Low-dose Drug Research Articles

Low-dose anti-VEGFR2 therapy promotes anti-tumor immunity in lung adenocarcinoma by down-regulating the expression of layilin on tumor-infiltrating CD8+T cells

PurposeOur study intended to explore how low-dose anti-angiogenic drugs affected anti-tumor immunity of tumor-infiltrating exhausted CD8+T cells and achieved better clinical response when combined with immunotherapy. We set out to find potential targets or predictive biomarker on CD8+T cells for immunotherapy.MethodsWe tested different doses of anti-VEGFR2 antibody combined with anti-PD1 antibody to treat LUAD in vivo and analyzed tumor-infiltrating CD8+T cells by flow cytometry. CD8+T cells overexpressing LAYN were co-cultured with LA795 cell lines to identify the function of LAYN in CD8+T cells. We also analyzed clinical samples from advanced LUAD patients treated with anti-angiogenesis therapy combined with immunotherapy.ResultsLow-dose anti-VEGFR2 antibody combined with anti-PD1 antibody treatment delayed tumor growth and prolonged the survival time of tumor-bearing mice. The number of tumor-infiltrating CD8+T cells was reduced and the expression of LAYN was down-regulated in tumor-infiltrating CD8+T cells in the low-dose anti-VEGFR2 combination group. It was found that LAYN inhibited the killing function of CD8+T cells. In patients with advanced LUAD who received anti-angiogenesis therapy combined with immunotherapy, the LAYN+CD8+T cell subpopulation in good responders was significantly higher than that in poor responders. Furthermore, we demonstrated the expression of LAYN was regulated by upstream transcription factor NR4A1.ConclusionLow-dose anti-VEGFR2 antibody combined with anti-PD1 antibody therapy promoted anti-tumor immunity and the downregulation of LAYN in tumor-infiltrating CD8+T cells played an important role in this process. These findings had implications for improving the efficacy of immune checkpoint blockade therapy and further optimized clinical treatment guidelines in advanced LUAD.

Benefits of Long-Term Continuation of Low-Dose Methimazole Therapy in the Prevention of Recurrent Hyperthyroidism in Graves' Hyperthyroid Patients: A Randomized Prospective Controlled Study.

Background The long-term continuation of the low-dose antithyroid drug (ATD) beyond the standard duration of ATD therapy of 12–18 months to prevent recurrent hyperthyroidism (RH) is recommended with low quality of evidence. Objectives To examine whether long-term continuation of low-dose ATD beyond the recommended duration of treatment would provide a benefit in the prevention of RH in patients with Graves' hyperthyroidism (GH) who achieved euthyroid status with a standard course of ATD therapy. Methods A 36-month prospective randomized controlled study was conducted in 184 patients who had first diagnosed GH and were treated with a standard regimen of ATD therapy using methimazole (MMI) until achieving euthyroidism that was stably maintained for at least 6 months with a low-dose of (2.5–5 mg/day) MMI. All patients had neither a history of adverse effects from MMI, recurrent GH, severe and active ophthalmopathy nor conditions known to affect thyroid function before randomization. The patients were randomized into 2 groups: one group (92 cases) was assigned to discontinue (DISCONT-MMI) and the other (92 cases) was assigned to continue low-dose MMI (CONT-MMI) that was taken at the time of enrollment. The patients in both groups were followed up at 3, 6, 12, 18, 24, 30, and 36 months. The rate of RH was compared between both groups, and the adverse effects and risk factors of RH were also studied. Results At the end of the 36-month study, 83 cases in CONT-MMI and 90 cases in DISCONT-MMI were eligible for analysis. The cumulative rates of RH in CONT-MMI were significantly lower than those in DISCONT-MMI at every follow-up time point (1.2% vs. 11.2%, 6.8% vs. 18.4%, 11.0% vs. 27.2%, 11.0% vs. 35.0%, and 11.0% vs. 41.2% at 6, 12, 18, 24, and 36 months, respectively; p < 0.01). Cox proportional hazard multivariate analysis showed that there were 2 factors independently associated with the risk of RH, including continuation of low-dose MMI therapy, which decreased the risk of RH by 3.8 times (HR = 0.26, p = 0.007, 95% CI = 0.10–0.70) and age onset of hyperthyroidism before 40 years, which increased the risk of RH by 2.9 times (HR = 2.9, p = 0.015, 95% CI = 1.23–6.88). Neither minor nor major adverse effects of low-dose MMI therapy were observed during the study period. Conclusions In Graves' hyperthyroid patients with no or nonsevere ophthalmopathy who have completed a standard course of methimazole therapy without an adverse effect and have achieved an euthyroid status that is stably maintained with low-dose methimazole, a long-term continuation of the low-dose methimazole of 2.5–5 mg daily is effective and safe in the prevention of recurrent hyperthyroidism or maintenance of euthyroid status as long as the low-dose methimazole is continued. (TCTR20170705002).

