Nanotechnology-Based Strategy for Enhancing Therapeutic Efficacy in Pancreatic Cancer: Receptor-Targeted Drug Delivery by Somatostatin Analog.

A novel nanotechnology-based drug delivery system (DDS) targeted at pancreatic cancer cells was developed, characterized, and tested. The system consisted of liposomes as carriers, an anticancer drug (paclitaxel) as a chemotherapeutic agent, and a modified synthetic somatostatin analog, 5-pentacarbonyl-octreotide, a ligand for somatostatin receptor 2 (SSTR2), as a targeting moiety for pancreatic cancer. The cellular internalization, cytotoxicity, and antitumor activity of the DDS were tested in vitro using human pancreatic ductal adenocarcinoma (PDAC) cells with different expressions of the targeted SSTR2 receptors, and in vivo on immunodeficient mice bearing human PDAC xenografts. The targeted drug delivery system containing paclitaxel exhibited significantly enhanced cytotoxicity compared to non-targeted DDS, and this efficacy was directly related to the levels of SSTR2 expression. It was found that octreotide-targeted DDS proved exceptionally effective in suppressing the growth of PDAC tumors. This study underscores the potential of octreotide-targeted liposomal delivery systems to enhance the therapeutic outcomes for PDAC compared with non-targeted liposomal DDS and Paclitaxel-Cremophor® EL, suggesting a promising avenue for future cancer therapy innovations.

Human induced pluripotent stem cell-derived planar neural organoids assembled on synthetic hydrogels.

The tailorable properties of synthetic polyethylene glycol (PEG) hydrogels make them an attractive substrate for human organoid assembly. Here, we formed human neural organoids from iPSC-derived progenitor cells in two distinct formats: (i) cells seeded on a Matrigel surface; and (ii) cells seeded on a synthetic PEG hydrogel surface. Tissue assembly on synthetic PEG hydrogels resulted in three dimensional (3D) planar neural organoids with greater neuronal diversity, greater expression of neurovascular and neuroinflammatory genes, and reduced variability when compared with tissues assembled upon Matrigel. Further, our 3D human tissue assembly approach occurred in an open cell culture format and created a tissue that was sufficiently translucent to allow for continuous imaging. Planar neural organoids formed on PEG hydrogels also showed higher expression of neural, vascular, and neuroinflammatory genes when compared to traditional brain organoids grown in Matrigel suspensions. Further, planar neural organoids contained functional microglia that responded to pro-inflammatory stimuli, and were responsive to anti-inflammatory drugs. These results demonstrate that the PEG hydrogel neural organoids can be used as a physiologically relevant in vitro model of neuro-inflammation.

Supramolecular Hydrogels Developed from Mafenide and Indomethacin as a Plausible Multidrug Self-Delivery System as Antibacterial and Anti-inflammatory Topical Gels.

Following a structural rationale, a series of simple organic salts derived from mafenide (a drug for treating burn wounds) and n-alkyl carboxylic acids (Me-(CH2)n-COOH; n = 1-3, 10-15) and various nonsteroidal anti-inflammatory drugs (NSAIDs), namely, indomethacin (IND), diclofenac (DIC), meclofenamic acid (MEC), tolfenamic acid (TOL), and flufenamic acid (FLU) (designated as salts 1-14, respectively) were synthesized as potential hydrogelators. Gelation studies revealed that mafenide n-alkyl carboxylates with n = 11-14, i.e., salts 5-8, and the indomethacin salt of mafenide, i.e., salt 10, were hydrogelators. The corresponding hydrogels, namely, 5(HG)-8(HG) and 10(HG), were characterized by table-top and dynamic rheology and high-resolution transmission electron microscopy (HR-TEM). Single-crystal structures of the nongelator salts 1-3 and the gelator salt 10 were determined by X-ray diffraction. The results obtained from various studies, which included the solubility, biostability, biocompatibility (MTT assay), and anti-inflammatory (PGE2 assay) response of salt 10, the antibacterial response (zone inhibition assay) of salt 10, its components, and 10(HG), and the release of salt 10in vitro from the corresponding hydrogel bed to the bulk solvent at 37 °C in 24 h, suggested their plausible use in developing multidrug-derived topical hydrogels for self-delivery applications.

