Topical carvedilol delivery prevents UV-induced skin cancer with negligible systemic absorption.

The ß-blocker carvedilol prevents ultraviolet (UV)-induced skin cancer, but systemic drug administration may cause unwanted cadiovascular effects. To overcome this limitation, a topical delivery system based on transfersome (T-CAR) was characterized ex vivo and in vivo. T-CAR was visualized by Transmission Electron Microscopy as nanoparticles of spherical and unilamellar structure. T-CAR incorporated into carbopol gel and in suspension showed similar drug permeation and deposition profiles in Franz diffusion cells loaded with porcine ear skin. In mice exposed to a single dose UV, topical T-CAR gel (10 µM) significantly reduced UV-induced skin edema and cyclobutane pyrimidine dimer formation. In mice exposed to chronic UV radiation for 25 weeks, topical T-CAR gel (10 µM) significantly delayed the incidence of tumors, reduced tumor number and burden, and attenuated Ki-67 and COX-2 expression. The T-CAR gel was subsequently examined for skin deposition, systemic absorption and cardiovascular effects in mice. In mice treated with repeated doses of T-CAR gel (100 µM), the drug was undetectable in plasma, the heart rate was unaffected, but skin deposition was significantly higher than mice treated with oral carvedilol (32 mg/kg/day). These data indicate that the carbopol-based T-CAR gel holds great promise for skin cancer prevention with negligible systemic effects.

Nanotechnology-Based Celastrol Formulations and Their Therapeutic Applications.

Celastrol (also called tripterine) is a quinone methide triterpene isolated from the root extract of Tripterygium wilfordii (thunder god vine in traditional Chinese medicine). Over the past two decades, celastrol has gained wide attention as a potent anti-inflammatory, anti-autoimmune, anti-cancer, anti-oxidant, and neuroprotective agent. However, its clinical translation is very challenging due to its lower aqueous solubility, poor oral bioavailability, and high organ toxicity. To deal with these issues, various formulation strategies have been investigated to augment the overall celastrol efficacy in vivo by attempting to increase the bioavailability and/or reduce the toxicity. Among these, nanotechnology-based celastrol formulations are most widely explored by pharmaceutical scientists worldwide. Based on the survey of literature over the past 15 years, this mini-review is aimed at summarizing a multitude of celastrol nanoformulations that have been developed and tested for various therapeutic applications. In addition, the review highlights the unmet need in the clinical translation of celastrol nanoformulations and the path forward.

Cancer Chemoprevention Using Nanotechnology-Based Approaches.

Cancer research in pursuit of better diagnostic and treatment modalities has seen great advances in recent years. However, the incidence rate of cancer is still very high. Almost 40% of women and men are diagnosed with cancer during their lifetime. Such high incidence has not only resulted in high mortality but also severely compromised patient lifestyles, and added a great socioeconomic burden. In view of this, chemoprevention has gained wide attention as a method to reduce cancer incidence and its relapse after treatment. Among various stems of chemoprevention research, nanotechnology-based chemoprevention approaches have established their potential to offer better efficacy and safety. This review summarizes recent advances in nanotechnology-based chemoprevention strategies for various cancers with emphasis on lung and bronchial cancer, colorectal, pancreatic, and breast cancer and highlights the unmet needs in this developing field towards successful clinical translation.

Efficacy and Pharmacokinetic Considerations of Loratadine Nanoformulations and its Combinations for Pancreatic Cancer Chemoprevention.

