Abstract Pancreatic ductal adenocarcinoma (PDAC) is relatively uncommon yet remains one of the most lethal cancers worldwide. Its asymptomatic nature leads to delayed diagnosis, and by the time PDAC is detected, it has often progressed to an advanced, metastatic stage. Consequently, there is a critical need to identify new therapeutic strategies that can improve patient survival. Drug repurposing has emerged as a promising approach for rapidly expanding treatment options in PDAC. Our in-vitro screening suggested niclosamide (NIC) as a promising repurposed drug candidate for the treatment of PDAC. Various PDAC cell lines including gemcitabine resistant mia paca2 cells were susceptible to NIC induced apoptosis. Prior studies from various researchers also revealed role of NIC in killing cancer cells while compromising the tumor stromal barriers. However, its extremely poor water solubility often resulted in <10% oral bioavailability, which is not sufficient for anticancer activity. Poor lipid and organic solvent solubility limit the choices of nanoformulation approaches for NIC. We have explored a hydrophobic ion pairing approach with ionizable lipid for the development of self-nanoemulsifying drug delivery system (SNEDDS). Complexation between negatively charged NIC and lipophilic cation resulted in improved drug loading in SNEDDS while preventing the precipitation of drug in aqueous media. Different batches of NIC-SNEDDS were prepared using oleyl amine and ionizable lipid DLin-DMA. The particle size and zeta potential of the DLin-DMA based blank formulation were 18.35±0.99 nm and +18±0.69 mV, respectively, whereas the oleyl amine based blank formulation exhibited a particle size of 23.97±0.89 nm and a zeta potential of +32±0.77 mV. Due to very high positive charge blank formulation containing oleyl amine showed higher cytotoxicity. In contrast, the DLin-DMA blank formulation showed negligible cytotoxicity due to their ionizable nature - neutral at physiological pH and cationic at lower pH. Based on these results, DLin-DMA based nanoformulation was optimized for NIC. The optimized formulation NIC-SNEDDS exhibited a particle size of 23.67±1.2 nm and a zeta potential of +15.5±0.56 mV. NIC alone showed the IC50 of 2.33±1.5 µM in MIA PaCa2. The final formulation demonstrated an IC50 of 2.20±1.4 µM in MIA PaCa2 cells, confirming its promising anticancer activity. In PANC-1 cells, NIC-SNEDDS exhibited an IC50 of 3.09±1.1 µM IC50 compared to NIC alone (14.8 µM). Predictive pharmacokinetic modelling using Gastroplus indicated >75% oral bioavailability of the NIC oral formulation compared to suspension. Thus, a hydrophobic ion pairing approach with ionizable lipid enabled the development of a self-nanoemulsifying drug delivery system of niclosamide. Currently, we are investigating the effect of NIC on in vivopancreatic tumor bearing mice. Citation Format: Bhoomi Mukeshbhai Dholariya, Ketankumar Patel. Nanoformulation enabling repurposing of niclosamide for the treatment of pancreatic cancer: Rapidly soluble oral formulation for enhanced bioavailability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2429.

