Search

The quest for new approaches for generating novel bioactive designer proteins/peptides has continued with their success in various biomedical applications. Previously, we designed a 14-mer α-helical peptide with antimicrobial and antimycobacterial activities by employing a tandem repeat of the 7-mer, “KVLGRLV” human chemerin segment. Herein, we devised a new method of “sliding framework” with this segment to create amino acid scaffolds of varying sizes and sequences and explored the design of a peptide library with antibacterial and antimycobacterial activities. By utilizing 2 to 7 repeats of these 2 to 6-residue scaffolds, we designed and synthesized 30 peptides of 10–16 residue lengths. Thus, we identified novel AMPs with α-helical, β-sheet, and random coil structures, membrane-destabilizing, and intracellular modes of action, and 9 of them showed therapeutic indices between 100 and 750. Three and two of these nine peptides showed in vivoantibacterial and antitubercular efficacies against Escherichia coliATCC 25922 and Mycobacterium bovisBCG infections, respectively, in a mouse model.

To date, the use of corannulene has been restricted in the area of material science, but its application in biomedical research has yet to be established due to its nonsolubility in an aqueous environment and synthetic infeasibility. Herein, we detail the development of a new family of highly curved π-conjugated corannulene-containing unnatural α-amino acid (CAA) derivatives to overcome this challenge. These CAAs have been extended as novel constituents for the synthesis of corannulene-containing water-soluble cationic peptides (CCPs), which display inhibitory activity against broad-spectrum pathogenic bacteria along with drug-resistant bacteria via a membrane-damaging mechanism. Importantly, several of the synthesized peptides were found to be appreciably nonhemolytic against hRBCs and noncytotoxic against mammalian 3T3 cells. In vivoefficacy studies of the potent and least cytotoxic peptide 6ademonstrated clearance of bacteria from the spleen, liver, lung, and blood of mice infected with S. aureusATCC 25923.

Combustion of fossil fuel produces emissions and is one of the major environmental problems leading to climate change. Diesel engines are highly efficient but produce particulate emissions. These particulate emissions are considered dangerous to human health because inhaling particulates may cause respiratory and heart disease. Substituting fossil diesel fuel with renewable diesel fuel and using diesel particulate filters is one possibility to meet stringent legislative requirements. With this motivation, the present experimental investigation aimed to evaluate the particle size distribution (PSD), optical properties of particulate matter (PM) emitted, and the outcome of using an after-treatment system comprising of a diesel particle filter (DPF). This investigation aimed to make a comparative analysis of particulate emission upstream and downstream of the DPF with and without ultraviolet (UV) light (405 nm and 781 nm wavelength) turned on/off. Experiments were performed at (a) engine idle with a torque of 6 Nm at 750 rpm, IMEP of 1.35 bar and power of 0.5 kW, (b) engine at part load with a torque of 32 Nm at 1200 rpm, IMEP of 8.5 bar and power of 4.5 kW. Diesel engine was operated on two fuels (a) Diesel and (b) EHR7. Results showed that as and when UV light was turned on, a distinct nucleation mode that dominated the number concentration for both test fuels were observed. Downstream of the filter had relatively higher AAE values which show the contribution to climate change. Present experimental research is important for renewable fuel industries, industrial innovation's future, and the exhaust gas after-treatment system (EATS) community. The results contribute to knowledge for occupational exposure, human health, and the environment.

