safety-related benefits of naturally occurring polymers, we have focused on systems incorporating polysaccharides and derivatives into the hybrid structure. The aim of this review is to evaluate existing biopolymers with specific focus on lipopolysaccharide hybrid systems and their advancement toward enhancing oral drug delivery. Furthermore, we shall identify future research areas that require further exploration toward achieving an optimized hybrid system for easy translation into clinical use. In this review, we have appraised formulations that combined polysaccharides/derivatives with lipids in a single nanocarrier system. These formulations were grouped into lipid-core-polysaccharide-shell systems, polysaccharide-core-lipid-shell systems, self-emulsifying lipopolysaccharide hybrid systems, and hybrid lipopolysaccharide matrix systems. In these systems, we highlighted how the polysaccharide phase enhances the oral absorption of encapsulated bioactives with regard to their function and mechanism. The various lipopolysaccharide designs presented in this review demonstrated significant improvement in pharmacokinetics of bioactives. A multitude of studies found lipopolysaccharide hybrid systems as nascent nanoplatforms for the oral delivery of challenging bioactives due to features that favor gastrointestinal absorption and bioavailability improvement. With future research already geared toward product optimization and scaling up processes, as well as detailed pharmacological and toxicology pre-clinical testing, these versatile systems will have remarkable impact in clinical application.

Functionalized, Vertically Super-Aligned Multiwalled Carbon Nanotubes for Potential Biomedical Applications.

Currently, there is a lack of ultrasensitive diagnostic tool to detect some diseases such as ischemic stroke, thereby impacting effective and efficient intervention for such diseases at an embryonic stage. In addition to the lack of proper detection of the neurological diseases, there is also a challenge in the treatment of these diseases. Carbon nanotubes have a potential to be employed in solving the theragnostic challenges in those diseases. In this study, carbon nanotubes were successfully synthesized for potential application in the detection and treatment of the neurological diseases such as ischemic stroke. Vertically aligned multiwalled carbon nanotubes (VA-MWCNTs) were purified with HCl, carboxylated with H2SO4:HNO3 (3:1) and acylated with SOCl2 for use in potential targeting studies and for the design of a carbon-based electrode for possible application in the diagnosis of neurological diseases, including ischemic stroke. MWCNTs were washed, extracted from the filter membranes and dried in a vacuum oven at 60 °C for 24 h prior to functionalization and PEGylation. CNTs were characterized by SEM, TEM, OCA, DLS, CV and EIS. The HCl-treated CNT obtained showed an internal diameter, outer diameter and thickness of 8 nm, 34 nm and 75 µm, while these parameters for the H2SO4-HNO3-treated CNT were 8 nm, 23 nm and 41µm, respectively. PEGylated CNT demonstrated zeta potential, polydispersive index and particle size distribution of 6 mV, 0.41 and 98 nm, respectively. VA-MWCNTs from quartz tube were successfully purified, carboxylated, acylated and PEGylated for potential functionalization for use in targeting studies. For designing the carbon-based electrode, VA-MWCNTs on silicon wafer were successfully incorporated into epoxy resin for diagnostic applications. Functionalized MWCNTs were nontoxic towards PC-12 neuronal cells. In conclusion, vertically super-aligned MWCNTs have been successfully synthesized and functionalized for possible theragnostic biomedical applications in neurological disorders such as ischemic stroke.

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.

Bioplatform Fabrication Approaches Affecting Chitosan-Based Interpolymer Complex Properties and Performance as Wound Dressings.

Chitosan can form interpolymer complexes (IPCs) with anionic polymers to form biomedical platforms (BMPs) for wound dressing/healing applications. This has resulted in its application in various BMPs such as gauze, nano/microparticles, hydrogels, scaffolds, and films. Notably, wound healing has been highlighted as a noteworthy application due to the remarkable physical, chemical, and mechanical properties enabled though the interaction of these polyelectrolytes. The interaction of chitosan and anionic polymers can improve the properties and performance of BMPs. To this end, the approaches employed in fabricating wound dressings was evaluated for their effect on the property-performance factors contributing to BMP suitability in wound dressing. The use of chitosan in wound dressing applications has had much attention due to its compatible biological properties. Recent advancement includes the control of the degree of crosslinking and incorporation of bioactives in an attempt to enhance the physicochemical and physicomechanical properties of wound dressing BMPs. A critical issue with polyelectrolyte-based BMPs is that their effective translation to wound dressing platforms has yet to be realised due to the unmet challenges faced when mimicking the complex and dynamic wound environment. Novel BMPs stemming from the IPCs of chitosan are discussed in this review to offer new insight into the tailoring of physical, chemical, and mechanical properties via fabrication approaches to develop effective wound dressing candidates. These BMPs may pave the way to new therapeutic developments for improved patient outcomes.

Discovery of Novel Tankyrase Inhibitors through Molecular Docking-Based Virtual Screening and Molecular Dynamics Simulation Studies.