Abstract Cancer remains the leading cause of mortality worldwide, even in the post-COVID-19 era. Lung and brain cancers account for a substantial proportion of these deaths. Although multiple anticancer agents are available, single-agent therapies often fail to achieve durable responses due to limited efficacy or the development of drug resistance. Combination therapy is therefore recognized as a powerful strategy to enhance therapeutic efficacy and delay resistance.In this study, we investigated the synergistic potential of Idasanutlin (Ida), a second-generation MDM2 inhibitor, and Gemcitabine Elaidate (Gem Eli), a lipophilic prodrug of Gemcitabine, for the treatment of non-small cell lung cancer (NSCLC) and glioblastoma (GBM). Both molecules exhibit hydrophobic characteristics, prompting their incorporation into the lipid bilayer of liposomal carriers. Using a modified hydration method, we developed a liposomal nanoformulation co-loaded with Ida and Gem Eli (IG). A major challenge was the rapid insoluble precipitation of Ida, a brick-dust molecule. To address this, we introduced the cationic ionizable lipid DLin-DMA to enable the formation of a charge-tunable complex between anionic Ida and cationic DLin-DMA. Ionizable lipids remain neutral at physiological pH but acquire a positive charge in acidic conditions (e.g., the tumor microenvironment, pH ∼5.5), which facilitates tumor-targeted delivery while minimizing systemic toxicity. The IG formulation was evaluated in NSCLC cell lines (A549 and H460) and a GBM cell line (U-87), all harboring wild-type p53. Strong synergism was observed in NSCLC, with combination index values of 0.07 (A549) and 0.3 (H460). In contrast, U-87 cells demonstrated no synergism; instead, Gem Eli displayed antagonistic behavior, with a ∼7-10-fold increase in IC50 when combined with Ida across ratios ranging from 1:1 to 1:20. A 3D spheroid assay further confirmed antagonism in GBM, after 10 days of alternate-day treatment, IG, Gem Eli, and Ida reduced spheroid area by 81%, 61.9%, and 81%, respectively, compared to controls. Synergism in NSCLC was further validated using Combenefit analysis, which demonstrated robust synergy in 3D synergy maps. The optimized IG liposomes exhibited a particle size of 131.1 ± 0.68 nm, a PDI of 0.172 ± 0.13, and pH-responsive zeta potentials of -2.06 ± 0.06 (pH 7.4) and +8.88 ± 0.31 (pH 5.5), supporting their suitability for tumor-targeted delivery. Hemocompatibility testing in mouse red blood cells showed <1% hemolysis at concentrations up to 100 µM. Cryo-electron microscopy confirmed uniform particle morphology with no evidence of aggregation. Ongoing studies are focused on elucidating the cellular mechanisms underlying the observed antagonism in GBM. Citation Format: Bhoomi Mukeshbhai Dholariya, Akanksha S. Patel, Ketankumar Patel. Combination of MDM2 inhibitor and lipophilic gemcitabine: Strong synergism in lung cancer, while antagonism in brain cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6498.

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with 5-year survival rates below 12%. KRAS mutations (95% of cases) driving aberrant MAPK signaling—yet MEK inhibitors have failed due to rapid resistance, off target inhibition, and poor pharmacokinetics. There is an urgent need of paradigm-shifting approach that blocks MAPK pathway beyond conventional inhibitors. NST-628 (NST) is a potent pan-RAF-MEK molecular glue that provide dual blockade by preventing the activation of MEK and by blocking the RAF proteins, thus enabling prolonged inhibition of MAPK oncogenic signaling pathway. NST's physicochemical properties make oral delivery suboptimal, limiting clinical translation, prompting for a sustained-release injectable formulation of NST to ensure therapeutic efficacy. We developed a self-injectable, biodegradable, sustained-release depot formulation of NST (DepNeST). This represents the first extended-release formulation of a molecular glue for cancer therapy. We aim to a) To evaluate anticancer efficacy in 2D and 3D PDAC models; b) To optimize and characterize DepNeST for sustained NST release kinetics. NST demonstrated potent in-vitro cytotoxicity with an IC50 of 183.8 nM in MIA PaCa-2 and showed concentration dependent increase in cell size. NST treatment induced concentration-dependent cytoskeletal disruption in MIA PaCa-2, characterized by actin filament accumulation and aberrant lamellipodia/filopodia formation. Acridine orange and Giemsa staining confirmed chromatin condensation and marked morphological remodeling, reflecting NST-driven antitumoral activity. NST triggered 2-fold G0/G1 arrest in MIA PaCa-2 and inducing 1.8- to 2.2-fold increases in apoptosis (acute vs. chronic), effectively blocking proliferation and driving cell death. Multicellular 3D spheroid models demonstrate superior cytotoxicity with ∼50% reduction in spheroid area with NST compared to control. Live/Dead assays revealed extensive apoptosis in both regimens, with marked red fluorescence confirming cell death and validating NST's potency in clinically relevant 3D models. DepNeST was fabricated by dissolving biodegradable polymers in different concentrations in a biocompatible solvent, N-methyl pyrrolidone (NMP). Subsequently, NST was dissolved into a polymer-NMP solution. DepNeST formulation with constant PLGA and increasing Poloxamer 338 concentrations enhanced depot dissolution profile. The in-vitro release study demonstrated an initial burst release followed by a sustained release of NST from DepNeST over a period of 6 days. This first-ever investigation of NST-628 molecular glue in pancreatic cancer establishes DepNeST as a paradigm-shifting depot platform that delivers sustained MAPK suppression at reduced doses—potentially transforming therapeutic landscape for RAS/RAF-driven malignancies. Citation Format: Drishti Rathod, Ketankumar Patel, . Long acting injectable of pan-RAF-MEK molecular-glue: Metronomic exposure for the treatment of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5802.