The Indo-Gangetic Plain (IGP) region of India faces some of the most severe air pollution problems on Earth that threaten human health, food security, ecosystems, environmental sustainability, and the climate. The aim of this study is to identify and characterize the sources of key short-lived climate pollutants (SLCPs) – black carbon (BC), brown carbon (BrC), and ozone (O3) – as well as other pollutants [carbon monoxide (CO) and nitrogen oxides NOX= NO and NO2], and interlinked atmospheric processes of their formation and transformation at our long-term air pollution monitoring station in a remote rural IGP site, the Indo-Gangetic Plains Centre for Air Research and Education (IGP-CARE). Because of its location, measurements acquired at IGP-CARE provide otherwise new information on the key SLCPs in the IGP region at a remote and rural location. The year-long measurement data at this remote site provided new insights into the variability of SLCP concentration and interlinked atmospheric processes that affect air quality in the rural IGP region. Thirteen episodic events (E1–E13) of elevated BC and BrC concentrations were identified, which can largely be attributed to the local biomass burning activities in the neighboring rural communities. It is suggested that high concentrations of BrC were mostly primary in nature and thought to be co-emitted with BC from biomass burning. Also, secondary pollutant tropospheric O3showed elevated concentration. O3peaks were mostly attributed to local ozone formation. Nevertheless, on several occasions, O3emission was also attributed to regional urban areas. This study's most important finding is that BrC concentrations were relatively high throughout the year with very pronounced diurnal variation with distinct morning and evening peaks in general and a minimum at around noon time; this is hypothesized to be associated with daytime photochemical processes. Analyses using a conditional bivariate probability function (CBPF) and potential source contribution function (PSCF) suggest that regional sources likely affected the local concentrations of SLCPs. These results partly explain the high concentrations and spatial distributions of SLCPs at the local and regional scales at the IGP-CARE site in winter and autumn. In contrast, in the summer and monsoon seasons, strong convection likely favored the dilution of pollutants.

To design novel antimicrobial peptides by utilizing the sequence of the human host defense protein, chemerin, a seven-residue amphipathic stretch located in the amino acid region, 109–115, was identified, which possesses the highest density of hydrophobic and positively charged residues. Although this 7-mer peptide was inactive toward microorganisms, its 14-mer tandem repeat (Chem-KVL) was highly active against different bacteria including methicillin-resistant Staphylococcus aureus, a multidrug-resistant Staphylococcus aureusstrain, and slow- and fast-growing mycobacterial species. The selective enantiomeric substitutions of its two l-lysine residues were attempted to confer cell selectivity and proteolytic stability to Chem-KVL. Chem-8dK with a d-lysine replacement in its middle (eighth position) showed the lowest hemolytic activity against human red blood cells among Chem-KVL analogues and maintained high antimicrobial properties. Chem-8dK showed in vivoefficacy against Pseudomonas aeruginosainfection in BALB/c mice and inhibited the development of resistance in this microorganism up to 30 serial passages and growth of intracellular mycobacteria in THP-1 cells.

A technology for systemic and repeated administration of osteogenic factors for orthopedic use is an unmet medical need. Lactoferrin (∼80 kDa), present in milk, is known to support bone growth. We discovered a lactoferrin-mimetic peptide, LP2 (an 18-residue fragment from the N-terminus of the N-lobe of human lactoferrin), which self-assembles into a nano-globular assembly with a β-sheet structure in an aqueous environment. LP2 is non-hemolytic and non-cytotoxic against human red blood cells and 3T3 fibroblasts, respectively, and appreciably stable in the human serum. LP2 through the bone morphogenetic protein-dependent mechanism stimulates osteoblast differentiation more potently than the full-length protein as well as the osteoblastic production of osteoprotegerin (an anti-osteoclastogenic factor). Consequently, daily subcutaneous administration of LP2 to rats and rabbits with osteotomy resulted in faster bone healing and stimulated bone formation in rats with a low bone mass more potently than that with teriparatide, the standard-of-care osteogenic peptide for osteoporosis. LP2 has skeletal bioavailability and is safe at the 15× osteogenic dose. Thus, LP2 is a novel peptide that can be administered systemically for the medical management of hard-to-heal fractures.

