Novel strategies focused towards targeting drug substances specifically to brain tumor site would increase the therapeutic efficiency and reduce the toxicity of chemotherapeutics.

Neural cell adhesion molecule 1 (NCAM1; CD56) is expressed in up to 20% of acute myeloid leukemia (AML) patients. NCAM1 is widely used as a marker of minimal residual disease; however, the biological function of NCAM1 in AML remains elusive. In this study, we investigated the impact of NCAM1 expression on leukemogenesis, drug resistance, and its role as a biomarker to guide therapy. Beside t(8;21) leukemia, NCAM1 expression was found in most molecular AML subgroups at highly heterogeneous expression levels. Using complementary genetic strategies, we demonstrated an essential role of NCAM1 in the regulation of cell survival and stress resistance. Perturbation of NCAM1 induced cell death or differentiation and sensitized leukemic blasts toward genotoxic agents in vitro and in vivo. Furthermore, Ncam1 was highly expressed in leukemic progenitor cells in a murine leukemia model, and genetic depletion of Ncam1 prolonged disease latency and significantly reduced leukemia-initiating cells upon serial transplantation. To further analyze the mechanism of the NCAM1-associated phenotype, we performed phosphoproteomics and transcriptomics in different AML cell lines. NCAM1 expression strongly associated with constitutive activation of the MAPK-signaling pathway, regulation of apoptosis, or glycolysis. Pharmacological inhibition of MEK1/2 specifically inhibited proliferation and sensitized NCAM1+ AML cells to chemotherapy. In summary, our data demonstrate that aberrant expression of NCAM1 is involved in the maintenance of leukemic stem cells and confers stress resistance, likely due to activation of the MAPK pathway. Targeting MEK1/2 sensitizes AML blasts to genotoxic agents, indicating a role for NCAM1 as a biomarker to guide AML treatment.

The aim of the present study was to prepare mucoadhesive multiparticulate system for oral drug delivery using ionic gelation technique. Microspheres composed of various mucoadhesive polymers including HPMC of various grades like K4M, K15M, K100M, E50LV, Carbopol of grades 971P, 974P and polycarbophil were prepared. In this technique cross linking of sodium alginate with calcium chloride was done which retarded the release of drug from the mucoadhesive polymer. In the present work Metoprolol tararate was used as a model drug. Interaction studies performed using FTIR spectroscopy revealed that there was no drug to polymer interactions. The preliminary mucoadhesive strength studies performed for various polymers using rotating cylindrical method showed that HPMC had greater mucoadhesive properties than carbopol and polycarbophil. Microspheres so prepared were discrete, bulky, free flowing and showed an average encapsulation efficiency ranging from 50-60%. Particle size of the microspheres, as determined by the optical microscopy was found to be between 400-650 microm. The prepared formulations also exhibited a good mucoadhesive strength which was determined in in vitro conditions through falling film technique and was compared with ex vivo studies. The microspheres so prepared also exhibited a good swelling index which confirmed the strong mucoadhesive property of the formulation. Metoprolol release from the multiparticulate system was regulated and extended until 12 hours and exhibited a non fickian drug release kinetics approaching to zero order, as evident from the release rate exponent values which varied between 0.57 to 0.73. The stability studies performed on the optimized batches at 40 degrees C /75% RH for 90 days indicated no significant change in the physicochemical properties.

The present investigation focused on developing, optimizing, and evaluating a novel liposome-loaded nail lacquer formulation for increasing the transungual permeation flux of terbinafine HCl for efficient treatment of onychomycosis. A three-factor, three-level, Box-Behnken design was employed for optimizing process and formulation parameters of liposomal formulation. Liposomes were formulated by thin film hydration technique followed by sonication. Drug to lipid ratio, sonication amplitude, and sonication time were screened as independent variables while particle size, PDI, entrapment efficiency, and zeta potential were selected as quality attributes for liposomal formulation. Multiple regression analysis was employed to construct a second-order quadratic polynomial equation and contour plots. Design space (overlay plot) was generated to optimize a liposomal system, with software-suggested levels of independent variables that could be transformed to desired responses. The optimized liposome formulation was characterized and dispersed in nail lacquer which was further evaluated for different parameters. Results depicted that the optimized terbinafine HCl-loaded liposome formulation exhibited particle size of 182 nm, PDI of 0.175, zeta potential of -26.8 mV, and entrapment efficiency of 80%. Transungual permeability flux of terbinafine HCl through liposome-dispersed nail lacquer formulation was observed to be significantly higher in comparison to nail lacquer with a permeation enhancer. The developed formulation was also observed to be as efficient as pure drug dispersion in its antifungal activity. Thus, it was concluded that the developed formulation can serve as an efficient tool for enhancing the permeability of terbinafine HCl across human nail plate thereby improving its therapeutic efficiency.

