Undaria pinnatifida fucoidan nanoparticles loaded with quinacrine attenuate growth and metastasis of pancreatic cancer.

Pancreatic cancer is a devastating gastrointestinal tumor with limited Chemotherapeutic options. Treatment is restricted by its poor vascularity and dense surrounding stroma. Quinacrine is a repositioned drug with an anticancer activity but suffers a limited ability to reach tumor cells. This could be enhanced using nanotechnology by the preparation of quinacrine-loaded Undaria pinnatifida fucoidan nanoparticles. The system exploited fucoidan as both a delivery system of natural origin and active targeting ligand. Lactoferrin was added as a second active targeting ligand. Single and dual-targeted particles prepared through nanoprecipitation and ionic interaction respectively were appraised. Both particles showed a size lower than 200 nm, entrapment efficiency of 80% and a pH-dependent release of the drug in the acidic environment of the tumor. The anticancer activity of quinacrine was enhanced by 5.7 folds in dual targeted particles compared to drug solution with a higher ability to inhibit migration and invasion of cancer. In vivo, these particles showed a 68% reduction in tumor volume compared to only 20% for drug solution. In addition, they showed a higher animals' survival rate with no hepatotoxicity. Hence, these particles could be an effective option for the eradication of pancreatic cancer cells.

Lactoferrin/Hyaluronic acid double-coated lignosulfonate nanoparticles of quinacrine as a controlled release biodegradable nanomedicine targeting pancreatic cancer.

Quinacrine is an antimalarial drug that was repositioned for treatment of cancer. This is the first work to enhance quinacrine activity and minimize its associated hepatotoxicity via loading into bio-degradable, bio-renewable lignosulfonate nanoparticles. Particles were appraised for treatment of pancreatic cancer, one of the most life-threatening tumors with a five-year survival estimate. Optimum nanocomposites prepared by polyelectrolyte interaction exhibited a particle size of 138 nm, a negative surface charge (-28 mV) and a pH dependent release of the drug in an acidic environment. Ligands used for active targeting (lactoferrin and hyaluronic acid) were added to nanoparticles' surface via layer by layer coating technique. The highest anticancer activity on PANC-1 cells was demonstrated with dual active targeted particles (3-fold decrease in IC50) along with an increased ability to inhibit migration and invasion of pancreatic cancer cells. In vivo studies revealed that elaborated nanoparticles particles showed the highest tumor volume reduction with enhanced survival without any toxicity on major organs. In conclusion, the elaborated nanoparticles could be considered as a promising targeted nanotherapy for treatment of pancreatic cancer with higher efficacy& survival rate and lower organ toxicity.

Novel fucoidan based bioactive targeted nanoparticles from Undaria Pinnatifida for treatment of pancreatic cancer.

Fucoidan is a marine polymer extracted from diverse types of brown algae. This polysaccharide showed great potential towards treatment of different types of cancer. In this study, the activity of fucoidan extracted from Undaria Pinnatifida was investigated against pancreatic cancer (one of the most life-threatening cancers). Then, in an attempt to enhance the polymer's activity against cancer cells, conversion the polymer solution to nanoparticles was suggested to enhance its delivery through pancreatic cancer surrounding stroma. Novel fucoidan based nanoparticles were elaborated by polyelectrolyte interaction with the positively charged, active targeting ligand lactoferrin. The formulation was optimized through the interplay between different factors. Effect of fucoidan solution along with its blank nanoparticles was tested on the viability of pancreatic cancer cells and its migration and invasion abilities. Results confirmed the cytotoxic ability of fucoidan against pancreatic cancer. IC50 value decreased by 2.3 folds when the polymer was converted to nanoparticles. The prepared nanosystems showed an enhanced ability to prevent pancreatic cancer cells' migration and invasion. Results suggested the potential of using these nanoparticles as bioactive dual-targeted system either blank or loaded with different anticancer agents for treatment for pancreatic cancer.

"Fucoidan, a natural biopolymer in cancer combating: From edible algae to nanocarrier tailoring".

Fucoidan is an edible algae that has long been used as part of east Asians' diet. Recently, various pharmacological activities of the polymer have been discovered including its ability to act as antimicrobial, anti-thrombotic, antiviral, anti-inflammatory and anti-cancer. This review is the first to focus on the anti-cancer ability of this biopolymer and factors affecting it. The review discusses the mechanism by which fucoidan can kill cancer cells efficiently without having chemotherapeutic side effects and the ability of fucoidan to act as an adjuvant to classic therapy. Furthermore, multifaceted nanotechnological applications of fucoidan in cancer treatment were reviewed. Fucoidan nanoparticles with efficient drug loading and release had been developed. The polymer had also been used as coating material for different organic and inorganic nanoparticles imparting biocompatibility characters to these systems. Most recently, there has been a focus on the role of fucoidan as active targeting ligand for cancer cells. The polymer could target P-selectin receptors over-expressed on cancer cells in nanomolar concentrations. Combining all these activities, fucoidan could be considered as one of the most important biopolymers combating cancer during tailoring of cancer nanomedicine. Finally, we discussed safety of fucoidan, challenges facing its application on industrial scale and future projections.

Oral Brain-Targeted Microemulsion for Enhanced Piperine Delivery in Alzheimer's Disease Therapy: In Vitro Appraisal, In Vivo Activity, and Nanotoxicity.

