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.

Solid Lipid Nanoparticles vs. Nanostructured Lipid Carriers: A Comparative Review.

Solid-lipid nanoparticles and nanostructured lipid carriers are delivery systems for the delivery of drugs and other bioactives used in diagnosis, therapy, and treatment procedures. These nanocarriers may enhance the solubility and permeability of drugs, increase their bioavailability, and extend the residence time in the body, combining low toxicity with a targeted delivery. Nanostructured lipid carriers are the second generation of lipid nanoparticles differing from solid lipid nanoparticles in their composition matrix. The use of a liquid lipid together with a solid lipid in nanostructured lipid carrier allows it to load a higher amount of drug, enhance drug release properties, and increase its stability. Therefore, a direct comparison between solid lipid nanoparticles and nanostructured lipid carriers is needed. This review aims to describe solid lipid nanoparticles and nanostructured lipid carriers as drug delivery systems, comparing both, while systematically elucidating their production methodologies, physicochemical characterization, and in vitro and in vivo performance. In addition, the toxicity concerns of these systems are focused on.

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.

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.

Phenyl boronic acid-modified lipid nanocarriers of niclosamide for targeting triple-negative breast cancer.

Aim: To study the active targeting efficacy of phenylboronic acid-modified niclosamide solid lipid nanoparticles (PBA-Niclo-SLN) in triple-negative breast cancer (TNBC). Materials & methods: PBA-Niclo-SLNs were formulated by an emulsification-solvent evaporation method using PBA-associated stearylamine (PBSA) as lipid. The drug uptake and the anticancer propensity of PBA-Niclo-SLN were studied in TNBC (MDA-MB231) cells and tumor-bearing mice. Results: PBA-Niclo-SLN formulation resulted in greater antitumor efficacy by inducing G0/G1 cell cycle arrest and apoptosis. Besides, PBA-Niclo-SLN effectively inhibited STAT3, CD44+/CD24- TNBC stem cell subpopulation, epithelial-mesenchymal transition markers. Besides, PBA-Niclo-SLN selectively accumulated at the tumor site with more significant tumor regression and improved the survivability in TNBC tumor-bearing mice. Conclusion: PBA-Niclo-SLN formulation would be an effective strategy to eradicate TNBC cells (breast cancer stem cells and nonbreast cancer stem cells) efficiently.

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.

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.

Cytosolic lipid excess-induced mitochondrial dysfunction is the cause or effect of high fat diet-induced skeletal muscle insulin resistance: a molecular insight.

Mitochondria play a central role in the energy homeostasis in eukaryotic cells by generating ATP via oxidative metabolism of nutrients. Excess lipid accumulation and impairments in mitochondrial function have been considered as putative mechanisms for the pathogenesis of skeletal muscle insulin resistance. Accumulation of lipids in tissues occurs due to either excessive fatty acid uptake, decreased fatty acid utilization or both. Consequently, elevated levels cytosolic lipid metabolites, triglycerides, diacylglycerol and ceramides have been demonstrated to adversely affect glucose homeostasis. Several recent studies indicate that reduced insulin-stimulated ATP synthesis and reduced expression of mitochondrial enzymes and PPAR-γ coactivator, in high fat feeding (lipid overload) are associated with insulin resistance. Despite the fact, few notable studies suggest mitochondrial dysfunction is prevalent in type 2 diabetes mellitus; it is still not clear whether the defects in mitochondrial function are the cause of insulin resistance or the consequential effects of insulin resistance itself. Thus, there is a growing interest in understanding the intricacies of mitochondrial function and its association with cytosolic lipid excess. This review therefore critically examines the molecular cascades linking cytosolic lipid excess and mitochondrial dysfunction in the pathogenesis of high fat diet-induced insulin resistance in skeletal muscle. The sequential processes following the excess intake of high fat diet in skeletal muscle includes, accumulation of cytosolic fatty acids, increased production of reactive oxygen species, mutations and ageing, and decreased mitochondrial biogenesis. The consequent mitochondrial dysfunction is then leading to decreased ß-oxidation, respiratory functions and glycolysis and increased glucolipotoxicity. These events collectively induce the insulin resistance in skeletal muscle.

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.

An effective treatment approach of DPP-IV inhibitor encapsulated polymeric nanoparticles conjugated with anti-CD-4 mAb for type 1 diabetes.

Nanotechnology based biomedical approaches and surface modification techniques made it easier for targeting specific site and improving the treatment efficacy. The present study reports on targeted polymeric nanoparticles conjugated with antibody as a site-specific carrier system for effective treatment of type 1 diabetes. Sitagliptin (SP)-loaded Poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NP) were prepared by nanoprecipitation cum solvent evaporation method and were characterized in terms of morphology, size, surface charge, and entrapment efficiency. Optimized batch demonstrated a particle size of 105.24 nm, with significant entrapment efficacy. In vitro release studies exhibited a controlled release pattern of 67.76 ± 1.30% in 24 h, and a maximum of 96.59 ± 1.26% at the end of 48 h. Thiol groups were introduced on the surface of SP-NPs whose concentration on SP-NPs was 27 ± 2.6 mmol/mol PLGA-NPs, anti-CD4 antibody clone Q4120 was conjugated to the thiolated SP-NPs via a sulfo-MBS cross-linker, ∼70% conjugation was observed. The in vitro cytotoxicity studies performed on RIN-5 F cells for mAb-SP-NPs presented an IC50 of 76 µg/mL, and the insulin release assay had revealed an increased release at 5.15 ± 0.16 IU/mL. The results indicate that mAb-SP-NPs allowed a controlled release of SP and thereby produced insulin levels comparable with control. Therefore, mAb-SP-NPs system appears to be effective in the treatment of auto immune diabetes, subject to further analysis.

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.

Nanocarrier based approaches for targeting breast cancer stem cells.

Breast cancer stem cells (BCSCs) are heterogeneous subpopulation of tumour initiating cells within breast tumours. They are spared even after chemotherapy and responsible for tumour relapse. Targeting BCSCs is, therefore, necessary to achieve radical cure in breast cancer. Despite the availability of agents targeting BCSCs, their clinical application is limited due to their off-target effects and bioavailability issues. Nanotechnology based drug carriers (nanocarriers) offer various advantages to deliver anti-BCSCs agents specifically to their target sites by overcoming their bioavailability issues. In this review, we describe various strategies for targeting BCSCs using nanocarriers.

Surface modified nano-lipid drug conjugates of positive allosteric modulators of M1 muscarinic acetylcholine receptor for the treatment of Alzheimer's disease.

Acetyl Cholinesterase (AChE) inhibitors such as Donepezil, Rivastigmine and Galantamine are approved by US-FDA as first line drugs to treat the cognitive symptoms of Alzheimer's disease (AD). Their beneficial effects are attributed to their ability to elevate endogenous acetylcholine (ACh) at the M1 muscarinic receptor in the brain. However, their side effects such as nausea, vomiting, dizziness, insomnia, loss of appetite and altered heart rate are related to non-specific activation of M2-M5 muscarinic subtypes in various tissues. It is logical, therefore, to develop agonists with M1 receptor selectivity. Unfortunately, this is limited due to a high degree of orthosteric site homology among the receptor subtypes. In contrast, their allosteric sites are unique and, therefore, allow selective targeting using positive allosteric modulators (PAMs). PAMs of M1 receptors are devoid of agonist activity, however, when bound they enhance the binding affinity of orthosteric ligand, ACh. The major limitation of these PAMs is their bioavailability in the brain. In the current hypothesis, we propose surface modified nano-lipid drug conjugates (LDC-NPs) of PAMs of M1 receptors to improve their bioavailability in brain. When co-administered with AChE inhibitors they are expected to increase their efficacy and reduce their therapeutic dose and side effects.