Multifunctional Lipid-Based Nanoparticles for Codelivery of Anticancer Drugs and siRNA for Treatment of Non-Small Cell Lung Cancer with Different Level of Resistance and EGFR Mutations.

Resistance to chemotherapy, enhanced proliferation, invasion, angiogenesis, and metastasis (RPIAM) represent major obstacles that limit the efficacy of cancer treatment especially in advanced stages of cancer. Overcoming or suppressing RPIAM can dramatically improve the treatment outcome. Non-small cell lung cancer (NSCLC) is frequently diagnosed in an advanced stage and often possesses intrinsic resistance to chemotherapy accompanied by the fast development of acquired resistance during the treatment. Oncogenic receptor tyrosine kinases (TKs), specifically epidermal growth factor (EGF) TKs, play an important role in the activation of MAPK/PI3K/Akt/STAT pathways, finally leading to the development of RPIAM. However, the suppression of EGF-TK by different drugs is limited by various defensive mechanisms and mutations. In order to effectively prevent the development of RPIAM in NSCLC, we formulated and tested a multicomponent and multifunctional cancer targeted delivery system containing Nanostructured Lipid Carriers (NLCs) as vehicles, luteinizing hormone release hormone (LHRH) as a cancer targeting moiety, EFG-TK inhibitor gefitinib and/or paclitaxel as anticancer drug(s), siRNA targeted to EGF receptor (EGFR) mRNA as a suppressor of EGF receptors, and an imaging agent (rhodamine) for the visualization of cancer cells. Experimental data obtained show that this complex delivery system possesses significantly enhanced anticancer activity that cannot be achieved by individual components applied separately.

Recent Developments on Therapeutic and Diagnostic Approaches for COVID-19.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made a serious public health threat worldwide with millions of people at risk in a growing number of countries. Though there are no clinically approved antiviral drugs and vaccines for COVID-19, attempts are ongoing for clinical trials of several known antiviral drugs, their combination, as well as development of vaccines in patients with confirmed COVID-19. This review focuses on the latest approaches to diagnostics and therapy of COVID-19. We have summarized recent progress on the conventional therapeutics such as antiviral drugs, vaccines, anti-SARS-CoV-2 antibody treatments, and convalescent plasma therapy which are currently under extensive research and clinical trials for the treatment of COVID-19. The developments of nanoparticle-based therapeutic and diagnostic approaches have been also discussed for COVID-19. We have assessed recent literature data on this topic and made a summary of current development and future perspectives.

Targeted Nanotherapeutics for Respiratory Diseases: Cancer, Fibrosis, and Coronavirus.

Systemic delivery of therapeutics for treatment of lung diseases has several limitations including poor organ distribution of delivered payload with relatively low accumulation of active substances in the lungs and severe adverse side effects. In contrast, nanocarrier based therapeutics provide a broad range of opportunities due to their ability to encapsulate substances with different aqueous solubility, transport distinct types of cargo, target therapeutics specifically to the deceased organ, cell, or cellular organelle limiting adverse side effects and increasing the efficacy of therapy. Moreover, many nanotherapeutics can be delivered by inhalation locally to the lungs avoiding systemic circulation. In addition, nanoscale based delivery systems can be multifunctional, simultaneously carrying out several tasks including diagnostics, treatment and suppression of cellular resistance to the treatment. Nanoscale delivery systems improve the clinical efficacy of conventional therapeutics allowing new approaches for the treatment of respiratory diseases which are difficult to treat or possess intrinsic or acquired resistance to treatment. The present review summarizes recent advances in the development of nanocarrier based therapeutics for local and targeted delivery of drugs, nucleic acids and imaging agents for diagnostics and treatment of various diseases such as cancer, cystic fibrosis, and coronavirus.

Multifunctional and stimuli-responsive nanocarriers for targeted therapeutic delivery.