Alzheimer's disease (AD) is a neurodegenerative disorder that has no cure till now. Piperine (PIP) is an alkaloid characterized by memory-enhancing properties but challenging oral delivery obstacles. The objectives of this study are as follows: preparation of microemulsion (ME) as a proposed oral PIP nanocarrier for treatment of Alzheimer's disease and testing its safety on the brain and other internal organs. This study employs bioactive surfactants in the common safe doses to improve PIP targeting to the brain. Selected ME systems encompassed Caproyl 90 (oil)/Tween 80/Cremophor RH 40 (surfactant) and Transcutol HP (co-surfactant). The particle size of the prepared formulations was less than 150 nm with negative zeta potential. The in vivo results showed a superior effect of ME over free PIP. Colchicine-induced brain toxicity results showed the safety of ME on brain cells. Nevertheless, toxicological results showed a potential ME nephrotoxicity. Oral microemulsion increased PIP efficacy and enhanced its delivery to the brain resulting in better therapeutic outcome compared to the free drug. However, the toxicity of this nanosystem should be carefully taken into consideration on chronic use.

Novel piperine-loaded Tween-integrated monoolein cubosomes as brain-targeted oral nanomedicine in Alzheimer's disease: pharmaceutical, biological, and toxicological studies.

Alzheimer's disease (AD) is one of the most patient devastating central nervous system diseases with no curative therapy. An effective oral therapy with brain-targeting potential is required that is hampered by blood-brain barrier. Piperine (PIP) is a natural alkaloid with memory enhancing potentials. Oral PIP delivery suffers from its hydrophobicity and first-pass metabolism. In this study, novel Tween-modified monoolein cubosomes (T-cubs) were elaborated as bioactive nanocarriers for brain-targeted oral delivery of PIP. Seven liquid crystalline nanoparticles (cubosomes) were prepared testing different bioactive surfactants (Tween 80, poloxamer, and Cremophor). Full in vitro characterization was carried out based on particle size, zeta potential, polydispersity index, entrapment efficiency, and in vitro release. Morphological examination and structure elucidation were performed using transmission and polarizing microscopes. Sporadic dementia of Alzheimer's type was induced in 42 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor-α for inflammation. Liver and kidney toxicity studies were conducted as well. Among others, T-cubs exhibited optimum particle size (167.00±10.49 nm), polydispersity index (0.18±0.01), and zeta potential (-34.60±0.47 mv) with high entrapment efficiency (86.67%±0.62%). Cubs could significantly sustain PIP in vitro release. In vivo studies revealed T-cubs potential to significantly enhance PIP cognitive effect and even restore cognitive function to the normal level. Superiority of T-cubs over others suggested brain-targeting effect of Tween. Toxicological studies contended safety of cubs on kidney, liver, and even brain. T-cubs exhibited potential anti-inflammatory and anti-apoptotic activity of loaded PIP, indicating potential to stop AD progression that was first suggested in this article. Novel oral nanoparticles elaborated possess promising in vitro and in vivo characteristics with high safety for effective chronic treatment of AD.

Intranasal Piperine-Loaded Chitosan Nanoparticles as Brain-Targeted Therapy in Alzheimer's Disease: Optimization, Biological Efficacy, and Potential Toxicity.

Piperine (PIP) is a phytopharmaceutical with reported neuroprotective potential in Alzheimer's disease (AD). Oral PIP delivery suffers from its hydrophobicity and pre-systemic metabolism. In this article, mono-disperse intranasal chitosan nanoparticles (CS-NPs) were elaborated for brain targeting of PIP. Formula optimization was based on particle size (PS), zeta potential (ZP), polydispersity index (PDI), % entrapment efficiency (% EE), release studies, and transmission electron microscopy. AD was induced in 48 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor for inflammation. Spherical NPs with optimum % EE (81.70), PS (248.50 nm), PDI (0.24), and ZP (+56.30 mV) were elaborated. PIP-NPs could significantly improve cognitive functions as efficient as standard drug (donpezil injection) with additional advantages of dual mechanism (Ach esterase inhibition and antioxidant effect). CS-NPs could significantly alleviate PIP nasal irritation and showed no brain toxicity. This work was the first to report additional mechanism of PIP in AD via anti-apoptosis and anti-inflammatory effects. To conclude, mucoadhesive CS-NPs were successfully tailored for effective, safe, and non-invasive PIP delivery with 20-folds decrease in oral dose, opening a gate for a future with lower AD morbidity.

Intranasal Piperine-Loaded Chitosan Nanoparticles as Brain-Targeted Therapy in Alzheimer's Disease: Optimization, Biological Efficacy, and Potential Toxicity.

Piperine (PIP) is a phytopharmaceutical with reported neuroprotective potential in Alzheimer's disease (AD). Oral PIP delivery suffers from its hydrophobicity and pre-systemic metabolism. In this article, mono-disperse intranasal chitosan nanoparticles (CS-NPs) were elaborated for brain targeting of PIP. Formula optimization was based on particle size (PS), zeta potential (ZP), polydispersity index (PDI), % entrapment efficiency (% EE), release studies, and transmission electron microscopy. AD was induced in 48 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor for inflammation. Spherical NPs with optimum % EE (81.70), PS (248.50nm), PDI (0.24), and ZP (+56.30mV) were elaborated. PIP-NPs could significantly improve cognitive functions as efficient as standard drug (donpezil injection) with additional advantages of dual mechanism (Ach esterase inhibition and antioxidant effect). CS-NPs could significantly alleviate PIP nasal irritation and showed no brain toxicity. This work was the first to report additional mechanism of PIP in AD via anti-apoptosis and anti-inflammatory effects. To conclude, mucoadhesive CS-NPs were successfully tailored for effective, safe, and non-invasive PIP delivery with 20-folds decrease in oral dose, opening a gate for a future with lower AD morbidity. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3544-3556, 2015.