FOLFOXIRI Resistance Induction and Characterization in Human Colorectal Cancer Cells.

Simple SummaryWe created colorectal cancer in vitro models to study how an induced drug resistance profile can alter cell response and sensitivity to a treatment. By chronically exposing the cells to current first-line treatments (5-FU+folinic acid+oxaliplatin+SN38), resistance to the chemotherapy was obtained. We further investigated the mechanism underlying the acquired chemoresistance and highlighted the main up- and downregulated genes implicated. We also showed that optimized drug combination composed of tyrosine kinase inhibitors overcome chemotherapy-induced resistance.FOLFOXIRI, i.e., the combination of folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan, is a first-line treatment for colorectal carcinoma (CRC), yet non-personalized and aggressive. In this study, to mimic the clinical situation of patients diagnosed with advanced CRC and exposed to a chronic treatment with FOLFOXIRI, we have generated the CRC cell clones chronically treated with FOLFOXIRI. A significant loss in sensitivity to FOLFOXIRI was obtained in all four cell lines, compared to their treatment-naïve calls, as shown in 2D cultures and heterotypic 3D co-cultures. Acquired drug resistance induction was observed through morphometric changes in terms of the organization of the actin filament. Bulk RNA sequencing revealed important upregulation of glucose transporter family 5 (GLUT5) in SW620 resistant cell line, while in the LS174T-resistant cell line, a significant downregulation of protein tyrosine phosphatase receptor S (PTPRS) and oxoglutarate dehydrogenase-like gene (OGDHL). This acquired resistance to FOLFOXIRI was overcome with optimized low-dose synergistic drug combinations (ODCs) acting via the Ras-Raf-MEK-ERK pathway. The ODCs inhibited the cell metabolic activity in SW620 and LS174T 3Dcc, respectively by up to 82%.

Polymeric Nanoparticles—Tools in a Drug Delivery System in Selected Cancer Therapies

The increase in cancer cases is undoubtedly affecting the development of new therapeutic approaches. Polymeric nanoparticles are of great interest. Due to their relatively small size, the possibility of incorporating into them medicinal substances and the ease with which their physicochemical properties may be manipulated, they are being used as anticancer drug delivery systems. The aim of this review is to focus on the use of nanoscale polymeric particles in the treatment of colorectal cancer, breast cancer, ovarian cancer and glioblastoma multiforme, and to consider their potential use in cancer gene therapy. According to several reports, the use of polymer nanoparticles as drug carriers is promising in solid tumors. With their application, it is possible to precisely deliver medicinal substances to the tumor structure, to overcome the blood–brain barrier in the case of brain tumors, to reduce the side effects of anticancer agents on normal cells and to achieve a therapeutic effect with a lower drug dose. Additionally, a number of reports indicate that they can also be used in combination with other methods of cancer treatment, mainly radiotherapy.

Antihypertensive therapy of late arterial hypertension in children following successful coarctation correction.

Late arterial hypertension (AH) is the most significant complication of coarctation of the aorta (CoA). Only a few clinical studies described antihypertensive treatment of late AH following successful CoA repair. The primary objective of this multicentre cross-sectional study was to describe real-life antihypertensive therapy for late AH in children after hemodynamically successful CoA repair. The secondary objective was to describe antihypertensive therapy used within different haemodynamic phenotypes of AH. Blood pressure status, echocardiographic parameters and central blood pressure measurements were evaluated in 110 children aged 6-18 years following successful CoA repair with right arm blood pressure not exceeding leg blood pressure by at least 20 mmHg. AH was found in 62 (56%) patients including 47 who were already treated and 15 with new diagnosed AH of whom seven presented with masked hypertension. Among treated patients, 10 presented with masked hypertension. The dominant phenotype of AH among patients with uncontrolled AH was isolated systolic hypertension (32 patients out of 37; 87.5%). AH was controlled in 53% of treated patients. Fifty-three percent of hypertensive patients had elevated central SBP and 39% had left ventricular hypertrophy with various left ventricle geometry patterns, 23% of them had both. β-adrenergic receptor blockers were the most used antihypertensive drugs followed by angiotensin-converting enzyme inhibitors with doses within the lower recommended range. High prevalence of uncontrolled AH despite successful CoA repair and use of relatively low doses of antihypertensive drugs indicates the need of close blood pressure monitoring and more intensive and combined antihypertensive therapy.