Abstract Pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause of cancer death by 2030 yet remains largely untreatable. Limited therapeutic options and desmoplastic microenvironment collectively result in poor clinical outcome. This necessitates dual targeting strategies that can simultaneously disrupt the microenvironment barrier and eliminate oncogenic protein drivers. Focal adhesion kinase inhibitor: PND 1186 was selected to compromise the tumor stromal barrier while BRD4 degrading PROTAC was explored to inhibit the proliferation. To overcome pharmacokinetic barriers, we designed a dual-route nanomedicine platform: oral self-nanoemulsifying PND-1186 (PNDnano, FAK inhibitor) and intravenous albumin-anchored ARV-825 nanoliposomes (AAnano, BRD4 PROTAC). This study aims to: (a) develop and characterize PND and ARV nanoformulations, (b) evaluate anticancer efficacy in 2D/3D PDAC models, and (c) assess therapeutic efficacy in xenograft studies. PNDnano was developed by screening different excipients and ones exhibiting superior solubility of PND were selected for developing SNEDDS. AAnano was formulated via modified hydration method using DGS-NTA-Ni for surface conjugation of histidine-tagged human serum albumin. Both nanoformulations showed 2-3-fold higher in-vitro cytotoxic effect in PDAC cells compared to individual drugs alone. Combenefit analysis revealed robust synergistic cytotoxicity between ARV and PND in MIA PaCa-2, achieving maximum synergy (score = 28) at 0.5 µM ARV and 2 µM PND with a combination index of 0.8. Scratch assay revealed potent anti-migratory effects, with ARV+PND achieving superior inhibition (1.9-fold in MIA PaCa-2; 2.7-fold in BxPC-3) versus monotherapies. Clonogenic assays demonstrated >90% reduction in the number and area of colonies in PDAC cells, with complete eradication in MIA PaCa-2, following ARV+PND treatment. Combination treatment showed 4.4-fold decrease in invadopodia length, enhancing inhibition in invasiveness of spheroids. 3D spheroid assays revealed significant growth inhibition with the monotherapies and ∼63% reduction with combination therapy by day 8, demonstrating superior clinical relevance in PDAC. The anticancer effect of AAnano+PNDnano in the mice bearing subcutaneous tumor (MIA PaCa-2) xenograft model achieved 56.9% tumor suppression surpassing monotherapies. All treatment groups maintained stable body weights, indicating excellent tolerability with no systemic toxicity. This dual-targeting approach provides robust antitumor efficacy without systemic toxicity, addressing a critical unmet need in PDAC treatment. This strategy that simultaneously disrupts stromal barriers and eliminates oncogenic drivers, transcending conventional chemotherapy limitations and providing a translational framework for treating desmoplastic malignancies. Citation Format: Drishti Rathod, Ketankumar Patel. Harnessing combinatorial nanomedicine for simultaneous BRD4 degradation and stromal disruption against pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1258.

