Steroid hormone receptor based gene delivery systems as potential oral cancer therapeutics.

Glucocorticoid and Mineralocorticoid receptors are principally ligand-dependent intracellular transcription factors that are known to influence the development and growth of many human cancers. Our study investigates the potential of these receptors to act as a target for oral cancer treatment since findings in this regard are sparse till date. Leveraging the aberrant behavior of steroid hormone receptors (SHRs) in cancer, we have targeted oral cancer cells in 2D-culture using liposomes containing both synthetic as well as crude, natural SHR ligands isolated from an aqueous Indian medicinal plant. Lipoplexes thus formulated demonstrated targeted transfectability as indicated by expression of green fluorescent protein. Transfection of oral squamous cell carcinoma cells with exogenous, anticancer gene p53 lipoplexed with crude saponin-based liposome induced apoptosis of cancer cells via regulation of BAX and B-cell leukemia/lymphoma-2 (BCL2) protein levels at levels comparable with pre-established delivery systems based on synthetic SHR ligands. Our findings strongly indicate a possibility of developing plant saponin-based inexpensive delivery systems which would target cancer cells selectively with reduced risks of off target delivery and its side effects.

Delivery of chemotherapeutic drug targeting folate receptor to oral cancer cells using functionalized carbon nanospheres.

Folate receptor (FR) (α) has long been the subject of active interest as regards its potential to serve as a target for cancer therapy. FR has been found to be overexpressed in several cancers, including clinical samples of different stages from OSCC (oral squamous cell carcinoma) patients. However, no clear correlation or conclusive finding has been obtained so far which might indicate the efficacy of FR as a credible target for the treatment of OSCC. All cell lines to be used were assessed for FR-expression. Subsequently, we developed glucose-derived carbon nanospheres (CSPs) and primed them with a Folate-based cationic lipid FA8 and the chemotherapeutic drug doxorubicin (DOX). CSP based delivery systems along with pristine drug DOX were characterized and treated subsequently toin vitrocultures of OSCC cells and assessed for cancer cell targetability as well as cell death. Subsequently, treatment was administered to immunocompetent C57 mice carrying MOC2 based syngeneic OSCC tumours and assessed for tumour regression and toxicity. Ligand primed targeted CSPs exhibited commendable drug uptake as well as efficient induction of cell death. Further, receptor blocking studies revealed FR-mediated uptake, preferentially in cancer cells. Drug once delivered by ligand-primed CSPs was retained longer inside cells than pristine drug alone, indicating possibilities of better therapeutic outcome. In animal studies, CSP-FA8-DOX (Ligand primed targeted CSP) demonstrated significant regression in tumour size compared to pristine DOX as well as CSP-DOX (non-targeted CSP) treated animals. FR-mediated system CFD demonstrated targeted drug uptake and apoptotic death selectively in cancer cells. Significant tumour regression was also observedin vivo. Overall, it may be presumed that the FR is a therapeutic target with substantial potential in OSCC treatment.

Cerebral Venous Thrombosis as The Sole Presenting Manifestation of Human Immunodeficiency Virus and Hepatitis B Virus Co-Infection.

Background: Cerebral venous thrombosis (CVT) following either human immunodeficiency virus (HIV) infection or hepatitis B virus (HBV) infection is a very rare condition. Moreover, it has never been reported as the presenting manifestation of HIV and HBV co-infection, even more so when the patient had a normal CD4 count and no demonstrable opportunistic infections. We aimed to report the first case of an adult Indian male, an intravenous drug abuser who developed CVT as the presenting manifestation of HIV-HBV co-infection. Methods: Patient data were obtained from medical records from the Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education and Research & SSKM Hospital, Kolkata, West Bengal, India. Results: A 25-year-old male with a history of intravenous drug abuse and a normal CD4 count developed CVT as the presenting manifestation of HIV-HBV co-infection. His CD4 count was normal, and he had no demonstrable opportunistic infections. He had an uneventful recovery of the condition (CVT) following the institution of conventional anticoagulation therapy alongside anti-retroviral therapy. Conclusion: Whether illicit drug abuse or HIV/HBV infection itself or all in combination led to this thrombotic event cannot be precisely established. Notwithstanding, we recommend serologic testing for HIV and HBV in patients suffering from CVT with high-risk behavior.