FORMULATION DEVELOPMENT OF MOUTH DISSOLVING PRINTED FILM OF KETOROLAC AND IN VITRO EVALUATION

Objective: The present research work was carried out to prepare Ketorolac printed Oral Thin Films using a pneumatic pressure printer. In this research, we attempted to prepare a non-contact printing system by using pneumatic pressure-based printer that incorporates printing of active pharmaceutical ingredients onto a medical-grade Orodispersible film for developing personalized medication. Methods: In the present work Ketorolac Trometamol was used as a model drug. Placebo substrate was developed by using cellulosic polymers like HPMC, MCC, Neusilin, and starch to impart paper-like properties that are desirable for printing. It was evaluated for various physicochemical properties like disintegration time, mechanical strength, folding endurance, surface properties, etc. Polymers and plasticizers were evaluated for the development of drug loaded Printing ink. The drug-printed films were characterized for physicochemical properties and in vitro drug dissolution. Results: Various film-forming polymers were evaluated for the development of printing substrates. The F3 substrate had desired mechanical properties i.e. the thickness of 0.157±0.003, the tensile strength of 0.331±0.016, disintegration within 60 seconds, and this substrate also maintained its integrity after the printing of the drug ink. The HPMC-based ink (I4) with polyethylene glycol for modulating flow properties of ink in the concentration of 1.40%w/v was selected among various ink formulations. The drug release from the printed films was 98±1.94% in 1 h. Conclusion: Through this new drug printing technology the limitation of low drug dose loading associated with ink-jet and flexographic printing can be solved by increasing the drug loading ranges from micrograms to milligrams by a single pass of the print head.

Self-emulsifying Drug Delivery System for Oral Anticancer Therapy: Constraints and Recent Development.

Oral anticancer therapy faces several drawbacks: low aqueous solubility, poor and irregular absorption from gastrointestinal sites, high first-pass metabolism, food-influenced absorption, non-targeted delivery, severe systemic and local adverse effects, etc. Enhancement of oral bioavailability could reduce the drug load and associated adverse effects. Self-emulsifying drug delivery systems (SEDDS) can enhance in-vivo solubility and drug absorption from the gastrointestinal tract, bypass liver metabolism by lymphatic absorption and inhibit efflux transport. All these phenomena ultimately result in improved oral bioavailability. Anticancer drug delivery using the SEDDS has shown promising results for bioavailability and pharmacodynamic response. A handful of research studies have produced evidence of the successful loading of anticancer agents in SEDDS-based formulations. Various potent and established chemotherapeutic agents such as docetaxel, paclitaxel, etoposide, 5 Fluorouracil, doxorubicin etc., have been successfully formulated and evaluated. Improved bioavailability and reduction of dose might be possible by SEDDS. It could be effective for low-dose drugs. But, excessive surfactant- cosurfactant concentration, lacking predictive in-vitro models and adequate IVIVC, and unavailability of toxicity data are certain challenges for future researchers. No clinical trials have been recorded with anticancer drug-loaded SEDDS. Overcoming the challenges and further progression to clinical studies are required to avail the benefits of anticancer SEDDS.