Glioblastoma(GBM) is an aggressive brain tumor with dismal prognosis, necessitating innovative therapeutic strategies. Proteolysis-targeting chimeras(PROTACs), such as ARV-825, hetero-bifunctional degrader of BRD4 offer targeted protein degradation but suffer from poor aqueous solubility, high molecular weight, and limited permeability, resulting in low oral bioavailability. This study aimed to develop nanosuspension formulation (A-NS) of ARV-825 to enhance its solubility, stability, and oral absorption for GBM therapy. A-NS was prepared via dual centrifugation nano-milling using sodium lauryl sulfate, polyvinyl pyrrolidone, and SNAC as co-stabilizers and permeation enhancer. The formulation was characterized for particle size, zeta potential, and in-vitro dissolution. in-silico physiologically based pharmacokinetic(PBPK) simulations were used to predict oral bioavailability. ARV-825 and A-NS were evaluated for cytotoxicity and 3D spheroid disruption in TMZ-sensitive and resistant GBM cell lines. RNA sequencing was conducted to elucidate downstream genes and pathway alterations. A-NS achieved nanoscale size( 204 nm), enhanced solubility, and improved dissolution. PBPK modeling predicted substantial increase in oral bioavailability( 87

A series of 2-thienylidene substituted 3-oxo-2,3-dihydrobenzofuran-7-carboxamide derivatives was synthesized and evaluated to investigate structure-activity relationship for inhibiting PARP1 enzyme activity. These efforts led to the identification of a new isosteric lead compound 2, (Z)-5-((7-carbamoyl-3-oxobenzofuran-2(3H)-ylidene)methyl) thiophene-2-carboxylic acid (PARP1 IC50 = 20 nM). Subsequently, the pendant carboxyl group of 2 was coupled with several amines to access adenine binding pocket (ABP) of PARP1 active site. Among the resulting analogs, several derivatives with a structural diversity in PARP1 ABP binding motifs showed PARP1 IC50 values in the range of 17 nM - 640 nM. These derivatives also showed improved cellular inhibition of PARylation compared to lead 2. Collectively, PARP1 ABP binding moieties such as (R)-3-aminoquinuclidine in 9, 1-methylspiro[indoline-3,3'-piperidin]-2-one in 11 and benzimidazole in 13 and 15 were favorable and thus these derivatives will serve as refined leads for future SAR optimization.

In the present work, we evaluated the antifungal activities of two novel ebselen analogs, N-allyl-benzisoselenazol-3(2H)-one (N-allyl-bs) and N-3-methylbutylbenzisoselenazol-3(2H)-one (N-3mb-bs). Colorimetric and turbidity assays were performed to determine the minimum inhibitory concentration (MIC) of these compounds in S1 (fluconazole-sensitive) and S2 (fluconazole-resistant) strains of C. albicans. N-3mb-bs was more active than the N-allyl-bs compound. It is noteworthy that the concentration of N-3mb-bs observed to inhibit fungal growth by 50% (18.2 µM) was similar to the concentration observed to inhibit the activity of the yeast plasma membrane H+-ATPase (Pma1p) by 50% (19.6 µM). We next implemented a mouse model of vulvovaginal candidiasis (VVC) using the S1 strain and examined the mouse and yeast proteins present in the vaginal lavage fluid using proteomics. The yeast proteins detected were predominately glycolytic enzymes or virulence factors associated with C. albicans while the mouse proteins present in the lavage fluid included eosinophil peroxidase, desmocollin-1, and gasdermin-A. We then utilized the N-3mb-bs compound (12.5 mg/kg) in the mouse VVC model and observed that it significantly reduced the vaginal fungal burden, histopathological changes in vagina tissue, and expression of myeloperoxidase (MPO). All in all, the present work has identified a potentially promising drug candidate for VVC treatment.

Background: Vulvovaginal candidiasis is primarily caused by Candida albicans (C. albicans). Here, a novel organoselenium compound (G20) was synthesized and evaluated for anti-Candida activity. Methods: Growth-inhibition studies and medium acidification assays to assess the inhibition of the yeast plasma membrane H+-ATPase (Pma1p) were carried out in vitro using G20. A self-nanoemulsifying formulation (SNEP) of G20 was prepared and evaluated for antimycotic activity in a mouse model. Results: G20 inhibited the growth of C. albicans through a mechanism that, at least in part, involves the inhibition of Pma1p. The G20-SNEP formulation significantly reduced vaginal colonization and vaginal inflammation relative to yeast-infected but untreated control mice. Conclusion: G20-SNEP exhibits potent antimycotic activity in a mouse model of vulvovaginal candidiasis.