INTRODUCTION: Nanocarrier-based delivery systems offer multiple benefits to overcome limitations of the traditional drug dosage forms, such as protection of the drug, enhanced bioavailability, targeted delivery to disease site, etc. Nanocarriers have exhibited tremendous successes in targeted delivery of therapeutics to the desired tissues and cells with improved bioavailability, high drug loading capacity, enhanced intracellular delivery, and better therapeutic effect. A specific design of stimuli-responsive nanocarriers allows for changing their structural and physicochemical properties in response to exogenous and endogenous stimuli. These nanocarriers show a promise in site specific controlled release of therapeutics under certain physiological conditions or external stimuli. AREAS COVERED: This review highlights recent progresses on the multifunctional and stimuli-sensitive nanocarriers for targeted therapeutic drug delivery applications. EXPERT OPINION: The progress from single functional to multifunctional nanocarriers has shown tremendous potential for targeted delivery of therapeutics. On our opinion, the future of targeted delivery of drugs, nucleic acids, and other substances belongs to the site-targeted multifunctional and stimuli-based nanoparticles with controlled release. Targeting of nanocarriers to the disease site enhance the efficacy of the treatment by delivering more therapeutics specifically to the affected cells and substantially limiting adverse side effects upon healthy organs, tissues, and cells.

Integrated Pan-Cancer Map of EBV-Associated Neoplasms Reveals Functional Host-Virus Interactions.

Epstein-Barr virus (EBV) is a complex oncogenic symbiont. The molecular mechanisms governing EBV carcinogenesis remain elusive and the functional interactions between virus and host cells are incompletely defined. Here we present a comprehensive map of the host cell-pathogen interactome in EBV-associated cancers. We systematically analyzed RNA sequencing from >1,000 patients with 15 different cancer types, comparing virus and host factors of EBV+ to EBV- tissues. EBV preferentially integrated at highly accessible regions of the cancer genome, with significant enrichment in super-enhancer architecture. Twelve EBV transcripts, including LMP1 and LMP2, correlated inversely with EBV reactivation signature. Overexpression of these genes significantly suppressed viral reactivation, consistent with a "virostatic" function. In cancer samples, hundreds of novel frequent missense and nonsense variations in virostatic genes were identified, and variant genes failed to regulate their viral and cellular targets in cancer. For example, one-third of patients with EBV+ NK/T-cell lymphoma carried two novel nonsense variants (Q322X, G342X) of LMP1 and both variant proteins failed to restrict viral reactivation, confirming loss of virostatic function. Host cell transcriptional changes in response to EBV infection classified tumors into two molecular subtypes based on patterns of IFN signature genes and immune checkpoint markers, such as PD-L1 and IDO1. Overall, these findings uncover novel points of interaction between a common oncovirus and the human genome and identify novel regulatory nodes and druggable targets for individualized EBV and cancer-specific therapies. SIGNIFICANCE: This study provides a comprehensive map of the host cell-pathogen interactome in EBV+ malignancies.See related commentary by Mbulaiteye and Prokunina-Olsson, p. 5917.

Nanocarrier-based systems for targeted and site specific therapeutic delivery.

Systemic drug delivery methods such as oral or parenteral administration of free drugs possess relatively low treatment efficiency and marked adverse side effects. The use of nanoparticles for drug delivery in most cases substantially enhances drug efficacy, improves pharmacokinetics and drug release and limits their side effects. However, further enhancement in drug efficacy and significant limitation of adverse side effects can be achieved by specific targeting of nanocarrier-based delivery systems especially in combination with local administration. The present review describes major advantages and limitations of organic and inorganic nanocarriers or living cell-based drug and nucleic acid delivery systems. Among these, different nanoparticles, supramolecular gels, therapeutic cells as living drug carriers etc. have emerged as a new frontier in modern medicine.

An Easy Access to Organic Salt-Based Stimuli-Responsive and Multifunctional Supramolecular Hydrogels.

