Conquering chemoresistance in pancreatic cancer: Exploring novel drug therapies and delivery approaches amidst desmoplasia and hypoxia.

Pancreatic cancer poses a significant challenge within the field of oncology due to its aggressive behaviour, limited treatment choices, and unfavourable outlook. With a mere 10% survival rate at the 5-year mark, finding effective interventions becomes even more pressing. The intricate relationship between desmoplasia and hypoxia in the tumor microenvironment further complicates matters by promoting resistance to chemotherapy and impeding treatment efficacy. The dense extracellular matrix and cancer-associated fibroblasts characteristic of desmoplasia create a physical and biochemical barrier that impedes drug penetration and fosters an immunosuppressive milieu. Concurrently, hypoxia nurtures aggressive tumor behaviour and resistance to conventional therapies. a comprehensive exploration of emerging medications and innovative drug delivery approaches. Notably, advancements in nanoparticle-based delivery systems, local drug delivery implants, and oxygen-carrying strategies are highlighted for their potential to enhance drug accessibility and therapeutic outcomes. The integration of these strategies with traditional chemotherapies and targeted agents reveals the potential for synergistic effects that amplify treatment responses. These emerging interventions can mitigate desmoplasia and hypoxia-induced barriers, leading to improved drug delivery, treatment efficacy, and patient outcomes in pancreatic cancer. This review article delves into the dynamic landscape of emerging anticancer medications and innovative drug delivery strategies poised to overcome the challenges imposed by desmoplasia and hypoxia in the treatment of pancreatic cancer.

Targeting triple negative breast cancer stem cells using nanocarriers.

Breast cancer is a complex and heterogeneous disease, encompassing various subtypes characterized by distinct molecular features, clinical behaviors, and treatment responses. Categorization of subtypes is based on the presence or absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), leading to subtypes such as luminal A, luminal B, HER2-positive, and triple-negative breast cancer (TNBC). TNBC, comprising around 20% of all breast cancers, lacks expression of ER, PR, and HER2 receptors, rendering it unresponsive to targeted therapies and presenting significant challenges in treatment. TNBC is associated with aggressive behavior, high rates of recurrence, and resistance to chemotherapy. Tumor initiation, progression, and treatment resistance in TNBC are attributed to breast cancer stem cells (BCSCs), which possess self-renewal, differentiation, and tumorigenic potential. Surface markers, self-renewal pathways (Notch, Wnt, Hedgehog signaling), apoptotic protein (Bcl-2), angiogenesis inhibition (VEGF inhibitors), and immune modulation (cytokines, immune checkpoint inhibitors) are among the key targets discussed in this review. However, targeting the BCSC subpopulation in TNBC presents challenges, including off-target effects, low solubility, and bioavailability of anti-BCSC agents. Nanoparticle-based therapies offer a promising approach to target various molecular pathways and cellular processes implicated in survival of BSCS in TNBC. In this review, we explore various nanocarrier-based approaches for targeting BCSCs in TNBC, aiming to overcome these challenges and improve treatment outcomes for TNBC patients. These nanoparticle-based therapeutic strategies hold promise for addressing the therapeutic gap in TNBC treatment by delivering targeted therapies to BCSCs while minimizing systemic toxicity and enhancing treatment efficacy.

Engineered upconversion nanocarriers for synergistic breast cancer imaging and therapy: Current state of art.

Breast cancer is the most common type of cancer in women and is the second leading cause of cancer-related deaths worldwide. Early diagnosis and effective therapeutic interventions are critical determinants that can improve survival and quality of life in breast cancer patients. Nanotheranostics are emerging interventions that offer the dual benefit of in vivo diagnosis and therapeutics through a single nano-sized carrier. Rare earth metal-doped upconversion nanoparticles (UCNPs) with their ability to convert near-infrared light to visible light or UV light in vivo settings have gained special attraction due to their unique luminescence and tumor-targeting properties. In this review, we have discussed applications of UCNPs in drug and gene delivery, photothermal therapy (PTT), photodynamic therapy (PDT) and tumor targeting in breast cancer. Further, present challenges and future opportunities for UCNPs in breast cancer treatment have also been mentioned.

Phenylboronic acid modified lipid nanocarriers mediated co-delivery of immunocytokine TRAIL and gamma-secretase inhibitor to triple negative breast cancer cells and cancer stem cells.

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with high rates of tumor relapse and metastasis. The existing drugs for treatment of TNBC are unable to target the cells of origin (breast cancer stem cells) of TNBC. TNF-α related apoptosis inducing ligand (TRAIL) has propensity to target TNBC cells including cancer stem cells. However, resistance to TRAIL due to activation of anti-apoptotic mechanisms is a limitation for TRAIL based anticancer therapy for TNBC. In the present study we propose an hypothesis for effective targeting of triple negative breast cancer by overcoming TRAIL resistance.

DR5 antibody conjugated lipid-based nanocarriers of gamma-secretase inhibitor for the treatment of triple negative breast cancer.

In the present study, Death receptor-5 (DR5) antibody conjugated solid lipid nanoparticles (DR5-DAPT-SLNs) has been formulated for effective intracellular of γ-secretase inhibitor, N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) to cancer cells. Emulsification-solvent evaporation, followed by EDC cross-linking methods, was employed to prepare DR5 targeted DAPT-SLNs (DR5-DAPT-SLNs). The formulation was characterized by its particle size, shape, and surface charge. The in vitro & in vivo anticancer efficacy was studied in MDA-MB231 triple negative breast cancer (TNBC) cells and DMBA induced breast cancer model in mice, respectively. The results show that thatDR5-DAPT-SLNs is found to be a spherical shape with an average particle size of 187 ± 0.98 nm and having an average surface charge of 23 ± 2.3 mV. DR5-DAPT-SLNs have higher cytotoxicity in MDA-MB231 cells compared to DAPT-SLNs (non-targeted) and the bulk drug. However, in DR5 negative HEK 293 noncancer cells, the formulation shows minimal cytotoxic effects. The above results, therefore, demonstrate DR5 mediated uptake is responsible for improved cytotoxicity of DAPT. In the in vivo anticancer study, DR5-DAPT-SLNs show greater tumor regression when compared to DAPT-SLNs and the bulk drug. In conclusion, the results of the present study demonstrate that the DR5-DAPT-SLNs selectively target cancer cells and potentiate the anticancer efficacy of DAPT against TNBC cells.

Polysorbate-80 surface modified nano-stearylamine BQCA conjugate for the management of Alzheimer's disease.

Acetylcholinesterase (AChE) inhibitors such as donepezil, galantamine and rivastigmine are used for the management of dementia in Alzheimer's Disease (AD). These drugs elevate endogenous acetylcholine (ACh) levels at the M1 muscarinic receptor in the brain to achieve therapeutic benefits. However, their side effects, such as nausea, vomiting, dizziness, insomnia, loss of appetite, altered heart rate, etc., are related to non-specific peripheral activation of M2-M5 muscarinic subtypes. It is logical, therefore, to develop drugs that selectively activate brain M1 receptors. Unfortunately, the orthosteric site homology among the receptor subtypes does not permit this approach. An alternative approach is to use positive allosteric modulator (PAM) of M1 receptors like benzyl quinolone carboxylic acid (BQCA). PAMs although devoid of M1 agonist activity, however, when bound, enhance the binding affinity of orthosteric ligand, Ach. The current challenge with PAMS is their low brain half-life, permeability, and higher elimination rates. This study reports active targeting of brain M1 receptors using surface modified nano lipid-drug conjugates (LDC) of M1 PAM, BQCA, to treat AD. Polysorbate-80 (P-80) surface modified stearylamine (SA)-BQCA conjugated nanoparticles (BQCA-SA-P80-NPs) were prepared by conjugating BQCA to SA, followed by the formation of nanoparticles (NPs) using P-80 by solvent injection method. The BQCA-SA-P80-NPs are near-spherical with a particle size (PS) of 166.62 ± 1.24 nm and zeta potential (ZP) of 23.59 ± 0.37 mV. In the in vitro cytotoxicity (SH-SY5Y cells) and hemolysis assays, BQCA-SA-P80-NPs, show acceptable safety and compatibility. In mice, Alzheimer's model, BQCA-SA-P80-NPs significantly prevent STZ induced changes in memory, neuronal Aß1-42, p-Tau, APP, NF-κB, and BACE levels and neuronal cell death, when compared to untreated disease control and naïve BQCA treated group. Further, BQCA-SA-P80-NPs significantly improve the therapeutic efficacy of AChE inhibitor, donepezil (DPZ), indicating its potentiating effects. In vivo biodistribution studies in mice show selective accumulation of BQCA-SA-P80-NPs in the brain, suggesting an improved brain bioavailability and reduced peripheral side effects of BQCA. The study results demonstrate that BQCA-SA-P80-NPs can improve brain bioavailability and therapeutic efficacy of BQCA in AD.

Synthesis and Preclinical Evaluation of Indole Triazole Conjugates as Microtubule Targeting Agents that are Effective against MCF-7 Breast Cancer Cell Lines.

CDATA[Background: Microtubules are considered to be an important therapeutic target for most of the anticancer drugs. These are highly dynamic structures comprising of α-tubulin and ß-tubulin which are usually heterodimers and found to be involved in cell movement, intracellular trafficking, and mitosis inhibition of which might kill the tumour cells or inhibit the abnormal proliferation of cells. Most of the tubulin polymerization inhibitors, such as Vinca alkaloids, consist of Indole as the main scaffold. The literature also suggests using triazole moiety in the chemical entities, potentiating the inhibitory activity against cell proliferation. So, in our study, we used indole triazole scaffolds to synthesize the derivatives against tubulin polymerization. OBJECTIVE: The main objective of this study to synthesize indole triazole conjugates by using environmentally friendly solvents (green chemistry) and click chemistry. To carry out the MTT assay and tubulin polymerization assay for the synthesized indole triazole conjugates. METHODS: All the synthesized molecules were subjected to molecular docking studies using Schrodinger suite and the structural confirmation was performed by Mass, proton-NMR and carbon-NMR, documented in DMSO and CDCL3. Biological studies were performed using DU145 (prostate cancer), A-549 (lung cancer) and, MCF-7 (breast cancer), cell lines obtained from ATCC were maintained as a continuous culture. MTT assay was performed for the analogues using standard protocol. Cell cycle analysis was carried out using flow cytometry. RESULTS: The Indole triazole scaffolds were synthesized using the principles of Green chemistry. The triazole formation is mainly achieved by using the Click chemistry approach. Structural elucidation of synthesized compounds was performed using Mass spectroscopy (HR-MS), Proton-Nuclear Magnetic Spectroscopy (1H-NMR) and Carbon-Nuclear Magnetic Spectroscopy (13C-NMR). The XP-docked poses and free energy binding calculations revealed that 2c and 2g molecules exhibited the highest docking affinity against the tubulin-colchicine domain (PDB:1SA0). In vitro cytotoxic assessment revealed that 2c and 2g displayed promising cytotoxicity in MTT assay (with CTC50 values 3.52µM and 2.37µM) which are in good agreement with the computational results. 2c and 2g also arrested 63 and 66% of cells in the G2/M phase, respectively, in comparison to control cells (10%) and tubulin polymerization inhibition assay revealed that 2c and 2g exhibited significant inhibition of tubulin polymerization with IC50 values of 2.31µM, and 2.62µM, respectively in comparison to Nocodazole, a positive control, resulted in an IC50 value of 2.51µM. CONCLUSION: Indole triazole hybrids were synthesized using click chemistry, and docking studies were carried out using Schrodinger for the designed molecules. Process Optimization has been done for both the schemes. Twelve compounds (2a-2l) have been successfully synthesized and analytical evaluation was performed using NMR and HR-MS. In vitro evaluation was for the synthesized molecules to check tubulin polymerization inhibition for antiproliferative action. Among the synthesized compounds, 2c and 2g have potent anticancer activities by inhibiting tubulin polymerization.

Pulmonary delivery of nanostructured lipid carriers for effective repurposing of salinomycin as an antiviral agent.

Coronavirus disease outbreak caused a severe public health burden all over the world. Salinomycin (SAL) is a broad-spectrum antibiotic that had drawn attention in selective targeting of cancer and viral infections. Recent drug screen identified SAL as a potent antiviral agent against SARS-CoV-2. In this hypothesis, we discuss the potential of pulmonary delivery of SAL using nanostructured lipid carriers (NLCs) against SARS-CoV-2.

Novel drug delivery systems of ß2 adrenoreceptor agonists to suppress SNCA gene expression and mitochondrial oxidative stress in Parkinson's disease management.

INTRODUCTION: α-synuclein (SNCA), a major component of Lewy body is a pathological hallmark of Parkinson's disease (PD). Mutations in the SNCA gene cause misfolding and aggregation of SNCA protein, which results in neurodegeneration. Several studies have established the neuroprotective benefits of ß2-adrenoreceptor (ß2AR) agonists in PD However, ß2AR agonists are associated with peripheral side effects- tachycardia, palpitation, pulmonary edema, myocardial ischemia, and cardiac arrhythmia due to ßARactivation in peripheral tissues. PD therapy with ß2AR agonists, therefore, warrants a brain-specific delivery. AREA COVERED: This review highlights the SNCA mediated neurodegenerative pathways in PD and various treatment strategies under investigation to lower SNCA gene expression, primarily focusing on ß2AR mediated pathway. The review also discusses the beneficial and side effects of ß2AR agonists in PD treatment by reviewing clinical trials, epidemiological studies, and meta-analysis data. Here we depict the need to develop a novel drug delivery system to achieve brain-specific delivery of ß2AR agonists to overcome peripheral side effects and also propose various nano delivery strategies to achieve the same. EXPERT OPINION: Brain targeted delivery of ß2AR agonists via various nano delivery systems will significantly downregulate SNCA gene expression in PD and also overcomes peripheral side effects of ß2AR agonists.

Plausible mechanisms of Niclosamide as an antiviral agent against COVID-19.

Corona virus disease 2019 (COVID-19) pandemic caused 18 440 deaths world wide as of 25 March 2020 and posing a serious threat to public health. There is a need, therefore, for effective therapeutic strategies to cure this disease. However, high attrition rates, substantial costs and slow pace are the major limitations of novel drug discovery. Drug repurposing, by employing 'old' drugs to treat 'new' diseases is an attractive approach in drug discovery. Niclosamide (NIC) is an approved anti-helminthic drug with diverse antiviral mechanisms. In this work we hypothesize, the potential antiviral mechanisms of NIC against COVID-19.

HER2 targeted biological macromolecule modified liposomes for improved efficacy of capecitabine in breast cancer.

The present research reports the beneficial effects of surface modified chitosan and tumor-homing peptide conjugated liposomes of capecitabine (CAP) for treating breast cancer. Liposomal formulation of CAP was prepared by film hydration method using cholesterol-THP conjugate (CTHP-CAP-LPs) to achieve active targeting through HER2 receptors. CTHP-CAP-LPs significantly improved the specificity and efficacy of CAP by improving cell uptake, cytotoxicity and tumor regression in tumor bearing mice. CTHP-CAP-LPs, therefore, is a promising approach to improve the anticancer effects of CAP.

CD133 receptor mediated delivery of STAT3 inhibitor for simultaneous elimination of cancer cells and cancer stem cells in oral squamous cell carcinoma.

Oral Squamous Cell Carcinoma (OSCC) is one of the major causes of cancer related deaths worldwide. Presence of chemoresistant cancer stem cells is the major reason behind metastasis, tumor relapse and treatment resistance in OSCC. STAT 3 signalling plays a key role in survival of cancer stem cells (CSC's), Epithelial Mesenchymal Transition (EMT) mediated metastasis in OSCC. CD 133 is the surface marker for identification of cancer stem cells. In the present study we hypothesise the selective targeting of CSC's using CD 133 mediated delivery of STAT 3 inhibitor, Niclosamide to specifically target CSC's and Non CSC's.

Type-II endometrial cancer: role of adipokines.

BACKGROUND: Type-II endometrial cancer is an estrogen independent and one of the most lethal types of cancer having poor prognosis. Adipokines play a crucial role in the triggering Type-II EMC. In addition, adipokines modulators, therefore, may have beneficial effects in the treatment of Type-II endometrial cancer, which was clinically evidenced. AREAS COVERED: This review presents the role of various adipokines involved and also the suitable modulators to treat Type-II endometrial cancer. CONCLUSION: In the present review, we try to discuss the role of individual adipokines in the pathogenesis of Type-II endometrial cancer, and also the possible beneficial effects of adipokines modulator in the treatment of Type-II endometrial cancer.

Possible role of Thiazolidinedione in the management of Type-II Endometrial Cancer.

Type-II Endometrial Cancer (EMC) is one of the most common types of gynaecological cancer affecting more than 2.7 million people worldwide. Clinical evidence shows that adipokines levels are abnormally altered in Type-II EMC and reported to be one of the major responsible factor for uncontrolled proliferation and metastasis in Type-II EMC. Reversing the altered adipokine levels, therefore, help to control Type-II EMC proliferation and metastasis. In the present hypothesis we focus on the possible role of Thiazolidinediones in favourably altering the adipokine levels to benefit in the management of Type-II EMC.

Possible role of PPAR-γ and COX-2 receptor modulators in the treatment of Non-Small Cell lung carcinoma.

Non-Small Cell lung cancer (NSCLC) accounts for 85% of total lung cancers worldwide, affecting more than 1.5 million people every year. Recent studies reported that lung adenocarcinoma express Peroxisome Proliferator Activated Receptor-γ (PPAR-γ) which is believed to be inactivated due to cytoplasmic accumulation or somatic 'loss of function' of the gene. PPAR-γ reported to play an important role in cell proliferation, cell differentiation and apoptosis via inhibition of NF-kß pathway. Adenocarcinoma also overexpress cyclooxygenase-2 (COX-2), which is reported to promote angiogenesis and metastasis via TX-A2 production. Therefore, we hypothesize that activation of PPAR-γ (through PPAR-γ agonists) and inhibition of COX-2 (through COX-2 inhibitors) will have beneficial effects in the treatment of NSCLC.

Novel dermacozine-1-carboxamides as promising anticancer agents with tubulin polymerization inhibitory activity.

In the present study, novel dermacozine-1-carboxamides (8a-8n) were synthesized and screened for their in vitro cytotoxic activity against three different cancer cell lines: MCF-7 (breast cancer), A-549 (lung cancer) and DU145 (prostate cancer). All the compounds showed more efficiency against the DU145 cell line than against the MCF-7 and A-549 cell lines. Furthermore, 8a (CTC50: 7.02 µM) and 8l (CTC50: 6.32 µM) have been found to be more effective against the DU145 cells as they arrest the cell cycle at the G2/M phase by interfering with tubulin polymerization; these results indicate that these compounds act as potential anti-cancer agents by inhibiting tubulin polymerization.

Tumor homing peptide modified liposomes of capecitabine for improved apoptotic activity and HER2 targeted therapy in breast cancer: in vitro studies.

In the present study, we have formulated a liposomal formulation of cytotoxic agent capecitabine (CAP) to overcome its bioavailability issues. Then we have surface modified CAP loaded liposomes (CAP-LPs) with a tumour homing peptide (THP-CAP-LPs) to achieve site specific delivery to breast cancer cells. We found a significant cellular internalization of THP-CAP-LPs when compared to unmodified CAP-LPs. The cytotoxic effect of CAP was also significantly improved with THP-CAP-LPs by downregulating anti-apoptotic proteins and upregulating pro-apoptotic proteins as observed by Western blot analysis. THP-CAP-LPs mediated delivery of CAP can be, therefore, a promising approach for improving antitumor activity and reducing off-target effects.

Formulation-optimization of solid lipid nanocarrier system of STAT3 inhibitor to improve its activity in triple negative breast cancer cells.

In the present study, solid lipid nanoparticles (SLNs) have been formulated as a carrier system for effective intracellular delivery of STAT3 inhibitor, niclosamide (Niclo) to triple negative breast cancer (TNBC) cells. Emulsification-solvent evaporation method was employed in formulation of Niclo-loaded SLNs (Niclo-SLNs). The formula of Niclo-SLN was optimized by Box-Behnken design and characterized for their shape, size, and surface charge. The in vitro anti-cancer efficacy of Niclo-SLNs was studied in TNBC cells. The prepared Niclo-SLNs were found to be spherical with the particle size of 112.18 ± 1.73 nm and zetapotential of 23.8 ± 2.7 mV. In the in vitro anticancer study the Niclo SLNs show a better cytotoxicity than the naïve Niclo, which is attributed to improved cell uptake of SLN formulation. In conclusion, the results of the present study demonstrate that the formulation of Niclo as SLNs will improve the anticancer efficacy against TNBC.

Pharmacological targets of breast cancer stem cells: a review.

Breast cancers contain small population of tumor-initiating cells called breast cancer stem cells (BCSCs), which are spared even after chemotherapy. Recently, BCSCs are implicated to be a cause of metastasis, tumor relapse, and therapy resistance in breast cancer. BCSCs have unique molecular mechanisms, which can be targeted to eliminate them. These include surface biomarkers, proteins involved in self-renewal pathways, drug efflux transporters, apoptotic/antiapoptotic proteins, autophagy, metabolism, and microenvironment regulation. The complex molecular mechanisms behind the survival of BCSCs and pharmacological targets for elimination of BCSCs are described in this review.

RAGE receptor targeted bioconjuguate lipid nanoparticles of diallyl disulfide for improved apoptotic activity in triple negative breast cancer: in vitro studies.

In the present study, we have demonstrated receptor for advanced glycation endproducts (RAGE) as a target for delivery of drugs specifically to triple negative breast cancer cells. We have prepared solid lipid nanoparticle formulation of cytotoxic agent di-allyl-disulfide (DADS) to overcome its bioavailability issues. Then, we have surface modified DADS-loaded solid lipid nanoparticles (DADS-SLN) with RAGE antibody to achieve site-specific delivery of DADS to TNBC cells. We found a significant cellular internalization of RAGE surface modified DADS-SLN (DADS-RAGE-SLN) when compared to DADS-SLN. The cytotoxic effect of DADS was also significantly improved with DADS-RAGE-SLN by downregulating anti-apoptotic proteins and upregulating pro-apoptotic proteins as observed by western blot analysis. RAGE-targeted delivery of cytotoxic agents can be, therefore, a promising approach for improving antitumour activity and reducing off-target effects.