Polymeric in situ forming depots have emerged as highly promising drug delivery systems for long-acting applications. Their effectiveness is attributed to essential characteristics such as biocompatibility, biodegradability, and the ability to form a stable gel or solid upon injection. Moreover, they provide added versatility by complementing existing polymeric drug delivery systems like micro- and nanoparticles. The formulation's low viscosity facilitates manufacturing unit operations and enhances delivery efficiency, as it can be easily administered via hypodermic needles. The release mechanism of drugs from these systems can be predetermined using various functional polymers. To enable unique depot design, numerous strategies involving physiological and chemical stimuli have been explored. Important assessment criteria for in situ forming depots include biocompatibility, gel strength and syringeability, texture, biodegradation, release profile, and sterility. This review focuses on the fabrication approaches, key evaluation parameters, and pharmaceutical applications of in situ forming depots, considering perspectives from academia and industry. Additionally, insights about the future prospects of this technology are discussed.

In the present work, a series of N-terpenyl organoselenium compounds (CHB1-6) were evaluated for antimycotic activity by determining the minimum inhibitory concentration (MIC) for each compound in fluconazole (FLU)-sensitive (S1) and FLU-resistant (S2) strains of Candida albicans (C. albicans). The most active compounds in the MIC screen were CHB4 and CHB6, which were then evaluated for cytotoxicity in human cervical cancer cells (KB-3-1) and found to be selective for fungi. Next, CHB4 and CHB6 were investigated for skin irritation using a reconstructed 3D human epidermis and both compounds were considered safe to the epidermis. Using a mouse model of vulvovaginal candidiasis (VVC), CHB4 and CHB6 both exhibited antimycotic efficacy by reducing yeast colonization of the vaginal tract, alleviating injury to the vaginal mucosa, and decreasing the abundance of myeloperoxidase (MPO) expression in the tissue, indicating a reduced inflammatory response. In conclusion, CHB4 and CHB6 demonstrate antifungal activity in vitro and in the mouse model of VVC and represent two new promising antifungal agents.

The KRAS-G12C inhibitor ARS-1620, is a novel specific covalent inhibitor of KRAS-G12C, possessing a strong targeting inhibitory effect on KRAS-G12C mutant tumors. Overexpression of ATP-binding cassette super-family B member 1 (ABCB1/P-gp) is one of the pivotal factors contributing to multidrug resistance (MDR), and its association with KRAS mutations has been extensively studied. However, the investigations about the connection between the inhibitors of mutant KRAS and the level of ABC transporters are still missing. In this study, we investigated the potential drug resistance mechanism of ARS-1620 associated with ABCB1. The desensitization effect of ARS-1620 was remarkably intensified in both drug-induced ABCB1-overexpressing cancer cells and ABCB1-transfected cells as confirmed by cell viability assay results. This desensitization of ARS-1620 could be completely reversed when co-treated with an ABCB1 reversal agent. In mechanism-based studies, [3H] -paclitaxel accumulation assay revealed that ARS-1620 could be competitively pumped out by ABCB1. Additionally, it was found that ARS-1620 remarkably stimulated ATPase activity of ABCB1, and the HPLC drug accumulation assay displayed that ARS-1620 was actively transported out of ABCB1-overexpressing cancer cells. ARS-1620 acquired a high docking score in computer molecular docking analysis, implying ARS-1620 could intensely interact with ABCB1 transporters. Taken all together, these data indicated that ARS-1620 is a substrate for ABCB1, and the potential influence of ARS-1620-related cancer therapy on ABCB1-overexpressing cancer cells should be considered in future clinical applications.