All inkjet‐printed thermal sensors are manufactured based on a metal–insulator–metal (MIM) interface or capacitor architecture, for the adapted device size ranging from 16 to 36 mm2active area. Two different material inks, namely a nanoparticle conductive silver ink and an inorganic‐polymer‐based hybrid insulator ink, are applied layer by layer on a thin flexible polyimide substrate, for developing the printed MIM devices. To ensure the desired electronic conductivity and insulation from the layers, the manufacturing process steps and parameters are tuned, accordingly. The results show that the inkjet‐printed MIM devices could constitute up to 15 μm thickness and demonstrate average detection of a change in electrical capacitance ranging from 20 to 100 pF, when the temperature is varied between 100 and 300 °C. The investigations also summarize that the change in the electrical response is enough to detect an increment of 50 °C. The printed sensors also display high operational stability and repeatability, when subjected to thermal cycling. The printed thermal sensors display high operational stability and repeatability, when subjected to thermal cycling. The investigation summarizes the change in the electrical capacitance as a function of temperature increment over an elevated range of 100–300 °C.

The diagnosis and prognosis of the disease associated with lipid irregularity are areas of extreme significance. In this direction, fluoranthene based yellow fluorescent probes (FLUN-550, FLUN-552, FLUN-547) were designed and synthesized by conjugating the ethanolamine headgroup of the phospholipid phosphatidyl-ethanolamine present in biological membranes. Owing to unique photophysical properties and aqueous compatibility, these probes were successfully employed for staining lipid droplets (LDs) in preadipocytes and Leishmania donovanipromastigotes. Furthermore, using the fluorescent probes FLUN-550and FLUN-552we successfully imaged and quantitatively detected the excess accumulation of lipids in a liver section of Plasmodium yoeliiMDR infected mice (3- to 4-fold) and the tissue sections of third stage human cervical cancer patients (1.5- to 2-fold) compared to normal tissues. To the best of our knowledge, this is the first report of yellow fluorescent probes for imaging and quantitative detection of LDs in human cervical cancer tissues. These new yellow fluorescent lipid probes (FLUN-550and FLUN-552) showed great potential for diagnosis of cervical cancer patients.

The prospective design of nanocarriers for personalized oncotherapy should be an ensemble of targeting, imaging, and noninvasive therapeutic capabilities. Herein, we report the development of the inverse hexagonal nano-liquid crystalline (NLC) particles that are able to host formononetin (FMN), a phytoestrogen with known anticancer activity, and tetraphenylethene (TPE), an iconic optical beacon with aggregation-induced emission (AIE) signature, simultaneously. Ordered three-dimensional mesoporous internal structure and high-lipid-volume fraction of NLC nanoparticles (NLC NPs) frame the outer compartment for the better settlement of payloads. Embellishment of these nanoparticles by anisamide (AA), a novel sigma receptor targeting ligand using carbodiimide coupling chemistry ensured NLC’s as an outstanding vehicle for possible utility in surveillance of tumor location as well as the FMN delivery through active AIE imaging. The size and structural integrity of nanoparticles were evaluated by quasi-elastic light scattering, cryo field emission scanning electron microscopy small-angle X-ray scattering. The existence of AIE effect in the nanoparticles was evidenced through the photophysical studies that advocate the application of NLC NPs in fluorescence-based bioimaging. Moreover, confocal microscopy illustrated the single living cell imaging ability endowed by the NLC NPs. In vitro and in vivo studies supported the enhanced efficacy of targeted nanoparticles (AA-NLC-TF) in comparison to nontargeted nanoparticles (NLC-TF) and free drug. Apparently, this critically designed multimodal NLC NPs may establish a promising platform for targeted and image-guided chemotherapy for breast cancer.

Organic photodetectors (PDs) based on printing technologies will allow to expand the current field of PD applications toward large-area and flexible applications in areas such as medical imaging, security, and quality control, among others. Inkjet printing is a powerful digital tool for the deposition of smart and functional materials on various substrates, allowing the development of electronic devices such as PDs on various substrates. In this work, inkjet-printed PD arrays, based on the organic thin-film transistor architecture, have been developed and applied for the indirect detection of X-ray radiation using a scintillator ink as an X-ray absorber. The >90% increase of the photocurrent of the PDs under X-ray radiation, from about 53 nA without the scintillator film to about 102 nA with the scintillator located on top of the PD, proves the suitability of the developed printed device for X-ray detection applications.