PURPOSE: Pancreatic cancer (PC) is predicted to become the second leading cause of cancer associated deaths by 2020. Earlier, we confirmed the development and efficacy of our novel Loratadine Self-Microemulsifying-Drug-Delivery-System - Sulforaphane (LOR SMEDDS -SFN) nanoformulation in PC chemoprevention. In this report, we extend our studies to evaluate the PC chemoprevention efficacy of LOR SMEDDS - SFN. METHODS: The nanoformulation was subjected to in vitro colony formation assays, in vivo oral pharmacokinetics and stability studies. RESULTS: The colony formation assay using Panc-1 PC cells demonstrated a survival fraction of 0.74 with LOR-SFN (p < 0.001) which further reduced to 0.35 with LOR SMEDDS-SFN treatment (p < 0.0001) confirming the synergistic chemoprevention efficacy of the nanoformulation. Further, the oral pharmacokinetic studies of LOR SMEDDS-SFN showed 4-fold and 9-fold increase in Cmax (503.2 ± 5.8 ng/mL) and oral bioavailability (20,274.8 ± 3711.0 ng·h/mL) for LOR compared to LOR-SFN combination respectively assuring the enhanced performance by the SMEDDS. Additionally, the formulation exhibited statistically non-significant alteration in globule size, zeta potential, drug content and in vitro drug release during stability studies confirming its stability and pharmaceutical acceptability. CONCLUSION: Our studies have demonstrated a potential of LOR SMEDDS-SFN nanoformulation as an effective PC chemoprevention strategy.

Pancreatic Cancer: Recent Advances in Nanoformulation-Based Therapies.

Pancreatic cancer is the fourth leading cause of death in the United States and has a 5-year life expectancy of ~8%. Currently, only a few drugs have been approved by the United States Food and Drug Administration for pancreatic cancer treatment. Despite available drug therapy and ongoing clinical investigations, the high prevalence and mortality associated with pancreatic cancer mean that there is an unmet chemopreventive and therapeutic need. From ongoing studies with various novel formulations, it is evident that the development of smart drug delivery systems will improve delivery of drug cargo to the pancreatic target site to ensure and enhance the therapeutic/chemoprevention efficacy of existing drugs and newly designed drugs in the future. With this in view, nanotechnology is emerging as a promising avenue to enhance drug delivery to the pancreas via both passive and active targeting mechanisms. Research in this field has grown extensively over the past decade, as is evident from available scientific literature. This review summarizes the recent advances that have brought nanotechnology-based formulations to the forefront of pancreatic cancer treatment.

Loratadine self-microemulsifying drug delivery systems (SMEDDS) in combination with sulforaphane for the synergistic chemoprevention of pancreatic cancer.

Pancreatic cancer (PC), currently the third leading cause of cancer-related deaths in the USA, is projected to become the second leading cause, behind lung cancer, by 2020. The increasing incidence, low survival rate, and limited treatment opportunities necessitate the use of alternative approaches such as chemoprevention, to tackle PC. In this study, we report significant synergistic chemoprevention efficacy for the first time from a low-dose combination of a classical antihistaminic drug, Loratadine (LOR) and a neutraceutical compound, Sulforaphane (SFN) using a self-microemulsifying drug delivery system (SMEDDS) formulation. The formulation was developed using Quality by Design approach (globule size, 95.13 ± 7.9 nm; PDI, 0.17 ± 0.04) and revealed significant (p < 0.05) enhancement in the in vitro dissolution profile confirming the enhanced solubility of BCS class II drug LOR with SMEDDS formulation. The LOR-SFN combination revealed ~ 40-fold reduction in IC50 concentration compared to LOR alone in MIA PaCa-2 and Panc-1 cell lines respectively, confirming the synergistic enhancement in chemoprevention. Further, the nanoformulation resulted in ~ 7-fold and ~ 11-fold reduction in IC50 values compared to LOR-SFN combination. Hence, our studies successfully demonstrate that a unique low-dose combination of LOR encapsulated within SMEDDs with SFN shows significantly enhanced chemopreventive efficacy of PC.

Pancreatic Cancer: Recent Advances in Nanoformulation-Based Therapies.

Pancreatic cancer is the fourth leading cause of death in the United States and has a 5-year life expectancy of ~8%. Currently, only a few drugs have been approved by the United States Food and Drug Administration for pancreatic cancer treatment. Despite available drug therapy and ongoing clinical investigations, the high prevalence and mortality associated with pancreatic cancer mean that there is an unmet chemopreventive and therapeutic need. From ongoing studies with various novel formulations, it is evident that the development of smart drug delivery systems will improve delivery of drug cargo to the pancreatic target site to ensure and enhance the therapeutic/chemoprevention efficacy of existing drugs and newly designed drugs in the future. With this in view, nanotechnology is emerging as a promising avenue to enhance drug delivery to the pancreas via both passive and active targeting mechanisms. Research in this field has grown extensively over the past decade, as is evident from available scientific literature. This review summarizes the recent advances that have brought nanotechnology-based formulations to the forefront of pancreatic cancer treatment.