Vulvovaginal candidiasis (VVC), caused by Candida albicans, is a common infection in women affecting their quality of life. Standard antifungal drugs (e.g., fluconazole, itraconazole) are typically fungistatic or rendered ineffective due to drug resistance indicating an urgent need to build an arsenal of novel antifungal agents. To surmount this issue, we tested the hypothesis that the organoselenium compound ebselen (EB) possesses antifungal efficacy in a mouse model of VVC. EB is a poorly water-soluble drug and DMSO as a vehicle has the potential to exhibit cytotoxic effects when administered in vivo. EB loaded self-nanoemulsifying preconcentrate (EB-SNEP) was developed, characterized in vitro, and tested in a mouse model of VVC. In vivo studies carried out with EB-SNEP (12.5 mg/kg) showed a remarkable decrease in infection by ~562-fold compared to control (infected, untreated animals). Taken together, EB nanoemulsion proved to be an effective and promising antifungal agent.

Carvacrol (CAR), a phenolic monoterpenoid, has been extensively investigated for its antimicrobial and antifungal activity. As a result of its poor physicochemical properties, water soluble carvacrol prodrugs (WSCPs) with improved water solubility were previously synthesized and found to possess antimicrobial activity. Here, three novel CAR analogs, WSCP1, WSCP2, and WSCP3, were tested against fluconazole (FLU)-sensitive and -resistant strains where they showed greater antifungal activity than CAR against C. albicans. The probable mechanism by which the CAR prodrugs exert the antifungal activity was studied. Results from medium acidification assays demonstrated that the CAR and its synthetically designed prodrugs inhibit the yeast plasma membrane H+-ATPase (Pma1p), an essential target in fungi. In other words, in vitro data indicated that CAR analogs can prove to be a better alternative to CAR considering their improved water solubility. In addition, CAR and WSCP1 were developed into intravaginal formulations and administered at test doses of 50 mg/kg in a mouse model of vulvovaginal candidiasis (VVC). Whereas the CAR and WSCP1 formulations both exhibited antifungal efficacy in the mouse model of VVC, the WSCP1 formulation was superior to CAR, showing a remarkable decrease in infection by ~120-fold compared to the control (infected, untreated animals). Taken together, a synthetically designed prodrug of CAR, namely WSCP1, proved to be a possible solution for poorly water-soluble drugs, an inhibitor of an essential yeast pump in vitro and an effective and promising antifungal agent in vivo.

The emergence of multidrug resistance (MDR) has been a major issue for effective cancer chemotherapy as well as targeted therapy. One prominent factor that causes MDR is the overexpression of ABCB1 transporter. In the present study, we revealed that the Aurora kinase inhibitor GSK-1070916 is a substrate of ABCB1. GSK-1070916 is a newly developed inhibitor that is currently under clinical investigation. The cytotoxicity assay showed that overexpression of ABCB1 significantly hindered the anticancer effect of GSK-1070916 and the drug resistance can be abolished by the addition of an ABCB1 inhibitor. GSK-1070916 concentration-dependently stimulated ABCB1 ATPase activity. The HPLC drug accumulation assay suggested that the ABCB1-overexpressing cells had lower levels of intracellular GSK-1070916 compared with the parental cells. GSK-1070916 also showed high binding affinity to ABCB1 substrate-binding site in the computational docking analysis. In conclusion, our study provides strong evidence that ABCB1 can confer resistance to GSK-1070916, which should be taken into consideration in clinical setting.