Communication in non-communicable diseases (NCDs) and role of immunomodulatory nutraceuticals in their management.

Conveyance of pathogens between organisms causes communicable diseases. On the other hand, a non-communicable disease (NCD) was always thought to have no causative transmissible infective agents. Today, this clear distinction is increasingly getting blurred and NCDs are found to be associated with some transmissible components. The human microbiota carries a congregation of microbes, the majority and the most widely studied being bacteria in the gut. The adult human gut harbors ginormous inhabitant microbes, and the microbiome accommodates 150-fold more genes than the host genome. Microbial communities share a mutually beneficial relationship with the host, especially with respect to host physiology including digestion, immune responses, and metabolism. This review delineates the connection between environmental factors such as infections leading to gut dysbiosis and NCDs and explores the evidence regarding possible causal link between them. We also discuss the evidence regarding the value of appropriate therapeutic immunomodulatory nutritional interventions to reduce the development of such diseases. We behold such immunomodulatory effects have the potential to influence in various NCDs and restore homeostasis. We believe that the beginning of the era of microbiota-oriented personalized treatment modalities is not far away.

Cimetidine-Based Cationic Amphiphiles for In Vitro Gene Delivery Targetable to Colon Cancer.

Cimetidine, a histamine-2 (H2) receptor antagonist, has been found to have anticancer properties against a number of cancer-type cells. In this report, we have demonstrated that cimetidine can acts as a hydrophilic domain in cationic lipids and targetable to the gastric system by carrying reporter genes and therapeutic genes through in vitro transfection. Two lipids, namely, Toc-Cim and Chol-Cim consisting cimetidine as the main head group and hydrophobic moieties as alpha-tocopherol or cholesterol, respectively, were designed and synthesized. 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) is a well-known co-lipid employed to produce liposomes as uniform vesicles. The liposomes and lipoplexes were structurally and functionally evaluated for global surface charges and hydrodynamic diameters, and results found that both liposome and lipoplex size and surface charges are optimal to screen the transfection potentials. DNA-binding studies were analyzed as complete binding at all formulated N/P ratios. The liposomes and lipoplexes of both the lipids Toc-Cim and Chol-Cim show minimal cytotoxicity even though at higher concentrations. The results of the transfection experiments revealed that tocopherol-based cationic lipids (Toc-Cim) show finer transfection efficacy with optimized N/P ratios (2:1 and 4:1) in the colon cancer cell line. Toc-Cim lipoplexes show higher cellular uptake compare to Chol-Cim in the colon cancer cell line at 2:1 and 4:1 N/P ratios. Toc-Cim and Chol-Cim lipids showed highly compatible serum, examined up to 50% of the serum concentration. To evaluate the apoptotic cell death in CT-26 cells, exposed to Toc-Cim:p53 and Chol-Cim:p53 lipoplexes at 2:1 N/P ratios, superior results showed with Toc-Cim:p53. An effect of TP53 protein expression in CT-26 cell lines assayed by western blot, transfected with Toc-Cim:p53 and Chol-Cim:p53 lipoplexes, demonstrated the superior efficacy of Toc-Cim. All of the findings suggest that Toc-Cim lipid is relatively secure and is an effective transfection agent to colon cancer gene delivery.

Targeting steroid hormone receptors for anti-cancer therapy-A review on small molecules and nanotherapeutic approaches.