Herein, it is intended to show the effect of embedding an inkjet printed poly(3,4‐ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) track in an insulator polymer, impacting its electronic transition behavior, as a consequence of temperature variation. A transition from semiconductor‐to‐metal‐like behavior is observed, when the temperature is seen to exceed a certain value, which is of a nonchemical origin. Both the presented experimental and simulation results show how this transition really occurs. The proposed physical mechanism for explaining such a behavior is verified with good repeatability. The main conclusion indicates consideration of special precautions, while enclosing inkjet‐printed PEDOT:PSS‐based tracks or sensors operating under ambient conditions, along with fluctuations. This conclusion can potentially be applied to any other inkjet printed conductive organic polymer film embedded in an insulator that fulfills the conditions encountered in the experiments. The impact of this effect may be reduced and mitigated by using inkjet printing, in combination with other additive manufacturing technique. The results presented here are considered very important, as they lay the foundation for the correct compensation of the thermal drift of organic electronics‐based circuits. Herein, the effect of embedding an inkjet printed poly(3,4‐ethylenedioxythiophene) polystyrene sulfonate track in an insulator is shown, impacting its electronic transition from semiconductor‐to‐metal‐like behavior (nonchemical origin), as a consequence of temperature variation exceeding a certain value. The results are considered very important, as they lay the foundation for the correct compensation of the thermal drifts for organic electronics.

ABSTRACTPiscidin-1 possesses significant antimicrobial and cytotoxic activities. To recognize the primary amino acid sequence(s) in piscidin-1 that could be important for its biological activity, a long heptad repeat sequence located in the region from amino acids 2 to 19 was identified. To comprehend the possible role of this motif, six analogs of piscidin-1 were designed by selectively replacing a single isoleucine residue at a d (5th) position or at an a (9th or 16th) position with either an alanine or a valine residue. Two more analogs, namely, I5F,F6A-piscidin-1 and V12I-piscidin-1, were designed for investigating the effect of interchanging an alanine residue at a d position with an adjacent phenylalanine residue and replacing a valine residue with an isoleucine residue at another d position of the heptad repeat of piscidin-1, respectively. Single alanine-substituted analogs exhibited significantly reduced cytotoxicity against mammalian cells compared with that of piscidin-1 but appreciably retained the antibacterial and antiendotoxin activities of piscidin-1. All the single valine-substituted piscidin-1 analogs and I5F,F6A-piscidin-1 showed cytotoxicity greater than that of the corresponding alanine-substituted analogs, antibacterial activity marginally greater than or similar to that of the corresponding alanine-substituted analogs, and also antiendotoxin activity superior to that of the corresponding alanine-substituted analogs. Interestingly, among these peptides, V12I-piscidin-1 showed the highest cytotoxicity and antibacterial and antiendotoxin activities. Lipopolysaccharide (12 mg/kg of body weight)-treated mice, further treated with I16A-piscidin-1, the piscidin-1 analog with the highest therapeutic index, at a single dose of 1 or 2 mg/kg of body weight, showed 80 and 100% survival, respectively. Structural and functional characterization of these peptides revealed the basis of their biological activity and demonstrated that nontoxic piscidin-1 analogs with significant antimicrobial and antiendotoxin activities can be designed by incorporating single alanine substitutions in the piscidin-1 heptad repeat.

One of the greatest challenges in the field of printed electronics is the performance stability of the devices fabricated by the different printing technologies e.g. inkjet or gravure printing technology. The performance instability can be defined in terms of the device breakdown or by other effects like the emergence of leakage current under the constant high voltage inputs (especially the dielectric within the transistor architecture). The reasons behind this phenomenon can be various, but the most prominent indication can be detected from the materials used and the deposition methodology. For this purpose the herein work is presented, targeting on the all inkjet-printed organic thin film transistor (OTFT), but keeping the focus on the basic building block for fabricating inkjet-printed OTFTs. In this case it is the metal-insulator-metal (MIM) layer structure. Herein, the MIM structures are inkjet-printed, and then characterized optically and electrically. The dielectric layers for the MIM structures are printed using three different dielectric ink materials either individually 1) Single component system; or in combination with each other as in form of bi-layer stack 2) Multiple component system. The thickness of the printed dielectric layers is varied for these MIM structures. The electrical characterization is performed with respect to current vs. applied voltage and is done for a large number of iterations. The leakage current is of interest and shows a negative and positive trend towards the single component system and multiple component system for the dielectric layers in the MIM characterization structures respectively.