Abstract Pancreatic ductal adenocarcinoma is a very common type of pancreatic cancer and is one of the deadliest cancers. Gemcitabine (Gem), is still the mainstay drug for the treatment of PDAC. Gem is a hydrophilic drug which requires nucleoside transporters for its efficient uptake. Once inside the cell, Gem is converted to an active triphosphate form which inhibits DNA synthesis and causes apoptosis. However, Gem gets inactivated by cytidine deaminase (CDA). Long term treatment with Gem leads to increased CDA production thereby developing resistance. We hypothesize that combination of Gem with CDA inhibitor like Zebularine (Zeb), could prevent the intracellular degradation of Gem. Combination can potentially result in enhancing the anti-cancer activity of Gem, reduced dose and dosing frequency and minimizing side effects. The objectives of our study were; (a) to investigate the cytotoxic interaction of Gem and Zeb alone and in combination (b) Evaluating effect of various apoptosis and proliferation markers using flow cytometry and western blot assay. Initially we explored the anti-proliferative effects of Gem and Zeb as a single drug and in combination on MiaPaca-2 cells using MTT assay. Combination index was calculated using chou talalay method and Combenefit software. Effect of Gem, Zeb, and combination treatment on the cell viability of 3D tumor spheroids and its area was carried out using fluorescence microscopy and ImageJ software respectively. Apoptosis study was carried out using Annexin V apoptosis kit.Gem and Zeb exhibited dose-dependent inhibition in viability of MiaPaca-2 cells with an IC50 of 0.48 and 67.82 µM, respectively. The combination index of 0.09 suggest “very strong synergism” (Table 1). 3D spheroid treated with combination exhibited a highly distorted surface with significantly higher number of dead cells. Our research confirms that this synergistic combination can be a breakthrough approach for the treatment of PDAC. Table 1.IC50 of Gem, Zeb and combination of Gem+Zeb in Miapaca2 cellsDrugMolar RatioIC50 of GemIC50 of ZebCombination IndexSingle-0.4867.82Gem1:100.0440.40.09 Citation Format: Manali Patki, Aishwarya Saraswat, Shraddha Bhutkar, Vikas Dukhande, Ketankumar Patel. Combination of gemcitabine and cytidine deaminase inhibitor: A breakthrough cocktail for the treatment of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1059.

Death from an accidental or intentional overdose of sleeping tablets has increased exponentially in the USA. Furthermore, the simultaneous consumption of sleeping tablets with alcoholic beverages not only intensifies the effect of sleeping tablets but also leads to blackouts, sleepwalking, and death in many cases. In this article, we proposed a unique and innovative technology to prevent multi-tablet and alcohol-associated abuse of sleeping tablet. Agonist- and antagonist-loaded polymeric filaments of appropriate Eudragit® polymers were prepared using hot melt extrusion. Metoprolol tartrate and hydrochlorothiazide were used as model drugs in place of zolpidem tartrate (agonist-BCS class I) and flumazenil (antagonist-BCS class IV), respectively. Crushed filaments were converted into a tablet with a novel rapidly soluble co-processed alkalizing agent. Dissolution studies of single tablet and multiple tablets (5) in fasted state simulated gastric fluid (FaSSGF) confirmed that the release of the agonist was significantly (p < 0.0001) reduced in multi-tablet dissolution. Furthermore, the release of antagonist was significantly higher when tablet was exposed to FaSSGF+20% ethanol and various alcoholic beverages. Thus, appropriate use of Eudragit® polymer’s chemistry could help design a tablet to prevent the release of agonist in case of overdose and simultaneous release of antagonist when consumed with alcohol.

M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to increased ABCG2 substrate drugs accumulation. Furthermore, M3814 can stimulate the ABCG2 ATPase activity in a concentration-dependent manner without affecting the ABCG2 protein expression or cell surface localization of ABCG2. Moreover, the molecular docking analysis indicated a high affinity between M3814 and ABCG2 transporter at the drug-binding cavity. Taken together, our work reveals M3814 as an ABCG2 modulator and provides a potential combination of co-administering M3814 with ABCG2 substrate-drugs to overcome MDR.