Already low drug dose antagonism of the renin-angiotensin aldosterone system decreases 1-year mortality and rehospitalization in old heart failure patients

AimsHospitalization for heart failure treatment (HHF) is an incisive event in the course of HF. Today, the large majority of HHF patients is ≥ 65 years and discharge HF drugs are most often not applied at dose levels acknowledged to provide prognostic benefit. This study therefore aims to investigate the treatment effect size of discharge HF drugs in old HHF patients. MethodsDrugs are analyzed according to pharmacological class. Individual discharge HF drug dose is reported as percentage of guidelines-recommended target dose. Primary endpoint was 1-year all-cause mortality (ACM) after discharge; the secondary endpoint combined 1-year ACM and first cardiovascular hospitalization within 1 year after discharge. Comparison between 65–80 years and > 80 years old study participants tested the relative treatment effect size as a function of respective age group. ResultsThe 875 consecutive HHF patients had a median age of 82 years [76–87 years]; 48.6 % were females. Betablocker and diuretic treatment did not change the incidence of endpoints. Inhibition of the renin-angiotensin system (RASi), when compared to no treatment, decreased the incidence of endpoints both at the 1–25 % and the > 25 % target dose level. Antagonists of the mineralocorticoid receptor (MRA), when compared to no treatment, decreased the secondary endpoint at the 1–25 % target dose level but not at the > 25 % target dose level. The relative treatment effect size of RASi or MRA corresponded between the age strata for both endpoints. ConclusionLow-dose RASi and MRA had beneficial effects in these old HHF patients.

Intervention to severe lower trachea obstruction supported by extracorporeal membrane oxygenation in a human immunodeficiency virus patient: A case report and literature review

Here we reported a case, male, 33 years old, diagnosed with human immunodeficiency virus (HIV) infection 5 months ago, but he didn’t take antiretroviral drugs regularly. He was admitted to intensive care unit emergently due to hypoxemia, hypercapnia, and hypotension. CT showed severe lower trachea obstruction caused by soft tissue. After rapid bedside assessment, the patient was considered to need endotracheal operation, but he couldn‘t tolerate intubation and mechanical ventilation. Extracorporeal membrane oxygenation (ECMO) was used. Hemodynamics improved significantly along with rehydration and low-dose vasoactive drugs. Subsequently, the patient underwent rigid bronchoscopy, airway tumor resection and Y-type silicone stent implantation. Postoperatively protective endotracheal intubation and mechanical ventilation was followed. ECMO was weaned off after the operation, and endotracheal cannula was removed 6 h later. The pathological examination of excisional tissue showed lung squamous cell carcinoma. Finally, the patient was discharged safely and went to local hospital for further treatment. From this case, we conclude that ECMO could play a key role for those who need endotracheal surgery while cannot endure conventional intubation and mechanical ventilation.

Effect of different molecular weight and terminal group PLGA on docetaxel nanoparticles: characterization and cytotoxic activity of castration-resistant prostate cancer cells

The choice of polymer and its compatibility with drug used determine the fate of nanoparticle in therapy. There has been limited sources about effect of resomer differentiation in nanoparticle related with physical and chemical properties and also biological activities of product. Therefore, we aimed to formulate docetaxel-loaded polylactic-co-glycolic acid nanoparticles with different molecular weights (Resomer 502 and 504) and terminal groups (Resomer 502H and 504H) and to investigate the effect of these resomers on nanoparticle character, prostate cancer, and healthy cells. Docetaxel-loaded PLGA nanoparticles were prepared by single emulsion solvent evaporation method. Surface characterizations were carried out by zeta sizer and scanning electron microscopy. Encapsulation efficiency, in vitro drug release profiles, and cytotoxic activity were determined. Main effect on the surface morphology of nanoparticles was the molecular weight of the polymer. The groups with acid terminal function have higher encapsulation and reaction efficiency. In all formulations, in vitro release was observed after 334 h at pH 7.4 and 240 h at pH 5.6. Also, the groups with high molecular weight showed selective cytotoxicity. These resomers especially RG 504 and RG 504H have potential to be used as a low-dose and high-efficiency extended-release drug delivery system in the treatment of prostate cancer.

Synergistic Integration and Pharmacomechanical Function of Enzyme-Magnetite Nanoparticle Swarms for Low-Dose Fast Thrombolysis.

Magnetic micro-/nanoparticles are extensively explored over the past decade as active diagnostic/therapeutic agents for minimally invasive medicine. However, sufficient function integration on these miniaturized bodies toward practical applications remains challenging. This work proposes a synergistic strategy via integrating particle functionalization and bioinspired swarming, demonstrated by recombinant tissue plasminogen activator modified magnetite nanoparticles (rtPA-Fe3 O4 NPs) for fast thrombolysis in vivo with low drug dosage. The synthesized rtPA-Fe3 O4 NPs exhibit superior magnetic performance, high biocompatibility, and thrombolytic enzyme activity. Benefiting from a customized magnetic operation system designed for animal experiments and preclinical development, these agglomeration-free NPs can assemble into micro-/milli-scale swarms capable of robust maneuver and reconfigurable transformation for on-demand tasks in complex biofluids. Specifically, the spinning mode of the swarm exerts focused fluid shear stresses while rubbing on the thrombus surface, constituting a mechanical force for clot breakdown. The synergy of the NPs' inherent enzymatic effect and swarming-triggered fluid forces enables amplified efficacy of thrombolysis in an in vivo occlusion model of rabbit carotid artery, using lower drug concentration than clinical dosage. Furthermore, swarming-enhanced ultrasound signals aid in imaging-guided treatment. Therefore, the pharmacomechanical NP swarms herein represent an injectable thrombolytic tool joining advantages of intravenous drug therapy and robotic intervention.

Inhaled therapy for COVID-19: Considerations of drugs, formulations and devices

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent responsible for the COVID-19 pandemic, has outspread at full tilt across the world. Although several effective vaccines continue to be deployed, reliable antiviral treatments have yet to be developed against this disease. Currently, available therapeutics for COVID-19 include repurposed, and a few novel drugs. Many drugs have been promising in preclinical studies, but a majority of these drugs have shown little or no efficacy in clinical studies. One of the major reasons is the insufficient drug concentration in the lung, the primary target site of infection for SARS-CoV-2, from the administration of drugs through oral or intravenous routes. Higher effective doses administered through these routes could also lead to adverse side effects. For this reason, inhaled treatments are being tested as an efficient approach for COVID-19, allowing lower doses of drugs ensuring higher concentrations of the drug(s) in the lung. The inhaled treatment combining two or more antiviral drugs will increase potency and reduce the possibility of selecting for SARS-CoV-2 variants with reduced drug susceptibility. Finally, the appropriate drug combination needs to be delivered using a suitable system. Here, we review the current treatment for COVID-19 and their limitations, discussing the advantages of mono and combinational inhaled therapy with a brief outline of the recently reformulated anti-SARS-CoV-2 agents as inhaled formulations. The selection of appropriate delivery devices for inhalation and associated key considerations including the formulation challenges are also discussed.

Perspectives for Uses of Propolis in Therapy against Infectious Diseases.

Propolis has gained wide popularity over the last decades in several parts of the world. In parallel, the literature about propolis composition and biological properties increased markedly. A great number of papers have demonstrated that propolis from different parts of the world is composed mainly of phenolic substances, frequently flavonoids, derived from plant resins. Propolis has a relevant role in increasing the social immunity of bee hives. Experimental evidence indicates that propolis and its components have activity against bacteria, fungi, and viruses. Mechanisms of action on bacteria, fungi, and viruses are known for several propolis components. Experiments have shown that propolis may act synergistically with antibiotics, antifungals, and antivirus drugs, permitting the administration of lower doses of drugs and higher antimicrobial effects. The current trend of growing resistance of microbial pathogens to the available drugs has encouraged the introduction of propolis in therapy against infectious diseases. Because propolis composition is widely variable, standardized propolis extracts have been produced. Successful clinical trials have included propolis extracts as medicine in dentistry and as an adjuvant in the treatment of patients against COVID-19. Present world health conditions encourage initiatives toward the spread of the niche of propolis, not only as traditional and alternative medicine but also as a relevant protagonist in anti-infectious therapy. Production of propolis and other apiary products is environmentally friendly and may contribute to alleviating the current crisis of the decline of bee populations. Propolis production has had social-economic relevance in Brazil, providing benefits to underprivileged people.

PD-L1-Targeted Co-Delivery of Two Chemotherapeutics for Efficient Suppression of Skin Cancer Growth.

To overcome the severe side effects of cancer chemotherapy, it is vital to develop targeting chemotherapeutic delivery systems with the potent inhibition of tumour growth, angiogenesis, invasion and migration at low drug dosages. For this purpose, we co-loaded a conventional antiworm drug, albendazole (ABZ), and a TOPK inhibitor, OTS964, into lipid-coated calcium phosphate (LCP) nanoparticles for skin cancer treatment. OTS- and ABZ-loaded LCP (OTS-ABZ-LCP) showed a synergistic cytotoxicity against skin cancer cells through their specific cancerous pathways, without obvious toxicity to healthy cell lines. Moreover, dual-targeting the programmed death ligand-1 (PD-L1) and folate receptor overexpressed on the surface of skin cancer cells completely suppressed the skin tumour growth at low doses of ABZ and OTS. In summary, ABZ and OTS co-loaded dual-targeting LCP NPs represent a promising platform with high potentials against complicated cancers where PD-L1/FA dual targeting appears as an effective approach for efficient and selective cancer therapy.

Taxane monotherapy regimens for the treatment of recurrent epithelial ovarian cancer.

Taxane monotherapy regimens for the treatment of recurrent epithelial ovarian cancer.

Active coating of immediate-release evogliptin tartrate to prepare fixed dose combination tablet with sustained-release metformin HCl

This study was aimed to develop a fixed dose combination (FDC) tablet containing a low dose of evogliptin tartrate (6.87 mg) for immediate release combined with a high dose (1000 mg) of sustained-release (SR) metformin HCl appropriate for once daily dosing the treatment of type 2 diabetes. To prepare the FDC tablets, an active coating was used in this study, whereby evogliptin tartrate film was layered on a matrix core tablet containing metformin HCl. To overcome the problem caused by a low-dose drug in combination with a relatively large matrix tablet containing high-dose drug, it was also aimed to confirm the formulation and coating operation for satisfactory content uniformity, and to describe the chemical stability during storage of the amorphous active coating layer formulation in relation to molecular mobility. Furthermore, the in vitro release and in vivo pharmacokinetic profiles of metformin HCl and evogliptin tartrate in the FDC active coating tablet were compared to those of the commercially marketed reference drugs, Diabex XR® (Daewoong, Seoul, Korea) containing metformin HCl and Suganon® (Donga ST, Seoul, Korea) containing evogliptin tartrate. In conclusion, the newly developed FDC active coating tablet in this study was confirmed to be bioequivalent to the reference marketed products in beagle dogs, with satisfactory content uniformity and stability.

Abstract 1403: ROS metabolism and autophagy as potential targets to improve head and neck cancer treatment

Abstract Introduction: Cancer cells exhibit a high degree of plasticity to adapt the rapidly changing tumor microenvironment (TME), in part by altering cellular metabolic pathways at a faster and more efficient pace than normal cells. Cancer cell plasticity, with genetic and epigenetic alterations, promote the diversity of cancer cells contributing to heterogeneity within the tumor. Head and neck cancer (HNC) is a notable example of this diversity; HNC tumors harbor cells with a wide genetic and metabolic heterogeneity, including cancer stem cells (CSC). Despite current treatment approaches, more than 40% of HNC patients have disease recurrence. Thus, we developed a multimodal approach to effectively prevent the development of radio/drug-resistance. Experimental Procedures: Nuclear-localized mkate2 expressing HNC cell numbers detected for every 6 hours by using IncuCyte S3 instrument. Apoptotic cells detected via NucView 488 Caspase-3 substrate and ROS levels determined using CellROX green simultaneously with cell numbers in the IncuCyte S3 instrument. Synergy scores calculated according to viability in SynergyFinder 2.0 web-application. Results: Our preliminary data profiling of metabolic regulators as radiosensitizer indicate that auranofin (AUR, thioredoxin reductase inhibitor) and buthionine sulfoximine (BSO, γ-glutamylcysteine synthetase inhibitor), given in combination with radiation (RT+AUR+BSO): 1) significantly inhibit proliferation in HNC cell lines, 2) increase ROS accumulation, and 3) reduce the surviving fraction of cells in colony forming assays compared to individual/dual agent applications. Furthermore, we added an autophagy inhibitor, SAR405, in our treatment regimen because of the crosstalk between ROS levels and autophagy. Human (FaDu and UM-SCC-47) and murine (MOC1 and MOC2) HNC cell were treated with +/-AUR+/-BSO+/-SAR405 and high-throughput combinatorial screening of cell numbers obtained over time. The combination of AUR+BSO+SAR405 registered a higher synergy score than the double combinations. Furthermore, as compared to single or double drug applications, the AUR+BSO+SAR405 group had a greater apoptotic cell rate and ROS levels. Conclusion: We present here a high-throughput method to screen multi-drug synergy. Multi-modal approach is important to prevent recurrence by providing a broader effect on heterogenous cancer cells in tumor. Moreover, multi-drug combinations allow usage of lower doses of drugs effectively, hence lowers the treatment-related adverse effects. This approach indicated the possibility of HNC treatment by increasing the ROS levels beyond the containable threshold which is consistent with the recent findings about the alterations in redox metabolism, particularly upregulation in thioredoxin and glutathione pathways, in many cancer types. In vivo experiments are ongoing to evaluate the potential of this combination for clinical studies. Citation Format: Zafer Gurel, Qianyun Luo, Michael S. Luy, Randall J. Kimple. ROS metabolism and autophagy as potential targets to improve head and neck cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1403.