The aim of the present study was to prepare gellan gum microspheres of Sildenafil citrate, for intranasal delivery to avoid the first pass metabolism. The microspheres were prepared using spray drying method. The microspheres were evaluated for characteristics like particle size, incorporation efficiency, swelling ability, zeta potential, in-vitro mucoadhesion, ex-vivo mucoadhesion, thermal analysis, XRD study and invitro drug release. Treatment of in-vitro data to different kinetic equations indicated diffusion controlled drug delivery from gellan gum microspheres. The results of DSC and XRD studies revealed the molecular amorphous dispersion of Sildenafil citrate into the gellan gum microspheres. Microspheres so prepared were discrete, bulky, free flowing and showed an average encapsulation efficiency ranging from 95-98%. The formulation exhibited a good mucoadhesive strength which was determined in in vitro conditions through falling film technique and was compared with ex vivo studies. The microspheres so prepared also exhibited a good swelling index which confirmed the strong mucoadhesive property of the formulation.

Skin is the most visible and vulnerable organ of the integumentary system. Psoriasis is a chronic inflammatory skin disorder with an equal prevalence rate in males and females globally. Psoriasis is seen today beyond a cosmetic turmoil as it significantly impacts the socioeconomic life of the patients. Patients with severe psoriasis report feeling denounced and isolated. Despite detailed understanding of the molecular mechanisms and pathogenesis of psoriasis, issues like the autoimmune cause of inflammation and role of external, genetic, cutaneous, and systemic factors on initiation, progression, and treatment of psoriasis are still ambiguous. The present review summarizes immunogenic pathophysiology of psoriasis with a cascade of events from stimuli-based release of self-nucleotides to the hyperproliferation of keratinocytes leading to psoriasis. The review emphasizes challenges and hurdles toward the efficient treatment of psoriasis. The review also provides a detailed understanding of conventional and novel treatment strategies including drug delivery approaches and patented technologies for therapeutic and preventive approaches leading to improved outcome for psoriasis patients. The review summarizes a brief insight on biologics and gene therapy that has resulted in a paradigm shift in the treatment strategies for psoriasis management.

A revolutionary paradigm shift is being observed currently, towards the use of therapeutic biologics for disease management. The present research was focused on designing an efficient dosage form for transdermal delivery of α-choriogonadotropin (high molecular weight biologic), through biodegradable polymeric microneedles. Polyvinylpyrrolidone-based biodegradable microneedle arrays loaded with high molecular weight polypeptide, α-choriogonadotropin, were fabricated for its systemic delivery via transdermal route. Varied process and formulation parameters were optimized for fabricating microneedle array, which in turn was expected to temporally rupture the stratum corneum layer of the skin, acting as a major barrier to drug delivery through transdermal route. The developed polymeric microneedles were optimized on the basis of quality attributes like mechanical strength, axial strength, insertion ratio, and insertion force analysis. The optimized polymeric microneedle arrays were characterized for in vitro drug release studies, ex vivo drug permeation studies, skin resealing studies, and in vivo pharmacokinetic studies. Results depicted that fabricated polymeric microneedle arrays with mechanical strength of above 5 N and good insertion ratio exhibited similar systemic bioavailability of α-choriogonadotropin in comparison to marketed subcutaneous injection formulation of α-choriogonadotropin. Thus, it was ultimately concluded that the designed drug delivery system can serve as an efficient tool for systemic delivery of therapeutic biologics, with an added benefit of overcoming the limitations of parenteral delivery, achieving better patient acceptability and compliance.

The findings, research outcomes and patents related to nanocrystal formulations, reported in the present review confirm the potential of the stated system as a drug delivery tool. The review emphasizes on the urge for further exploration required in the area of nanocrystal system for enhancing its efficiency as a drug delivery and a diagnostic tool.