Novel nano-drug combination therapeutic regimen demonstrates significant efficacy in the transgenic mouse model of pancreatic ductal adenocarcinoma.

The current work studied the chemopreventive efficacy of orally administered chitosan coated solid-lipid nanoparticle (c-SLN) encapsulated aspirin (ASP), curcumin (CUR) and free sulforaphane (SFN), ACS-cSLN, in the LSL-Kras G12D/+; Pdx-1 Cre/+ transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC). In vitro uptake study and intracellular localization of ODA-FITC labeled ASP and CUR c-SLNs were performed in Panc-1 and MIA PaCa-2 cells by fluorescence microscopy. LSL-Kras G12D/+; Pdx-1 Cre/+ transgenic mice (n = 30) were randomly divided into 5 groups. Treatment groups were orally gavaged with ACS c-SLNs in three doses: low (2 + 4.5 + 0.16 mg/kg), medium (20 + 45 + 1.6 mg/kg) and high (60 + 135 + 4.8 mg/kg), respectively. After 20 weeks of treatment, mice pancreas were harvested, stained with dye and scored according to various pancreatic intraepithelial neoplasms (PanIN) categories by an independent observer. In vitro, cellular uptake evaluated on Panc-1 and MIA PaCa-2 cells resulted in higher fluorescence intensities, indicating increased cellular uptake of ASP and CUR c-SLNs. For further evidence, the addition of lysoID (red fluorescence) demonstrated location and uptake of ASP and CUR c-SLNs into the lysosome. In vivo, treatment with ACS c-SLN for 20-weeks did not cause obvious adverse effects on growth and no statistically significant differences in body weight were observed between groups. However, the weight (mean ± SEM) of pancreas at the end of the study was higher in blank c-SLN group (223.6 ± 42.2 mg) compared to low (138.0 ± 26.0 mg; not significant [NS]), medium (145.0 ± 9.0 mg; NS), and high (133.8 ± 20.3 mg; NS) ACS c-SLN treated groups, demonstrating the efficacy of ACS c-SLN nanoformulations. The low, medium and high dose of ACS c-SLN combinations exhibited a reduction in tumor incidence (PanIN count) by 16.6% (P < 0.01), 66.8% (P < 0.01), and 83.4% (P < 0.01), respectively. These studies provide further proof for the use of an oral, low dose nanotechnology-based combinatorial regimen for the chemoprevention of PDAC.

Curcumin Cocrystal Micelles-Multifunctional Nanocomposites for Management of Neurodegenerative Ailments.

Curcumin, a potent antioxidant polyphenol with neuroprotective and antiamyloid activities, has significant potential in the treatment of neurodegenerative disorders such as Alzheimer's disease. However, its clinical translation is delayed due to poor bioavailability. For effective use of curcumin in Alzheimer's disease, it is imperative to increase its bioavailability with enhanced delivery at a therapeutic site that is, brain. With this objective, pharmaceutical cocrystals of curcumin were developed and incorporated in micellar nanocarriers for nose-to-brain delivery. For cocrystals, an antioxidant hydrophilic coformer was strategically selected using molecular modeling approach. The cocrystals were formulated using a planetary ball mill, and the process was optimized using 32 factorial design followed by characterization using differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectroscopy analysis. The cocrystal micelles exhibited globule size of 28.79 ± 0.86 nm. Further, curcumin cocrystal and co-crystal micelles exhibited a significantly low (p value <0.01) IC50 concentration for antioxidant activity as compared to curcumin corroborating superior antioxidant performance. In vivo studies revealed about 1.7-fold absolute bioavailability of curcumin cocrystal micelles with Cmax of 1218.38 ± 58.11 ng/mL and showed significantly high brain distribution even beyond 6 hours of dosing. Thus, the studies confirmed enhanced bioavailability, higher brain uptake, retention, and delayed clearance with curcumin cocrystal micellar nanocarriers.