ABSTRACTThis study was performed to investigate the mechanistic aspects of cell death induced by a clerodane diterpene (K-09) in Leishmania donovanipromastigotes that was previously demonstrated to be safe and orally active against visceral leishmaniasis (VL). K-09 caused depolarization of the mitochondrion and the generation of reactive oxygen species, triggering an apoptotic response in L. donovanipromastigotes. Mitochondrial dysfunction subsequently resulted in the release of cytochrome cinto the cytosol, impairing ATP production. Oxidative stress caused the depletion of reduced glutathione, while pretreatment with antioxidant N-acetyl cysteine (NAC) was able to abrogate oxidative stress. However, NAC failed to restore the mitochondrial membrane potential or intracellular calcium homeostasis after K-09 treatment, suggesting that the generation of oxidative stress is a downstream event relative to the other events. Caspase-3/-7-like protease activity and genomic DNA fragmentation were observed. Electron microscopy studies revealed gross morphological alterations typical of apoptosis, including severe mitochondrial damage, pyknosis of the nucleus, structural disruption of the mitochondrion-kinetoplast complex, flagellar pocket alterations, and the displacement of organelles. Moreover, an increased number of lipid droplets was detected after K-09 treatment, which is suggestive of altered lipid metabolism. Our results indicate that K-09 induces mitochondrial dysfunction and oxidative stress-mediated apoptotic cell death in L. donovanipromastigotes, sharing many features with metazoan apoptosis. These mechanistic insights provide a basis for further investigation toward the development of K-09 as a potential drug candidate for VL.

We investigated whether particles suitable for delivery to alveolar macrophages may provide a means of targeting rapamycin, an inducer of autophagy, to alveolar macrophages as a host-directed antituberculosis agent. Inhalable particles were prepared by spray-drying and characterized using laser scattering and electron microscopy. Their aerodynamic diameter was calculated from bulk and tapped densities. In vitro drug release was studied in PBS containing 1% SDS. In vitro uptake of particles by THP-1 derived macrophages was studied by flow cytometry. Cytotoxicity of the particles toward macrophages and their efficacy against intracellular Mycobacterium tuberculosiswere studied using a methyltetrazolium assay and counting bacterial colonies obtained when cell lysates were plated on agar. The encapsulation efficiency was 88.8 ± 1.13% and drug content 22 ± 4% w/w. The particles had a median diameter of 2.88 ± 0.8 μm and appeared as collapsed spheres. Their calculated aerodynamic diameter was about 1 μm. In vitro drug release from the particles was first-order and extended beyond 10 days. Flow cytometry indicated that the particles were taken up by macrophages within 3 h. Macrophages exposed to the particles or rapamycin in solution at a concentration of 100 μg/mL over a 24 h period maintained 79.37 ± 0.72% and 58.33 ± 1.39% viability, respectively. Efficacy studies concluded that particles were more effective in clearing intracellular mycobacteria than rapamycin in solution. It was concluded that the preparation was suitable for formulating as a dry powder inhalation to test efficacy of inhaled, macrophage-targeted rapamycin against TB.

ABSTRACTLeishmania, like other eukaryotes, contains large amounts of actin and a number of actin-related and actin binding proteins. Our earlier studies have shown that deletion of the gene corresponding to Leishmaniaactin-depolymerizing protein (ADF/cofilin) adversely affects flagellum assembly, intracellular trafficking, and cell division. To further analyze this, we have now created ADF/cofilin site-specific point mutants and then examined (i) the actin-depolymerizing, G-actin binding, and actin-bound nucleotide exchange activities of the mutant proteins and (ii) the effect of overexpression of these proteins in wild-type cells. Here we show that S4D mutant protein failed to depolymerize F-actin but weakly bound G-actin and inhibited the exchange of G-actin-bound nucleotide. We further observed that overexpression of this protein impaired flagellum assembly and consequently cell motility by severely impairing the assembly of the paraflagellar rod, without significantly affecting vesicular trafficking or cell growth. Taken together, these results indicate that dynamic actin is essentially required in assembly of the eukaryotic flagellum.

N-(4-Hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid is under clinical evaluation as a therapeutic agent in a variety of cancers. Its mechanism(s) of action involves multiple overlapping pathways that still remain unclear. In glioma cells its mechanism of action is not well elucidated. Here, we show that 4-HPR and not all-trans retinoic acid and 9-cis retinoic acid effectively induce apoptosis in glioma cells. 4-HPR-induced apoptosis is associated with hydroperoxide production and loss of mitochondrial membrane potential (ΔΨm). Ultrastructural changes further indicate 4-HPR-induced mitochondrial swelling, endoplasmic reticulum (ER) dilation as well as close proximity of mitochondria and ER. As suggested by dilated ER, 4-HPR treatment increased the free cytosolic Ca2+ as well as mitochondrial Ca2+. Chelation of extracellular Ca2+ by EGTA did not prevent Ca2+ elevation, thus suggesting involvement of intracellular calcium stores in the release. Buffering of intracellular calcium by BAPTA-AM did not prevent 4-HPR-induced apoptosis; however, blocking the release of Ca2+ from ER by heparin inhibited apoptosis, indicating the role of depletion of Ca2+ from ER stores in apoptosis. 4-HPR treatment also resulted in an increase in Bax levels along with its translocation to mitochondria that promote mitochondrial membrane permeabilization. 4-HPR-induced apoptosis was further associated with the release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to cytosol and nucleus, respectively, along with caspase-3 and caspase-7 activation. However, AIF nuclear translocation, peripheral chromatin condensation and apoptosis were not completely prevented by general caspase inhibitors, thus suggesting involvement of a caspase-dependent and caspase-independent pathway in 4-HPR-induced apoptosis. Taken together, these results suggest the role of mitochondrial-mediated pathway and ER stress as a key event in 4-HPR-induced apoptosis in glioma cells.

Naturally occurring cationic antimicrobial peptides (AMPs) mostly adopt α-helical structures in bacterial membrane mimetic environments. To explore the design of novel β-sheet AMPs, we identified two short cationic amphipathic β-strand segments from the crystal structure of the innate immune protein, MyD88. Interestingly, of these, the 10-residue arginine–valine-rich synthetic MyD88-segment, KRCRRMVVVV (M3), exhibited β-sheet structure when bound to the outer membrane Gram-negative bacterial component, LPS. Isothermal titration calorimetric data showed that M3 bound to LPS with high affinity, and the interaction was hydrophobic in nature. Supporting these observations, computational studies indicated strong interactions of multiple and consecutive valine residues of M3 with the acyl chain of LPS. Moreover, M3 adopted nanosheet and nanofibrillar structure in 25% acetonitrile/water and isopropanol, respectively. M3 showed substantial antibacterial activities against both Gram-positive and Gram-negative bacteria which it appreciably retained in the presence of human serum and physiological salts. M3 was non-hemolytic against human red blood cells and non-cytotoxic to 3T3 cells up to 200 μM and to mice in vivo at a dose of 40 mg/kg. Furthermore, M3 neutralized LPS-induced pro-inflammatory responses in THP-1 cells and rat bone marrow-derived macrophages. Consequently, M3 attenuated LPS-mediated lung inflammation in mice and rescued them (80% survival at 10 mg/kg dose) against a lethal dose of LPS. The results demonstrate the identification of a 10-mer LPS-interacting, β-sheet peptide from MyD88 with the ability to form nanostructures and in vivo activity against LPS challenge in mice. The identified M3-template provides scope for designing novel bioactive peptides with β-sheet structures and self-assembling properties.