The steroid hormone receptors (SHRs) among nuclear hormone receptors (NHRs) are steroid ligand-dependent transcription factors that play important roles in the regulation of transcription of genes promoted via hormone responsive elements in our genome. Aberrant expression patterns and context-specific regulation of these receptors in cancer, have been routinely reported by multiple research groups. These gave an window of opportunity to target those receptors in the context of developing novel, targeted anticancer therapeutics. Besides the development of a plethora of SHR-targeting synthetic ligands and the availability of their natural, hormonal ligands, development of many SHR-targeted, anticancer nano-delivery systems and theranostics, especially based on small molecules, have been reported. It is intriguing to realize that these cytoplasmic receptors have become a hot target for cancer selective delivery. This is in spite of the fact that these receptors do not fall in the category of conventional, targetable cell surface bound or transmembrane receptors that enjoy over-expression status. Glucocorticoid receptor (GR) is one such exciting SHR that in spite of it being expressed ubiquitously in all cells, we discovered it to behave differently in cancer cells, thus making it a truly druggable target for treating cancer. This review selectively accumulates the knowledge generated in the field of SHR-targeting as a major focus for cancer treatment with various anticancer small molecules and nanotherapeutics on progesterone receptor, mineralocorticoid receptor, and androgen receptor while selectively emphasizing on GR and estrogen receptor. This review also briefly highlights lipid-modification strategy to convert ligands into SHR-targeted cancer nanotherapeutics. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Biology-Inspired Nanomaterials > Lipid-Based Structures Therapeutic Approaches and Drug Discovery > Emerging Technologies.

The prospects of nanotherapeutic approaches for targeting tumor-associated macrophages in oral cancer.

OSCC (oral squamous cell carcinoma) is currently one of the most formidable cancers plagued by challenges like low overall survivability, lymph node associated metastasis, drug resistance, and poor diagnostics. The tumor microenvironment (TME) and its constituent stromal elements are crucial modulators of tumor growth and treatment response, more specifically so with regards to resident tumor associated macrophages (TAMs) and their liaison with the different stromal elements in the tumor niche (Figure 1). Interestingly, there isn't much information on TAM-targeted nanotherapy in OSCC where the first line of therapeutics for oral cancer is surgery with other therapeutics such as chemo- and radiotherapy acting only as adjuvant therapy for oral cancer. In the face of this real time situation, there have been some successful attempts at targeted therapy for OSCC cells and we believe they might elicit favorable responses against TAMs as well. Demanding our immediate attention, this review intends to provide a glimpse of the prevailing anti-TAM treatment strategies, which present great prospect for an uncharted territory like OSCC.

Proteome profile of telencephalon associates attenuated neurogenesis with chronic stress induced mood disorder phenotypes in zebrafish model.

Debilitating mental illness like depression and related mood disorders is due to the disruption in circuitry that controls emotion, motivation, and reward, characterized by disparate phenotypes like decrease in socialization, motivation, threshold for threat apprehension, etc. Chronic stress is a major factor in the etiology of these disorders. Here, using a chronic unpredictable stress (CUS) paradigm the characterization of an array of mood disorder phenotypes in adult zebrafish, in comparison to normal control unstressed fish, was achieved using a battery of behavioral assays including novel ones comprising social interaction test, feed approach test, threat response test and novel tank test. For the predictive validity of the model for mood disorders, the mitigative role of a slow (imipramine) and fast (ketamine) acting antidepressant was assessed. The molecular changes associated with CUS-induced mood disorder phenotype was investigated utilizing a high throughput method called isobaric tag for relative and absolute quantification (iTRAQ) in telencephalon, the region critically associated with the processing of emotional information in the fish brain. Out of 222 proteins identified to be significantly altered, 58 were differentially expressed across the stress and antidepressant-treatment groups at more than one fold (in log2) change. Of these proteins, some were implicated in earlier studies on mood disorders such as CABP1, PER2, mTOR, etc. The enrichment of altered proteins by Ingenuity Pathway Analysis (IPA) led us to mTOR and opioid signaling pathways, the top canonical pathways affected in the fish telencephalon. Interestingly, most of the pathways affected converge at the one controlling cell proliferation thus indicating altered neurogenesis, which was validated using immunohistochemistry for cell proliferation markers BrdU, SOX2, and BLBP. The study concludes that molecules that regulate telencephalon neural progenitor cell proliferation or neurogenesis are crucially involved in chronic stress-induced mood disorders by affecting the circuitry that controls emotion and reward.

Potential Therapeutic Application of Zinc Oxide Nanoflowers in the Cerebral Ischemia Rat Model through Neuritogenic and Neuroprotective Properties.