By exploiting orthogonal hydrogen bonding involving supramolecular synthons and hydrophobic/hydrophilic interactions, a new series of simple organic salt based hydrogelators derived from pyrene butyric acid and its ß-alanine amide derivative, and various primary amines has been achieved. The hydrogels were characterised by microscopy, table-top rheology and dynamic rheology. FTIR, variable-temperature (1) H NMR and emission spectroscopy established the role of various supramolecular interactions such as hydrogen bonding and π-π stacking in hydrogelation. Single-crystal X-ray diffraction (SXRD) studies supported the conclusion that orthogonal hydrogen bonding involving amide-amide and primary ammonium monocarboxylate (PAM) synthons indeed played a crucial role in hydrogelation. The hydrogels were found to be stimuli-responsive and were capable of sensing ammonia and adsorbing water-soluble dye (methylene blue). All the hydrogelators were biocompatible (MTT assay in RAW 264.7 cells), indicating their suitability for use in drug delivery.

A supramolecular topical gel derived from a non-steroidal anti-inflammatory drug, fenoprofen, is capable of treating skin inflammation in mice.

A new series of bioconjugates derived from a non-steroidal anti-inflammatory drug (NSAID), namely fenoprofen, has been synthesised by amidation with various biogenic molecules such as ß-alanine, aminocaproic acid and tyramine with the aim of converting the NSAID into a supramolecular gelator for plausible biomedical applications. One such bioconjugate (2) showed gelation ability with methylsalicylate (MS) and 1% menthol in methyl salicylate (MMS) solvents. These gels were characterized by table top rheology, high resolution-transmission electron microscopy (HR-TEM) and dynamic rheology. Gelator 2 was found to be biostable both in proteolytic enzymes and in blood serum of BALB/c mouse under physiological conditions. It was also found to be biocompatible, as revealed by the methyl thiazolyldiphenyl tetrazolium bromide (MTT) assay in mouse macrophage RAW 264.7 and mouse myoblast C2C12 cells. The anti-inflammatory response (prostaglandin E2 assay, denoted PGE2 assay) of 2 was comparable to that of the parent drug fenoprofen calcium salt. Finally, a topical gel formulation of 2 displayed in vivo self-delivery application in treating imiquimod (IMQ) induced skin inflammation in BALB/c mice.

Cetirizine derived supramolecular topical gel in action: rational design, characterization and in vivo self-delivery application in treating skin allergy in mice.

A conventional drug delivery system requires a delivery vehicle which often faces various problems such as inefficient drug loading into the delivery vehicle and its release, cytotoxicity and biodegradability of the delivery vehicle, etc., whereas a supramolecular gel based self-delivery system delivers a gelator drug at the target site without using any vehicle thereby getting rid of such problems. Here, a simple salt formation strategy has been employed to convert a well known anti-allergic drug (cetirizine) to a supramolecular gelator for the purpose of making a topical gel for in vivo self-delivery applications. The salt of cetirizine and tyramine (salt 3) displays excellent gelation properties in methylsalicylate/menthol. The gels are characterised by electron microscopy, and table top- and dynamic rheology. The gelator salt 3 displays excellent physiological stability in phosphate buffer saline (PBS) and it is biocompatible in mouse macrophage RAW 264.7 and mouse myoblast C2C12 cell lines. A methylsalicylate/menthol topical gel of salt 3 is successfully self-delivered in treating the 2,4-dinitrochlorobenzene (DNCB)-induced allergic skin condition in mice.

A novel naproxen derivative capable of displaying anti-cancer and anti-migratory properties against human breast cancer cells.

BACKGROUND: Increasingly, the role of chronic inflammation and its mediators in tumor generation and progression is gaining importance in the field of cancer research. In this context, candidature of non steroidal anti-inflammatory drugs (NSAIDs) as potential anti-tumor therapeutic agent is being evaluated globally. In the present study we have evaluated the anti-cancer effect of a series of newly synthesized naproxen derivatives on human breast cancer cell lines. METHODS: MCF-7 (poorly invasive) and MDA-MB-231 (highly invasive) cells were treated with different concentrations of naproxen sodium and its derivatives in vitro, and the underlying mechanism of action was monitored by employing studies related to induction of apoptosis, activation of caspases, cell-cycle progression, synthesis of PGE2 and cellular migration. RESULTS: After a preliminary screening using MCF-7 and MDA-MB-231 cells, it was evident that naproxen derivative 4 has a better killing property compared to its parent compound naproxen sodium (NS). On further investigation, it was apparent that the observed growth inhibitory activity on MDA-MB-231 cells after treatment with 4, was not due to cell cycle arrest but due to an early induction of apoptosis and subsequent induction of caspases 3 and 9. Derivative 4 could also inhibit COX activity in MDA-MB-231 cells as evidenced by reduction in prostaglandin E2 secretion. Moreover, 4 was capable of delaying the overall migration rate of MDA-MB-231 cells in vitro. CONCLUSION: In this study we report that a naproxen-derivative (4) has powerful anti-inflammatory and anti-tumor properties as it induces appreciable amount of apoptosis in breast cancer cell line, and can also delay migration of cancer cells (MDA-MB-231) which would in turn delay cancer cell invasion and formation of secondary tumours in primary breast cancer patients. Thus, we propose that 4 is worthy of further investigation due to its potential as a therapeutic agent in anti-tumor treatment regimen.

Designing a simple organic salt-based supramolecular topical gel capable of displaying in vivo self-delivery application.

The supramolecular synthon approach has been exploited to design simple salt-based supramolecular gelators derived from a non-steroidal anti-inflammatory drug (NSAID) - naproxen; one such biocompatible anti-inflammatory gelator salt was converted into a topical gel that showed excellent in vivo self-delivery application in treating imiquimod (IMQ)-induced skin inflammation in mice.

Butterfly species richness and diversity in the Trishna Wildlife Sanctuary in South Asia.

Several wildlife sanctuaries in the world are home to the surviving populations of many endemic species. Trishna wildlife sanctuary in northeast India is protected by law, and is home to the last surviving populations of Asian bison (Bos gorus Smith), spectacle monkey (Trachypithecus phayrie Blyth), capped langur (Trachypithecus pileatus Blyth), slow loris (Nycticebus coucang Boddaert), wild cat (Felis chaus Schreber), and wild boars (Sus scrofa L.), among many other animals and plants. The sanctuary was explored for species richness and diversity of butterflies. A six-month-long study revealed the occurrence of 59 butterfly species that included 21 unique species and 9 species listed in the threatened category. The mixed moist deciduous mature forest of the sanctuary harbored greater species richness and species diversity (39 species under 31 genera) than other parts of the sanctuary, which is comprised of regenerated secondary mixed deciduous forest (37 species under 32 genera), degraded forests (32 species under 28 genera), and open grassland with patches of plantations and artificial lakes (24 species under 17 genera). The majority of these species showed a distribution range throughout the Indo-Malayan region and Australasia tropics, and eight species were distributed in the eastern parts of South Asia, including one species, Labadea martha (F.), which is distributed in the eastern Himalayas alone. Estimator Chao 2 provided the best-predicted value of species richness. The steep slope of the species accumulation curve suggested the occurrence of a large number of rare species, and a prolonged gentle slope suggested a higher species richness at a higher sample abundance. The species composition of vegetation-rich habitats showed high similarity in comparison to vegetation-poor habitats.

ß-Amino acid and amino-alcohol conjugation of a nonsteroidal anti-inflammatory drug (NSAID) imparts hydrogelation displaying remarkable biostability, biocompatibility, and anti-inflammatory properties.

A well-known nonsteroidal anti-inflammatory drug (NSAID), namely, naproxen (Np), was conjugated with ß-alanine and various combinations of amino alcohols and l-alanine. Quite a few bioconjugates, thus synthesized, were capable of gelling pure water, NaCl solution (0.9 wt %), and phosphate-buffered saline (PBS) (pH 7.4). The hydrogels were characterized by rheology and electron microscopy. Hydrogelation was probed by FT-IR and temperature-variable (1)H NMR studies. Single-crystal X-ray diffraction (SXRD) of a nonhydrogelator and a hydrogelator in the series established a useful structure-property (gelation) correlation. MTT assay of the hydrogelators in the mouse macrophage RAW 264.7 cell line showed excellent biocompatibility. The prostaglandin E2 (PGE2) assay of the hydrogelators revealed their anti-inflammatory response, which was comparable to that of the parent NSAID naproxen sodium (Ns).