Toward the design of new proline-rich peptidomimetics, a short peptide segment, present in several proline-rich antimicrobial peptides (AMPs), was selected. Fatty acids of varying lengths and spermine were conjugated at the N- and C-terminals of the peptide, respectively. Spermine-conjugated lipopeptides, C10-PR-Spn and C12-PR-Spn, exhibited minimum inhibitory concentrations within 1.5–6.2 μM against the tested pathogens including resistant bacteria and insignificant hemolytic activity against human red blood cells up to 100 μM concentrations and demonstrated resistance against trypsin digestion. C10-PR-Spn and C12-PR-Spn showed synergistic antimicrobial activity against multidrug-resistant methicillin-resistant Staphylococcus aureuswith several tested antibiotics. These lipopeptides did not permeabilize bacterial membrane-mimetic lipid vesicles or damage the Escherichia colimembrane like the nonmembrane-lytic AMP, buforin-II. The results suggested that C10-PR-Spn and C12-PR-Spn could interact with the 70S ribosome of E. coliand inhibit its protein synthesis. C10-PR-Spn and C12-PR-Spn demonstrated superior clearance of bacteria from the spleen, liver, and kidneys of mice, infected with S. aureusATCC 25923 compared to levofloxacin.

HR+/HER2– metastatic breast cancer (MBC) is one of the most common and life-threatening conditions diagnosed in women. The endocrine therapy using an orally active CDK4/6 inhibitor, ribociclib (RB), is the most intriguing approach for treating HR+/HER2– MBC. However, the repeated three to six cycles of multiple dosing and non-targeted distribution of RB led to severe neutropenia; hepatobiliary, gastrointestinal, and renal toxicities, and QT interval prolongation. Here, a novel organic solvent-free HA–PVA–PVP (hyaluronic acid–polyvinyl alcohol–polyvinyl pyrrolidone) composed of a microneedle (MN) array is formulated to deliver RB, integrated with amphiphilic conjugated polymer (HA–GMS)-anchored ultradeformable transfersomes. This unique MN array efficiently crafts microchannels in the skin, allowing HA-RB-Ts to internalize into the tumor cells through lymphatic and systemic absorption and interact with CD44 both spatially and temporally with an amplification of drug release time up to 6-folds. The pharmacokinetic and tissue distribution studies portray drug concentrations within the therapeutic window as long as 48 h, facilitating thrice-a-week frequency with the lower dose, and rule out severe toxicities, with a significant reduction in 8.3-fold RB concentration in vital organs that ultimately enhances the survival rate. Thus, the novel MN system pursues a unique embeddable feature and offers an effective, self-administrable, biodegradable, and chronic treatment option for patients requiring long-term cancer treatments.

Biochanin A (BCA) is a natural methoxylated-isoflavone and has been stated to have various therapeutic potentials. However, poor aqueous solubility and low oral bioavailability circumscribed its usage as a therapeutic molecule. Therefore, nano-sized BCA-phospholipid complex (nBCA-PLCs) was developed using solvent evaporation and ultra-sonication method to enhance the poor aqueous solubility and low oral bioavailability of BCA. The optimized nBCA-PLCs showed monodisperse spherical particles with a mean diameter of 329.63 ± 35.71 nm (PDI 0.288 ± 0.03), the zeta potential of (−) 53.9 ± 1.24 mV and drug entrapment efficiency of about 94.62 ± 4.19%. In vitrorelease study revealed that more than 99% drug was released from developed nBCA-PLCs. The formation of nBCA-PLCs complex and the loss of a crystalline state of BCA in the developed formulation were confirmed by solid-state characterizations including DSC, FTIR, and powder XRD. In situsingle-pass intestinal permeability (SPIP) study showed a significant increase (2.04 fold) in the effective intestinal permeability (Peff) of BCA from nBCA-PLCs as compared with plain BCA suspension. Similarly, the oral administration of BCA-PLCs and nBCA-PLCs in Sprague Dawley (SD)rats showed 2.4-fold and 7.2 fold increase in relative bioavailability of BCA from BCA-PLCs and nBCA-PLCs, respectively as compared with plain BCA suspension. Thus, the developed nBCA-PLCs can be promising to overcome the poor aqueous solubility and increase the oral bioavailability of this poorly aqueous soluble molecule.

The combination of metabolic modulators with chemotherapy holds vast promise for effective inhibition of tumor progression and invasion. Herein, a ratiometric codelivery platform is developed for metformin (MET), a known metabolic modulator and topotecan (TPT), a chemotherapeutic drug, by engineering lipid bilayer–camouflaged mesoporous silica nanoparticles (LB‐MSNs). In an attempt to deliver and maintain high tumor site concentrations of MET and TPT, a novel ion pairing–assisted loading procedure is developed using pamoic acid (PA) as an in situ trapping agent. PA, a hydrophobic counterion, increases the hydrophobicity of MET and TPT and facilitates MSNs with exceptionally high payload capacity (>40 and 32 wt%, respectively) and controlled release profile. Further, the synergy between MET and TPT determined by a modeling approach helps to afford synchronized delivery of both the drugs. Coloaded MET and TPT LB‐MSNs present synergistic cytotoxicity against MDA‐MB‐231/4T1 cells and effectively promote apoptosis via mitochondrial membrane depolarization and cell cycle arrest. Extended pharmacokinetic profiles in preclinical models with fourfold to sevenfold longer circulation half‐life and 7.5–100 times higher tumor site concentrations correspond to a significant increase in pharmacodynamic efficacy. Taken together, the developed codelivery approach effectively addresses the challenges in the chemotherapeutic efficacy of MET and TPT collectively. Lipid bilayer–camouflaged mesoporous silica nanoparticlesare engineered to codeliver metformin and topotecan using novel hydrophobic ion pair–assisted loading approach. Ratiometric codelivery of metformin and topotecan provides extended pharmacokinetics and tumor distribution with synergistic tumor killing efficacy in vitro and in vivo. The developed loading procedure can be a platform for the controlled delivery of water soluble ionic drugs.

ABSTRACTThe potential of a tumor cell to metastasize profoundly depends on its microenvironment, or “niche” interactions with local components. Tumor-associated-macrophages (TAMs) are the most abundant subpopulation of tumor stroma and represent a key component of tumor microenvironment. The dynamic interaction of cancer cells with neighboring TAMs actively drive cancer progression and metastatic transformation through intercellular signaling networks that need better elucidation. Thus, current study was planned for discerning paracrine communication networks operational between TAMs, and breast cancer cells with special reference to cancer cell invasion and dissemination to distant sites. Here, we report role of MIP-1β in enhancing invasive potential of metastatic breast cancer MDA-MB-231 and MDA-MB-468 cells. In addition, the poorly metastatic MCF-7 cells were also rendered invasive by MIP-1β. The MIP-1β-driven cancer cell invasion was dependent on upregulated expression levels of MYO3Agene, which encodes an unconventional myosin super-family protein harboring a kinase domain. Ex ovostudy employing Chick-embryo-model and in vivoSyngenic 4T1/BALB/c mice-model further corroborated aforementioned in vitrofindings, thereby substantiating their physiological relevance. Concordantly, human breast cancer specimen exhibited significant association between mRNA expression levels of MIP-1β and MYO3A. Both, MIP-1β and MYO3Aexhibited positive correlation with MMP9, an established molecular determinant of cancer cell invasion. Higher expression of these genes correlated with poor survival of breast cancer patients. Collectively, these results point toward so far undisclosed MIP-1β/MYO3Aaxis being operational during metastasis, wherein macrophage-derived MIP-1β potentiated cancer cell invasion and metastasis via up regulation of MYO3Agene within cancer cells. Our study exposes opportunities for devising potential anti-metastatic strategies for efficient clinical management of breast cancer.