Neuritogenesis, a complex process of the sprouting of neurites, plays a vital role in the structural and functional restoration of cerebral ischemia-injured neuronal tissue. Practically, there is no effective long-term treatment strategy for cerebral ischemia in clinical practice to date due to several limitations of conventional therapies, facilitating the urgency to develop new alternative therapeutic approaches. Herein, for the first time we report that pro-angiogenic nanomaterials, zinc oxide nanoflowers (ZONF), exhibit neuritogenic activity by elevating mRNA expression of different neurotrophins, following PI3K/Akt-MAPK/ERK signaling pathways. Further, ZONF administration to global cerebral ischemia-induced Fischer rats shows improved neurobehavior and enhanced synaptic plasticity of neurons via upregulation of Neurabin-2 and NT-3, revealing their neuroprotective activity. Altogether, this study offers the basis for exploitation of angio-neural cross talk of other pro-angiogenic nano/biomaterials for future advancement of alternative treatment strategies for cerebral ischemia, where neuritogenesis and neural repair are highly critical.

Improved delivery of doxorubicin using rationally designed PEGylated platinum nanoparticles for the treatment of melanoma.

Efficient delivery of chemotherapeutic drugs to tumor cells is one of the crucial issues for modern day cancer therapy. In this article, we report the synthesis of poly ethylene glycol (PEG) assisted colloidal platinum nanoparticles (PtNPs) by borohydride reduction method at room temperature. PtNPs are stable at room temperature for more than 2 years and are stable in serum and phosphate buffer (pH = 7.4) solution for one week. PtNPs show biocompatibility in different normal cell lines (in vitro) and chicken egg embryonic model (ex vivo). Further, we designed and fabricated PtNPs-based drug delivery systems (DDS: PtNPs-DOX) using doxorubicin (DOX), a FDA approved anticancer drug. Various analytical techniques were applied to characterize the nanomaterials (PtNPs) and DDS (PtNPs-DOX). This DDS exhibits inhibition of cancer cell (B16F10 and A549) proliferation, observed by different in vitro assays. PtNPs-DOX induces apoptosis in cancer cells observed by annexin-V staining method. Intraperitoneal (IP) administration of PtNPs-DOX shows substantial reduction of tumor growth in subcutaneous murine melanoma tumor model compared to control group with free drug. Up-regulation of tumor suppressor protein p53 and down regulation of SOX2 and Ki-67 proliferation markers in melanoma tumor tissues (as observed by immunofluorescence and western blot analysis) indicates probable molecular mechanism for the anticancer activity of DDS. Considering the in vitro and pre-clinical (in vivo) results in murine melanoma, it is believed that platinum nanoparticle-based drug delivery formulation could be exploited to develop an alternative therapeutic nanomedicine for cancer therapy in the near future.

Silver Prussian Blue Analogue Nanoparticles: Rationally Designed Advanced Nanomedicine for Multifunctional Biomedical Applications.

The development of simple, cost-effective, and advanced multifunctional technology is the need of the hour to combat cancer as well as bacterial infections. There have been reports of silver nanoparticles (AgNPs), silver salts, and Prussian blue (PB) being used for medicinal purposes which are clinically approved. In this context, in the present communication, we incorporated PB and silver salts (silver nitrate) to develop silver PB analogue nanoparticles (SPBANPs), a new nanomedicine formulation as a safer and effective mode of treatment strategy (2-in-1) for both cancer and bacterial infections. Considering all fundamental issues of nanomedicine, along with understanding of the biological impact of PB, we designed a simple, fast, efficient, cheap, and eco-friendly method for the synthesis of [poly(N-vinyl-2-pyrrolidone)]-stabilized silver hexacyanoferrate nanoparticles (silver PB analogue: Ag3[Fe(CN)6] abbreviated as SPBANPs). Various analytical tools were used to analyze and characterize the nanomaterials (SPBANPs). The SPBANPs were highly stable for several weeks in various phosphate buffers with a range of physiological pH conditions (pH = 6-8). The nanoparticles showed biocompatibility in vivo in C57BL6/J mice that encouraged us to screen the nanoparticles for various biomedical applications. The SPBANPs themselves exhibited remarkable inhibition of cancer cell proliferation (B16F10, A549, MCF-7, and SK-OV-3) in vitro. Substantial inhibition of melanoma tumor growth was observed in the C57BL6/J mouse model (aggressive murine melanoma model: B16F10) after intraperitoneal administration of the SPBANPs without any anticancer drug. Additionally, the SPBANPs exhibited excellent antibacterial activity in various Gram-negative (Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa) and Gram-positive (Bacillus subtilis) bacteria. Interestingly, this nanoformulation itself works as a drug delivery vehicle, as well as an anticancer and antibacterial agent. The in vitro and in vivo results together demonstrate that this biocompatible nanoformulation (SPBANPs) without an anticancer drug or antibiotic could be explored to develop as a multifunctional therapeutic agent (2-in-1) for the treatment of cancer and bacterial infections in the near future.

Crafting Carbazole-Based Vorinostat and Tubastatin-A-like Histone Deacetylase (HDAC) Inhibitors with Potent in Vitro and in Vivo Neuroactive Functions.

Small-molecule inhibitors of HDACs (HDACi) induce hyperacetylation of histone and nonhistone proteins and have emerged as potential therapeutic agents in most animal models tested. The established HDACi vorinostat and tubastatin-A alleviate neurodegenerative and behavioral conditions in animal models of neuropsychiatric disorders restoring the neurotrophic milieu. In spite of the neuroactive pharmacological role of HDACi (vorinostat and tubastatin-A), they are limited by efficacy and toxicity. Considering these limitations and concern, we have designed novel compounds 3-11 as potential HDACi based on the strategic crafting of the key pharmacophoric elements of vorinostat and tubastatin-A into architecting a single molecule. The molecules 3-11 were synthesized through a multistep reaction sequence starting from carbazole and were fully characterized by NMR and mass spectral analysis. The novel molecules 3-11 showed remarkable pan HDAC inhibition and the potential to increase the levels of acetyl H3 and acetyl tubulin. In addition, few novel HDAC inhibitors 4-8, 10, and 11 exhibited significant neurite outgrowth-promoting activity with no observable cytotoxic effects, and interestingly, compound 5 has shown comparably more neurite growth than the parent compounds vorinostat and tubastatin-A. Also, compound 5 was evaluated for possible mood-elevating effects in a chronic unpredictable stress model of Zebrafish. It showed potent anxiolytic and antidepressant-like effects in the novel tank test and social interaction test, respectively. Furthermore, the potent in vitro and in vivo neuroactive compound 5 has shown selectivity for class II over class I HDACs. Our results suggest that the novel carbazole-based HDAC inhibitors, crafted with vorinostat and tubastatin-A pharmacophoric moieties, have potent neurite outgrowth activity and potential to be developed as therapeutics to treat depression and related psychiatric disorders.

Dual targeting of folate receptor-expressing glioma tumor-associated macrophages and epithelial cells in the brain using a carbon nanosphere-cationic folate nanoconjugate.

Glioblastoma multiforme (GBM), the highly invasive form of glioma, exhibits the highest mortality in patients with brain malignancies. Increasing glioma patients' survivability is challenging, as targeting only tumor-associated malignant cells would not reduce the overall aggressiveness of the tumor mass. This is due to the inadequacy in countering pro-proliferative, invasive and metastatic factors released by tumor-mass associated macrophages (TAMs). Hence, strategically, dual targeting both tumor cells and TAMs is necessary for effective glioma treatment and increased survivability. Conventional FR-targeting systems can easily target cancer cells that overtly express folate receptors (FRs). However, FRs are expressed only moderately in both glioma cells and in TAMs. Hence, it is more challenging to coordinate dual targeting of glioma cells and TAMs with lower levels of FR expression. A recently developed carbon nanosphere (CSP) with effective blood-brain barrier (BBB) penetrability was modified with a new folic acid-cationic lipid conjugate (F8) as a targeting ligand. The uniqueness of the cationic lipid-folate conjugate is that it stably associates with the negatively charged CSP surface at about >22 mol% surface concentration, a concentration at least 5-fold higher than what is achieved for conventional FR-targeting delivery systems. This enabled dual uptake of the CSP on TAMs and tumor cells via FRs. A doxorubicin-associated FR-targeting formulation (CFD), in an orthotopic glioma model and in a glioma subcutaneous model, induced the maximum anticancer effect with enhanced average mice survivability twice that of untreated mice and without any systemic liver toxicity. Additionally, we observed a significant decrease of TAM-released pro-aggressive factors, TGF-ß, STAT3, invasion and migration related sICAM-1, and other cytokines indicating anti-TAM activity of the CFD. Taken together, we principally devised, to the best of our knowledge, the first FR-targeting nano-delivery system for targeting brain-associated TAMs and tumor cells as an efficient glioma therapeutic.

Aurora kinase B siRNA-loaded lactoferrin nanoparticles potentiate the efficacy of temozolomide in treating glioblastoma.

AIM: To investigate the efficacy of lactoferrin nanoparticles (LfNPs) in delivering siRNA across the blood-brain barrier to treat glioblastoma multiforme (GBM) and with an additional objective of potentiation of conventional temozolomide (TMZ) chemotherapy. METHODS: Aurora kinase B (AKB) siRNA-loaded nanoparticles (AKB-LfNPs) were prepared with milk protein, lactoferrin, by water in oil emulsion method. AKB-LfNPs were tested in cell lines and in GBM orthotopic mouse model with and without TMZ treatment. RESULTS: AKB silencing, cytotoxicity and cell cycle arrest by these LfNPs were shown to be effective on GL261 cells. Tumor growth was significantly lower in AKB-LfNPs alone and in combination with TMZ treated mice and increased the survival by 2.5-times. CONCLUSION: Treatment of AKB-LfNPs to GBM mice improves life expectancy and has potential to combine with conventional chemotherapy.

Synthesis and biological evaluation of longanlactone analogues as neurotrophic agents.

Longanlactone analogues were synthesized using a route featuring Friedel-Crafts acylation, Sonogashira coupling and 1,3-dipolar cycloaddition reactions. Structure-activity relationships were investigated for neurotrophic activity. Compound 6 was found to have the most potent neurotrophic activity among all the synthesized analogues in Neuro2a cells as evidenced by a battery of in vitro/cell based assays for assessment of neurogenic and potential neurotrophic activity including neurite outgrowth assay and real time PCR for popular markers of augmented neurotrophic activity. Compound 6 might serve as a template for further development of highly effective neurotrophic molecules.

Isolation, Synthesis and AChE Inhibitory Potential of Some Novel Cinnamyl Esters of Taraxerol, the Major Metabolite of the Mangrove Bruguiera cylindrica.

Systematic chemical screening of the leaves of Bruguiera cylindrica, the tree mangrove of Rhizophoraceae family, afforded five single and pure compounds. The structures of the isolated compounds were established by their spectroscopic data as taraxerol (1), 3ß-(E)-coumaroyltaraxerol (2), 3ß-(Z)-coumaroyltaraxerol (3), ß-sitosterol (4), and eicosanol (5). In view of significant accumulation and interesting biological activities, taraxerol (1) was chemically transformed to synthesize a series of ten cinnamyl esters in very good to excellent yields. The synthesized analogues along with the parent compound were evaluated for their AChE inhibitory potential, BBB permeability and cytotoxicity against Neuro 2A cell line. Among the tested samples, compound 9 showed promising AChE inhibition with significantly low IC50 values, low cytotoxicity and high BBB permeability. Hence, compound 9 can be considered as a lead molecule for further development as potent AChE inhibitor.

Oestrogen receptor-mediated liposomal drug delivery for treating melanoma.

Function of steroid hormone oestrogen that transactivates oestrogen receptor (ER) is expressed in multiple organs. Except for malignancies of gynaecological organs, ER remains largely unutilised as a target to treat cancers of ER-expressing brain, prostate, skin etc. We have previously developed oestrogen targeting cationic lipid molecule (ES-C10), which showed targeted killing of ER + breast and skin cancer cells. In this study, we explored the targeting ability of ES-C10 as a ligand as well as its additive killing effect (if any), when incorporated in two different liposomes (DCME and DCDE), carrying two anticancer molecules MCIS3 and Docetaxel™, respectively. DCME and DCDE exhibited higher cytotoxicity in ER + cancer cells than in ER - cancer or in non-cancer cells. Both liposomes induced ER-mediated cytotoxicity and caspase 3-induced apoptosis in ER + melanoma cells. Further, decreased levels of pAkt, and increased levels of PTEN and p53 were also observed. Both the targeted liposomes were least haemolytic. These selectively delivered drug-cargoes to tumour mass over other vital organs and induced better anti-tumour effect, which led to increased survivability than their respective controls. In conclusion, we demonstrated the development of two independent liposomal drug-delivery systems associated with an anticancer, oestrogen-structure based ligand for efficient, ER-mediated anti-melanoma effect.

Large Amino Acid Transporter 1 Selective Liposomes of l-DOPA Functionalized Amphiphile for Combating Glioblastoma.

Despite significant progress in neurosurgery and radiation therapy during the past decade, overall survivability (OS) of glioblastoma patients continues to be less than 2 years. The scope of systemic chemotherapy is greatly limited by poor drug transport across the blood brain barrier (BBB) and, thereby, suboptimal drug accumulation in glioma tissue. To this end, use of large amino acid transporter-1 (LAT1) overexpressed both on brain capillary endothelial cells (BCECs) and glioma cells has begun. Prior reports on the use of LAT1 mediated delivery of model drugs showed their brain accumulations. However, in depth in vivo glioblastoma regression studies aimed at examining the therapeutic potential of LAT1 mediated delivery of potent chemotherapeutics to brain tumor tissues have not yet been undertaken. Herein, we report on the development of a nanometric (100-135 nm) promising LAT1 selective liposomal drug carrier prepared from a novel l-3,4-dihydroxyphenylalanine (l-DOPA) functionalized amphiphile (Amphi-DOPA). In vitro studies using Rh-PE labeled liposomes of Amphi-DOPA both in untreated glioma (GL261) cells and in GL261cells preincubated with LAT1 antibody revealed LAT1 mediated cellular uptake. Intravenously administered NIR-dye labeled liposomes of Amphi-DOPA in glioblastoma-bearing mice showed preferential accumulation of the dye in brain tissue. Notably iv administration of WP1066-loaded liposomes of Amphi-DOPA enhanced the overall survivability of C57BL/6J mice bearing orthotopically established mouse glioblastoma by ∼60% compared to that for the untreated mouse group. Furthermore, we show that the OS of established glioblastoma-bearing mice can be significantly enhanced (by >300% compared to that for the untreated mouse group) when the presently described LAT1 mediated targeted chemotherapy with WP1066-loaded liposomes of Amphi-DOPA is combined with in vivo DC-targeted DNA vaccination using a survivin (a glioblastoma antigen) encoded DNA vaccine. The present findings open a new door for LAT1 mediated systemic chemotherapy of glioblastoma.

A 2-oxa-spiro[5.4]decane scaffold displays neurotrophic, neurogenic and anti-neuroinflammatory activities with high potential for development as a versatile CNS therapeutic.

Following our recent discovery of a new scaffold exhibiting significant neurotrophic and neurogenic activities, a structurally tweaked analogue, embodying a 2-oxa-spiro [5.4]decane framework, has been conceptualised and found to be more potent and versatile. It exhibits enhanced neurotrophic and neurogenic action in in vitro, ex vivo and in vivo models and also shows robust neuroprotection in mouse acute cerebral stroke model. The observed attributes are traceable to the predominant activation of the TrkB-PI3K-AKT-CREB pathway. In addition, it also exhibits remarkable anti-neuroinflammatory activity by concurrently down-regulating pro-inflammatory cytokines IL-1α and IL-6, thereby providing a unique molecule with a trinity of neuroactivities, i.e. neurotrophic, neurogenic and anti-inflammatory. The new chemical entity disclosed here has the potential to be advanced as a versatile therapeutic molecule to treat stroke, depression, and possibly other neuropsychiatric disorders associated with attenuated neurotrophic/ neurogenic activity, together with heightened neuroinflammation.