Non-invasive caffeinated-nanovesicles as adipocytes-targeted therapy for cellulite and localized fats.

Caffeine (CAF) is a non-selective adenosine A1 receptor antagonist which predominates in fat cells. When CAF binds to adenosine receptors, it increases cyclic adenosine monophosphate; inhibiting adipogenesis and inducing fat lipolysis. Resveratrol (RSV) is an antioxidant polyphenol possessing different anti-obesity mechanisms. Topical application of both hydrophilic CAF and lipophilic RSV is limited. This study aimed to develop novel caffeinated-resveratrol bilosomes (CRB) and caffeine-bilosomes (CB) that could non-invasively target and deposit in fat cells. RSV bilosomes (RB) were prepared as a non-targeted system for comparison. CRB showed nanosize (364.1 nm ±6.5 nm) and high entrapment for both active compounds. Rats treated topically with CRB revealed a significant decrease (P = 0.039) in body weight. Histological analysis of the excised skin demonstrated a reduction in the subcutaneous fatty layer thickness and a decrease in the size of connective tissue-imbedded fat cells. Kidney histological examination of RB-treated rats showed subcapsular tubular epithelial cells with cytoplasmic vacuolation. This reflects a systemic effect of RSV from the non-targeted RB compared to CRB, which had a targeting effect on the adipose tissue. In conclusion, CAF in CRB significantly enhanced RSV deposition in adipose tissue and assisted its local-acting effect for managing obesity and cellulite.

Controlled release, chitosan-tethered luteolin phytocubosomes; Formulation optimization to in-vivo antiglaucoma and anti-inflammatory ocular evaluation.

A chitosan-coated luteolin-loaded phytocubosomal system was prepared to improve the pharmacodynamic performance of luteolin in the treatment of glaucoma and ocular inflammation after topical ocular administration. Luteolin, a potent anti-oxidant herbal drug with poor aqueous solubility, was complexed with phospholipid. The prepared phytocubosomes were coated with chitosan, producing homogenously distributed nanosized particles (258 ± 9.05 nm) with a positive charge (+49 ± 6.09 mV), improved EE% (96 %), and increased concentration of encapsulated drug to 288 µg/ml. Polarized light microscopy revealed a cubic phase. Chitosan-coated phytocubosomes showed a sustained drug release profile (38 % over 24 h) and improved anti-oxidant activity (IC50 of 32 µg/ml). Ex vivo transcorneal permeation was higher by 3.60 folds compared to luteolin suspension. Irritancy tests confirmed their safety in ocular tissues after single and multiple administrations. The pharmacodynamic studies on glaucomatous rabbit eyes demonstrated 6.46-, 3.88-, and 1.89-fold reductions in IOP of chitosan-coated phytocubosomes compared to luteolin suspension, cubosomes, and phytocubosomes, respectively. Pharmacodynamic anti-inflammatory studies revealed faster recovery capabilities of chitosan-coated phytocubosomes over other formulations. Thus, chitosan-coated phytocubosomes could be a promising ocular hybrid system for delivering herbal lipophilic drugs such as luteolin.

Novel PEGylated cholephytosomes for targeting fisetin to breast cancer: in vitro appraisal and in vivo antitumoral studies.

Fisetin (FIS) is a multifunctional bioactive flavanol that has been recently exploited as anticancer drug against various cancers including breast cancer. However, its poor aqueous solubility has constrained its clinical application. In the current work, fisetin is complexed for the first time with soy phosphatidylcholine in the presence of cholesterol to form a novel biocompatible phytosomal system entitled "cholephytosomes." To improve fisetin antitumor activity against breast cancer, stearylamine bearing cationic cholephytosomes (mPHY) were prepared and furtherly modified with hyaluronic acid (HPHY) to allow their orientation to cancer cells through their surface exposed phosphatidylserine and CD-44 receptors, respectively. In vitro characterization studies revealed promising physicochemical properties of both modified vesicles (mPHY and HPHY) including excellent FIS complexation efficiency (Ë·100%), improved octanol/water solubility along with a sustained drug release over 24 h. In vitro cell line studies against MDA-MB-231 cell line showed about 10- and 3.5-fold inhibition in IC50 of modified vesicles compared with free drug and conventional drug-phospholipid complex, respectively. Preclinical studies revealed that both modified cholephytosomes (mPHY and HPHY) had comparable cytotoxicity that is significantly surpassing free drug cytotoxicity. TGF-ß1and its non-canonical related signaling pathway; ERK1/2, NF-κB, and MMP-9 were involved in halting tumorigenesis. Thus, tailoring novel phytosomal nanosystems for FIS could open opportunity for its clinical utility against cancer.

Limosomes versus hyalurolimosomes loaded with piperine for management of skin cancer.

Skin cancer is considered the fifth most commonly occurring cancer worldwide hampering both health and economy. Piperine had proven efficacy in fighting skin cancer cells. Unfortunately, this natural agent had limited ability to penetrate the skin. The aim of the current study was to formulate piperine-loaded limosomes and hyalurolimosomes incorporating limonene as an edge activator and hyaluronic acid as bioactive gelling agent for managing skin cancer. Titration method followed by homogenization was adopted to prepare the nanoliposomal formulations. Characterization involved size, & zeta potential measurements, examination using transmission electron microscope (TEM) and stability study. Biological evaluation of the antitumor activity of piperine nanoliposomal formulations against Ehrlich's (EAC) solid tumor was also performed. Drug loaded limosomes and hyalurolimosomes had particle size; 346.55 ± 8.55 & 372.70 ± 10.83 nm, respectively. Zeta potential was high enough to ensure their stability. TEM micrographs detected the surrounding layer of Hyaluronic acid formed around the spherical limosomal nano-carrier ensuring the formation of Hyalurolimosomes. All stored formulations showed non-significant differences compared with freshly prepared ones at p < 0.05. In addition, A DAD-HPLC method was developed and validated for Piperine analysis in the skin. Upon application of this method, it was found that hyalurolimosomes deliver double the concentration delivered by limosomes. The piperine hyalurolimosome group showed a significant reduction in tumor size with a smaller AUC compared to piperine gel, which was confirmed by in vivo studies. Consequently, hyalurolimosomes loaded with piperine is considered a promising nanocarrier system and a step forward better management of skin cancer introducing new hope in beating this deadly disease.

Carrageenan tethered ion sensitive smart nanogel containing oleophytocubosomes for improved ocular luteolin delivery.

Ophthalmic delivery of luteolin (LU) was studied after formulating a carrageenan-based novel ion-sensitive in situ gel (ISG) incorporating oleophytocubosomes for prolonged ocular residence time and improved ocular bioavailability of the poorly absorbed herbal drug luteolin. The prepared oleophytocubosomes and ISG were compared with LU suspension. Optimized oleophytocubosomes possessed small, homogenously distributed negatively charged particles with high entrapment efficiency. Polarized light microscope revealed a cubic phase. Optimized ISG matrix composed of 0.4% kappa carrageenan (KC), and 2% hydroxypropylmethylcellulose (HPMC) demonstrated rapid gelation, high resistance to dilution, increased viscosity after gelation, and strong mucoadhesive properties. oleophytocubosomes exerted improved drug release, while a more sustained release was observed for ISG oleophytocubosomes. The antioxidant activity of both formulations was significantly higher than that of LU suspension. Oleophytocubosome and ISG oleophytocubosome revealed significantly higher apparent permeability coefficients of 3.62 and 2.90 folds, respectively, compared to LU suspension. Irritation tests showed the safety of both formulations for single- and multiple-ocular administration. In-vivo studies demonstrated that the ISG system showed prolonged antiglaucoma effects and a faster anti-inflammatory effect, followed by oleophytocubosomes.

Self-assembled fisetin-phospholipid complex: Fisetin-integrated phytosomes for effective delivery to breast cancer.

Nowadays, fisetin (FIS) is extensively studied as potent anticancer surrogate with a multitarget actions against various types of cancers including breast cancer. However, its poor aqueous solubility handicapped its clinical utility. The current work endeavored, for the first time, to develop FIS phytosomes (FIS-PHY) for improving its physicochemical properties and subsequently its anticancer activity. Optimization of FIS- phytosomes involved different preparation techniques (Thin film hydration and ethanol injection) and different FIS: phospholipid molar ratios (1:1, 1:2, and 1:3). Complex formation was confirmed by complexation efficiency, infrared spectroscopy (IR), solubility studies and transmission electron microscope. The optimized FIS-PHY of 1:1 M ratio (PHY1) exhibited a nanometric particle size of 233.01 ± 9.46 nm with homogenous distribution (PDI = 0.27), negative zeta potential of - 29.41 mV, 100% complexation efficiency and controlled drug release over 24 h. In-vitro cytotoxicity study showed 2.5-fold decrease in IC50 of PHY1 compared with free FIS. Also, pharmacodynamic studies confirmed the promoted cytotoxicity of PHY1 against breast cancer through modulating TGF-ß1/MMP-9 molecular pathways of tumorigenesis. Overall, overcoming FIS drawbacks were successfully achieved through development of innovative biocompatible phytosomal system.

Fucoidan/hyaluronic acid cross-linked zein nanoparticles loaded with fisetin as a novel targeted nanotherapy for oral cancer.

Fisetin (FS) is an anticancer drug having potential role in oral tumors management. However, its clinical application is limited due to its hydrophobicity and instability. Bioactive polymers-based nanosystems have a great potential in cancer therapy. Herein, different biopolymers were selected for their anticancer activity and targeting ability for nanoparticles preparation namely; fucoidan (FU), zein (Zn) and hyaluronic acid (HA). The selected FS-loaded cross-linked Zn nanoparticles (ZFH) which contains HA& FU for Zn nanoparticles stabilization showed the most suitable particle size (196 ± 6.53 nm), mean surface net charge (-38.8 ± 1.47 mV) and entrapment efficiency (98 ± 1.2 %). This is the first study to utilize both HA &FU not only for stabilization but also for dual targeting effect due to their targeting ability to multiple tumor targets. In-vitro anticancer activity of ZHF revealed remarkable uptake by SCC-4 cells with significant cytotoxic action. Further, ZHF was appraised using 4-nitroquinoline 1-oxide (4-NQO)-induced oral cancer in-vivo; ZHF significantly reduced OSCC-specific serum biomarkers levels, histologic tumor grade and increased caspase-3 level. Moreover, potential of destroying two key tumor regulatory cells; TECs and CSCs, was evaluated using their specific markers. The elaborated ZFH nanoparticles could be considered as promising targeted nanotherapy for oral cancer treatment with enhanced efficacy and survival rate.

Pectin coated nanostructured lipid carriers for targeted piperine delivery to hepatocellular carcinoma.

Piperine (PIP) is a herbal drug with well-known anticancer activity against different types of cancer including hepatocellular carcinoma. However, low aqueous solubility and extensive first-pass metabolism limit its clinical use. In this study, positively charged PIP-loaded nanostructured lipid carriers (PIP-NLCs) were prepared via melt-emulsification and ultra-sonication method followed by pectin coating to get novel pectin-coated NLCs (PIP-P-NLCs) targeting hepatocellular carcinoma. Complete in vitro characterization was performed. In addition, cytotoxicity and cellular uptake of nanosystems in HepG2 cells were evaluated. Finally, in vivo anticancer activity was tested in the diethylnitrosamine-induced hepatocellular carcinoma mice model. Successful pectin coating was confirmed by an increased particle size of PIP-NLCs from 150.28 ± 2.51 nm to 205.24 ± 5.13 nm and revered Zeta potential from 33.34 ± 3.52 mV to -27.63 ± 2.05 mV. Nanosystems had high entrapment efficiency, good stability, spherical shape, and sustained drug release over 24 h. Targeted P-NLCs enhanced the cytotoxicity and cellular uptake compared to untargeted NLCs. Furthermore, PIP-P-NLCs improved in vivo anticancer effect of PIP as proved by histological examination of liver tissues, suppression of liver enzymes and oxidative stress environment in the liver, and alteration of cell cycle regulators. To conclude, PIP-P-NLCs can act as a promising approach for targeted delivery of PIP to hepatocellular carcinoma.

Novel berberine-loaded hyalurosomes as a promising nanodermatological treatment for vitiligo: Biochemical, biological and gene expression studies.

Vitiligo is a depigmentation disorder that affects 0.5-2% of the world population. It has a severe impact on a patient's quality of life and even causes suicidal attempts. Up to date, no curative therapy is available which have created a substantial demand for novel vitiligo treatments. Berberine (BRB) is an isoquinoline alkaloid with promising pharmacological effects. However, it suffers from poor membrane permeability hindering its topical application. The current work is the first to design and assess topical BRB-loaded hyalurosomes for targeted vitiligo treatment. BRB-hyalurosomes are hyaluronan-immobilized phospholipid nanovesicles that showed promising invitro physicochemical properties. Novel ex vivo studies were performed using full-thickness human skin to mimic its dermal application. Furthermore, in-vivo studies were conducted using a vitiligo-induced mouse model followed by biochemical, histological and immunohistochemical investigations. In addition, gene expression of skin inflammatory markers was assessed using quantitative reverse-transcription PCR. Biological studies showed significant improvement of the biochemical markers in BRB-hyalurosomes group compared to the vitiligo-model group and BRB conventional gel. It is worthy to mention that placebo hyalurosomes demonstrated significant enhancement in the biological activity confirming its intrinsic activity. Conclusively, BRB-hyalurosomes is considered a novel nanodermatological tool that paving the way for its clinical application for vitiligo treatment.

Nanoemulsomes for Enhanced Oral Bioavailability of the Anticancer Phytochemical Andrographolide: Characterization and Pharmacokinetics.

Andrographolide (AG) is an antitumor phytochemical that acts against non-Hodgkin's lymphoma. However, AG shows low oral bioavailability due to extensive first-pass metabolism and P-glycoprotein efflux. Novel biocompatible lipoprotein-simulating nanosystems, emulsomes (EMLs), have gained significant attention due to their composition of natural components, in addition to being lymphotropic. Loading AG on EMLs is believed to mitigate the disadvantage of AG and enhance its lymphatic transport. This study developed a chylomicron-simulating system (EMLs) as a novel tool to overcome the AG oral delivery obstacles. Optimized EML-AG had a promising vesicular size of 281.62 ± 1.73 nm, a zeta potential of - 22.73 ± 0.06 mV, and a high entrapment efficiency of 96.55% ± 0.25%, which favors lymphatic targeting. In vivo pharmacokinetic studies of EML-AG showed significant enhancement (> sixfold increase) in the rate and extent of AG absorption compared with free AG. However, intraperitoneal injection of a cycloheximide inhibitor caused a significant decrease in AG absorption (~ 52%), confirming the lymphatic targeting potential of EMLs. