Novel gene therapy for drug-resistant melanoma: Synergistic combination of PTEN plasmid and BRD4 PROTAC-loaded lipid nanocarriers.

Patients suffering from BRAF mutant melanoma have tumor recurrence within merely 7 months of treatment with a potent BRAF inhibitor (BRAFi) like vemurafenib. It has been proven that diverse molecular pathways driving BRAFi resistance converge to activation of c-Myc in melanoma. Therefore, we identified a novel combinatorial therapeutic strategy by targeting loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene and upregulated BRD4 oncoprotein as Myc-dependent vulnerabilities of drug-resistant melanoma.

Development and in-depth characterization of BRAFi-resistant melanoma cell lines in vitro and in vivo.

Regardless of the clinical response and improved patient survival observed following treatment with BRAFi like Vemurafenib (Vem), rapid development of resistance still remains as a major obstacle in melanoma therapy. In this context, we developed and characterized two acquired Vem-resistant melanoma cell lines, A375V and SK-MEL-28V, and an intrinsically Vem-resistant cell line, RPMI-7951. Altered morphology and growth rate of the resistant cell lines displayed spindle-shaped cells with filopodia formation and enhanced proliferation rate as compared to parental cells.

Delineating effect of headgroup and preparation method on transfection versus toxicity of DNA-loaded lipid nanocarriers.

To perform a parallel comparison of key parameters affecting the safety and efficiency of lipid-based nanovectors (i.e., complexing headgroups, composition and preparation method).

In Vitro Assessment of Cisplatin/Hyaluronan Complex for Loco-Regional Chemotherapy.

Loco-regional chemotherapy is a strategy used to achieve more precise anticancer drug effect directly on tumor mass, while decreasing whole body exposure, which can lead to undesirable side effects. Thus, the loco-regional chemotherapy is conceptually similar to the targeted drug delivery systems for delivering chemotherapeutics to cancer cells in a certain location of the body. Recently, it has been demonstrated that a novel polymeric film containing the complex between cisplatin (cisPt) and hyaluronan (sodium salt of hyaluronic acid; NaHA) enhanced in vivo efficacy and safety of cisplatin (cisPt) by loco-regional delivery in pleural mesothelioma.

CRISPR/Cas9 Genome Editing for Tissue-Specific In Vivo Targeting: Nanomaterials and Translational Perspective.

Clustered randomly interspaced short palindromic repeats (CRISPRs) and its associated endonuclease protein, i.e., Cas9, have been discovered as an immune system in bacteria and archaea; nevertheless, they are now being adopted as mainstream biotechnological/molecular scissors that can modulate ample genetic and nongenetic diseases via insertion/deletion, epigenome editing, messenger RNA editing, CRISPR interference, etc.

Human solid tumors and clinical relevance of the enhanced permeation and retention effect: a 'golden gate' for nanomedicine in preclinical studies?

Nanocarriers passively accumulate in solid tumors through irregular wide fenestrations in neovasculature and increased retention due to poor lymphatic drainage, a phenomenon termed the enhanced permeation and retention (EPR) effect. Although several preclinical reports have described the role of EPR in nanomedicine, its role in human solid tumor is obscure. There are several distinct factors for tumors in mice versus humans, including size, heterogeneity and nanomedicine pharmacokinetics.

Topical Cream Carrying Drug-Loaded Nanogels for Melanoma Treatment.

In this study, nanogel creams carrying paclitaxel (PTX) and temozolomide (TMZ) were prepared for the topical treatment of melanoma. PTX and TMZ were first loaded in poly-(D,L-lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly-(D,L-lactide-co-glycolide) (PLAG-b-PEG-b-PLGA) thermosensitive nanogels, which made a transition from a free-flowing sol (formation of micellar network) at 25°C with the z-average particle size of c.a.

Palmitoyl Carnitine-Anchored Nanoliposomes for Neovasculature-Specific Delivery of Gemcitabine Elaidate to Treat Pancreatic Cancer.

Being the fourth most fatal malignancy worldwide, pancreatic cancer is on track to become the second leading cause of cancer-related deaths in the United States by 2030. Gemcitabine is a first-line chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine Elaidate (Gem Elaidate) is a lipophilic derivative which allows hENT1-independent intracellular delivery of gemcitabine and better pharmacokinetics and entrapment in a nanocarrier.

Drug delivery challenges and formulation aspects of proteolysis targeting chimera (PROTACs).

Proteolysis targeting chimeras (PROTACs) have been extensively explored for targeted proteasomal degradation of disease-related proteins with enormous potential in the treatment of intractable diseases. However, PROTACs are poorly soluble and permeable bulky molecules facing several bioavailability challenges irrespective of the route of administration. Our review lays out crucial challenges in the delivery of target protein degraders and nanoformulation approaches to overcome physicochemical and biological hurdles that can aid in transporting these target-protein degraders to the disease site.

Development of a safe pediatric liquisolid self-nanoemulsifying system of triclabendazole for the treatment of fascioliasis.

Fascioliasis, a common parasitic infection observed in the pediatric patient population, is a leading cause of concern in countries with poor/unhealthy water resources. To treat this condition first line agent such as triclabendazole (TBZ) has been the choice therapy. However, there is a major hurdle in exploiting TBZ.

Susceptibility of Lung Carcinoma Cells to Nanostructured Lipid Carrier of ARV-825, a BRD4 Degrading Proteolysis Targeting Chimera.

The present work was aimed at developing an optimized and modified nanostructured lipid carrier of BRD4 protein degrading Proteolysis Targeting Chimera (PROTAC) against non-small cell lung carcinoma. PROTACs are an emerging class of anticancer molecules with nanomolar activity but associated with significant solubility challenges. Lipid-based colloidal systems like nanostructured lipid carriers are widely explored for such highly lipophilic molecules.

Galactose-decorated liver tumor-specific nanoliposomes incorporating selective BRD4-targeted PROTAC for hepatocellular carcinoma therapy.

This research deals with the development of asialoglycoprotein receptors (ASGPR) directed nanoliposomes incorporating a novel BRD4 (Bromodomain-containing protein 4) protein-targeted PROTAC (Proteolysis Targeting Chimera), ARV-825 (ARV) (GALARV), and to investigate the anticancer efficacy of GALARV for specific delivery in hepatocellular carcinoma. GALARV were prepared using the modified hydration method and characterized for their physicochemical properties as well as anticancer activity using 2D and 3D cell culture models. ARV and GALARV (93.

Cannabidiol Inhibits Human Liver Microsomal Metabolism of Remdesivir.

The year 2020 began with the world being flounced with a wave of novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) disease, named COVID-19. Based on promising pre-clinical and clinical data, remdesivir (RDV) was the first drug to receive FDA approval and so far, it is the most common therapy for treatment of SARS-CoV-2/MERS-CoV. However, following intravenous administration, RDV metabolizes majorly by human liver carboxylesterase 1 (CES1) and marginally by the CYP3A4 enzyme in merely less than an hour.

Stromal disruption facilitating invasion of a 'nano-arsenal' into the solid tumor.

Owing to the indispensable role of nanotechnology in cancer therapy, it is imperative to comprehend every aspect limiting its therapeutic potential. Several preclinical reports have demonstrated the enhanced permeability and retention (EPR)-mediated preferential tumor uptake of nanoparticles. However, the therapeutic outcome of nanotherapeutics is severely compromised by heterogeneous drug distribution and insufficient penetration of nanomedicine in a solid tumor owing to the dense tumor extracellular matrix (ECM).

Development of Dual ARV-825 and Nintedanib-Loaded PEGylated Nano-Liposomes for Synergistic Efficacy in Vemurafnib-Resistant Melanoma.

A novel treatment strategy by co-targeting c-Myc and tumor stroma was explored in vemurafenib-resistant melanoma. BRD4 proteolysis targeting chimera (ARV-825) and nintedanib co-loaded PEGylated nanoliposomes (ARNIPL) were developed to incorporate a synergistic cytotoxic ratio. Both the molecules have extremely poor aqueous solubility.

In vitro assessment of a synergistic combination of gemcitabine and zebularine in pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with an extremely poor prognosis. Gemcitabine (Gem) is still the mainstay drug for the treatment of PDAC. However, rapid inactivation by cytidine deaminase (CDA) present in pancreatic cancer cells severely limits anticancer efficacy of Gem.

Aerosolized nanoliposomal carrier of remdesivir: an effective alternative for COVID-19 treatment .

To formulate an aerosolized nanoliposomal carrier for remdesivir (AL-Rem) against coronavirus disease 2019. AL-Rem was prepared using modified hydration technique. Cytotoxicity in lung adenocarcinoma cells, stability and aerodynamic characteristics of developed liposomes were evaluated.

A novel gene therapy for neurodegenerative Lafora disease via -loaded DLinDMA lipoplexes.

To develop novel cationic liposomes as a nonviral gene delivery vector for the treatment of rare diseases, such as Lafora disease - a neurodegenerative epilepsy. DLinDMA and DOTAP liposomes were formulated and characterized for the delivery of gene encoding laforin and expression of functional protein in HEK293 and neuroblastoma cells. Liposomes with cationic lipids DLinDMA and DOTAP showed good physicochemical characteristics.

Nanoformulation of PROteolysis TArgeting Chimera targeting 'undruggable' for the treatment of pancreatic cancer.

To explore the anticancer activity of a novel BRD4 protein degrader ARV-825 (ARV) and its nanoformulation development (ARV-NP) for treatment of pancreatic cancer. ARV-NP were prepared using nanoprecipitation method and characterized for their physicochemical properties and various anticancer cell culture assays. ARV-NP (89.