Tankyrase enzymes (TNKS), a core part of the canonical Wnt pathway, are a promising target in the search for potential anti-cancer agents. Although several hundreds of the TNKS inhibitors are currently known, identification of their novel chemotypes attracts considerable interest. In this study, the molecular docking and machine learning-based virtual screening techniques combined with the physico-chemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) profile prediction and molecular dynamics simulations were applied to a subset of the ZINC database containing about 1.7 M commercially available compounds. Out of seven candidate compounds biologically evaluated in vitro for their inhibition of the TNKS2 enzyme using immunochemical assay, two compounds have shown a decent level of inhibitory activity with the IC50 values of less than 10 nM and 10 µM. Relatively simple scores based on molecular docking or MM-PBSA (molecular mechanics, Poisson-Boltzmann, surface area) methods proved unsuitable for predicting the effect of structural modification or for accurate ranking of the compounds based on their binding energies. On the other hand, the molecular dynamics simulations and Free Energy Perturbation (FEP) calculations allowed us to further decipher the structure-activity relationships and retrospectively analyze the docking-based virtual screening performance. This approach can be applied at the subsequent lead optimization stages.

Lipid-drug conjugates and associated carrier strategies for enhanced antiretroviral drug delivery.

Mortality rate of patients infected with HIV-1 has been significantly reduced by using HAART. However, the virus to date has not been eradicated. Transmission of HIV-1 infection through sexual intercourse remains an ongoing challenge, with increased risk of infection occurring in women. Interestingly, ARV drugs can be chemically linked with lipids to produce lipid-drug conjugates (LDCs). This alters pharmacokinetic properties of ARV drugs and thereby resulting in improved effectiveness. Although LDCs can be administered without a delivery carrier, they are usually incorporated into suitable delivery systems such as lipid nanoparticles, polymeric nanoparticles, micelles, liposomes, emulsions, and carbon nanotubes. Given that LDCs have the potential to improve oral bioavailability, lipophilicity, toxicity, and drug targeting, it is of our great interest to review strategies of lipid-drug conjugation together with their delivery systems for enhanced antiretroviral efficacy.

Time-Domain Analysis of Molecular Dynamics Trajectories Using Deep Neural Networks: Application to Activity Ranking of Tankyrase Inhibitors.

Molecular dynamics simulations provide valuable insights into the behavior of molecular systems. Extending the recent trend of using machine learning techniques to predict physicochemical properties from molecular dynamics data, we propose to consider the trajectories as multidimensional time series represented by 2D tensors containing the ligand-protein interaction descriptor values for each time step. Similar in structure to the time series encountered in modern approaches for signal, speech, and natural language processing, these time series can be directly analyzed using long short-term memory (LSTM) recurrent neural networks or convolutional neural networks (CNNs). The predictive regression models for the ligand-protein affinity were built for a subset of the PDBbind v.2017 database and applied to inhibitors of tankyrase, an enzyme of the poly(ADP-ribose)-polymerase (PARP) family that can be used in the treatment of colorectal cancer. As an additional test set, a subset of the Community Structure-Activity Resource (CSAR) data set was used. For comparison, the random forest and simple neural network models based on the crystal pose or the trajectory-averaged descriptors were used, as well as the commonly employed docking and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) scores. Convolutional neural networks based on the 2D tensors of ligand-protein interaction descriptors for short (2 ns) trajectories provide the best accuracy and predictive power, reaching the Spearman rank correlation coefficient of 0.73 and Pearson correlation coefficient of 0.70 for the tankyrase test set. Taking into account the recent increase in computational power of modern GPUs and relatively low computational complexity of the proposed approach, it can be used as an advanced virtual screening filter for compound prioritization.

Lipopolysaccharide Polyelectrolyte Complex for Oral Delivery of an Anti-tubercular Drug.

Anti-tuberculosis drug delivery has remained a challenge due to inconsistent bioavailability and inadequate sustained-release properties leading to treatment failure. To resolve these drawbacks, a lipopolysaccharide polyelectrolyte complex (PEC) encapsulated with rifampicin (RIF) (as the model drug) was fabricated, using the solvent injection technique (SIT), with soy lecithin (SLCT), and low-molecular-weight chitosan (LWCT). The average particle size and surface charge of RIF-loaded PEC particulates was 151.6 nm and + 33.0 nm, respectively, with noted decreased particle size and surface charge following increase in SLCT-LWCT mass ratio. Encapsulation efficiency (%EE) and drug-loading capacity (%LC) was 64.25% and 5.84%, respectively. Increase in SLCT-LWCT mass ratio significantly increased %EE with a marginal reduction in %LC. In vitro release studies showed a sustained-release profile for the PEC particulate tablet over 24 h (11.4% cumulative release) where the dominant release mechanism involved non-Fickian anomalous transport shifting towards super case II release as SLCT ratios increased (6.4% cumulative release). PEC-tablets prepared without SIT presented with rapid Fickian-diffusion-based drug release with up to 90% RIF release within 4 h. Ex vivo permeability studies revealed that lipopolysaccharide PEComplexation significantly increased the permeability of RIF by ~ 2-fold within the 8-h study period. These results suggest successful encapsulation of RIF within a PEC structure while imparting increased amorphic regions, as indicated by x-ray diffraction, for potential benefits in improved drug dissolution, bioavailability, and dosing.

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.