Abstract 6158: Rewiring cancer associated fibroblasts using nanomedicines improves immunotherapy efficacy

Abstract The failure of large number of patients to respond to cancer immunotherapy remains a formidable challenge. The immunosuppressive tumor microenvironment (TME) can hinder the capability of cytotoxic T cells to fight cancer. In this regard, cancer associated fibroblasts (CAFs) are among the most abundant stromal cells in TME responsible for immunosuppression. Therefore, reversal of the immunosuppressive phenotype of CAFs and is a major therapeutic goal. Cancer cells secrete exosomes and other factors to reprogram fibroblasts and induce their differentiation into pro-tumorigenic CAFs. Also, cancer cells maintain the activated fibroblast phenotype via triggering major signaling pathways e.g., TGFβ1, FGFR, or β-catenin pathways in the fibroblasts. Here, our goal was to maintain a normalized quiescent phenotype of fibroblasts to enhance the efficacy of immune checkpoint blockade. We demonstrated that a tumor-targeted EpCAM antibody modified shikonin/GW4869 combination liposomes synergistically reduces the biogenesis and release of exosomes from A549 lung cancer cells which significantly inhibits differentiation of MRC5 lung fibroblasts into CAFs. In parallel, we showed the efficacy of TAS-120/ICG-001 FGFR-Wnt/β-catenin inhibitor combination liposomes decorated with GPR77 and CD10 targeting antibodies to switch the acquired activated CAFs phenotype to a quiescent one. Co-administration of both liposomes in low drug doses significantly enhanced the infiltration of cytotoxic CD8+ T cells and improved the antitumor efficacy of αPD-L1 antibody in LLC syngeneic mice model of lung cancer. In conclusion, simultaneous blockage of the tumoral exosome-mediated activation of fibroblasts and FGFR-Wnt/β-catenin signaling may constitute an outstanding immunotherapeutic modality. Citation Format: Ahmed Elzoghby, May Freag, Mostafa Mohammed, Krishna Maremanda, Hae Lin Jang, Shiladitya Sengupta. Rewiring cancer associated fibroblasts using nanomedicines improves immunotherapy efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6158.

Development and evaluation of antipsychotic drugs for externally triggered transdermal therapeutic systems

Cariprazine is a recent antipsychotic drug with an atypical neuropharmacological profile. It is promptly absorbed from the GI tract and suddenly metabolized by liver. Cariprazine has 6 h of plasma elimination half life, 9% of oral and 83% of protein binding. Administration of cariprazine in transdermal dosage form would be a lot of fascinating to regulate the mood for extended period by achieving the plasma concentration well higher than the therapeutic levels. With psychiatrical patients, schedules of daily medication should be followed to avoid adverse reactions which are notably difficult. Therefore, delivery of such drugs by transdermal route can be done. Development and maintenance of low dose drugs therapy is desired, which will limit the consequences of significant adverse effect and direct the issues of helpless consistence in the patients. Ideal quantity of the psychotropic drug can be given by transdermal route with least adverse reactions to overcome the psychic conditions. This will result in improving the health care services for long term mental illness management. In present work, we have synthesized the novel electrically responsive graft co-polymers using natural polymers with polyacrylamide and utilized for the preparation of cariprazine containing electrically responsive transdermal therapeutic systems (ETTS).

Characterization and tableting properties of microcrystalline cellulose derived from waste paper via hydrothermal method

Characterization and Evaluation of the Release Kinetics of a Model Poorly Water-Soluble and Low Dose Drug from Matrix Tablets Composed of Blends of Swellable and Erodible Polymers: Implications for Controlled and Complete ReleaseAiman A. Obaidat