Enterohemorrhagic Escherichia coli O157:H7 (EHEC) or Shiga toxin-producing E. coli (STEC) is known to cause sporadic and epidemic gastrointestinal infections with several incidences of outbreaks. Antibiotic-based therapy further worsens the condition by facilitating the release of Shiga toxins (Stx) and lipopolysaccharides (LPS). Hence, there is an urgent need to develop an antibiotic-free, safe, and effective therapeutic intervention for the treatment of EHEC infections. We proposed a novel therapeutic strategy to address this clinical problem-kill, capture, and inhibit. We aimed to formulate and characterize lauroyl arginate ethyl ester (LAE) and Retro-2 loaded self-nano emulsifying drug delivery systems (SNEDDS). Retro-2 is a recently developed novel class of molecule, which can selectively inhibit retrograde transport of Stx. In this paper, we first carried out preformulation studies of Retro-2, followed by the development of SNEDDS forming arginine anchored nanoglobules (AR-NG), characterization of LPS binding to AR-NG, and finally evaluation of activity against EHEC. Retro-2 showed extremely poor solubility at all gastrointestinal pH values, susceptibility to acidic environments, and good permeability. The positively charged AR-NG spontaneously formed a globule size of 102.8 +/- 1.9 nm with a surface charge of +52.15 +/- 3 mV and increased the solubility of Retro-2. Further, binding and aggregation of LPS and AR-NG were confirmed by particle size, polydispersity index, zeta potential, fluorescent intensity, turbidity analysis, and a limulus amebocyte lysate (LAL) test. Additionally, a significant reduction in LPS induced TNF-alpha was observed in AR-NG treated macrophages. Thus, in this paper, we demonstrate a very promising and innovative therapeutic approach based on the "kill (E. Coli), capture (released LPS), and inhibit (transport of Stx)" concept.

Background: Recrystallization of drug and incomplete drug release from liquisolid formulation are two major hurdles in the development of a supersaturated self-nanoemulsifying drug delivery system. The aim of this research work was to develop a solid supersaturated self-nanoemulsifying drug delivery system of fenofibrate (FB) for enhanced dissolution. Methods: FB loaded supersaturated self-nanoemulsifying preconcentrate (superSNEP) was prepared using dimethyl acetamide (DMA), medium chain triglycerides (MCT), and kolliphor EL. Co-processed excipients (CPE) prepared using inorganic microporous silica (Neusilin US2, Florite 100, or Aerosil 200) and hydrophilic polymers (Polyvinyl alcohol, HPMC, and Kollidon VA64) were evaluated for flow property, BET surface area, and adsorption capacity. Lipophilic fluorescent probe (coumarin-6) was used to investigate the extent of self-emulsification. The formulation was further characterized for solid state, in-vitro cytotoxicity in caco-2 cell line and in-vitro dissolution in a sink and non-sink conditions. Results: Optimized superSNEP with 20% w/v FB loading spontaneously formed nanoglobules of 40 +/- 2.7 nm. DMA based self-nanoemulsifying system was found to be nontoxic to Caco-2 cell even at a very high concentration. CPE prepared using PVA and Florite 100 (1:1 weight ratio) showed the highest adsorption capacity (1 mL/g) and complete release of oil as depicted by fluorescence study. DSC thermogram and PXRD of S-superSNEP confirmed that FB remained in a solubilized state. S-superSNEP showed significantly faster and higher dissolution of FB in sink and non-sink conditions compared to the plain API. Conclusion: DMA and PVA-F100 based novel co-processed excipient could be potentially useful for the development of solid supersaturated self-nanoemulsifying drug delivery system for enhancing dissolution of lipophilic drugs.

Background: Cancer is a chronic disease, its prevalence is increasing worldwide due to various advances exist for the diagnosis and treatment. Cancer occurs as a result of unusual growth of cells and invasion of nearby tissue and organs. At present, cancer is the second leading cause of death. Cancer distribution has a wide variation in different parts of the world. Objectives: To observe the pattern of different types of Cancer, Age and Gender wise distribution of common cancer in newly registered cancer patients at Cancer Treating Institute. Materials and Methods: This cross-sectional study conducted in newly registered cancer patients at D.B. Tejani Cancer Institute, Surat. Total 690 patients purposively selected from December 2015 to January 2016. Results: The most common sites of cancer in decreasing order were oral cavity (19%), female genital tract (15.1%), breast cancer (14.5%), gastrointestinal tract (11.3%), lympho-hematopoietic system (9.9%), respiratory tract (5.6%), and others. In less than 14 years, lymphatic leukemia was found to be the most common cancer in boys and ovarian cancer (25%) among girls. Conclusion: Tobacco-related cancer was more common among more than 15-year-old males, while breast cancer was the most common type of cancer in females.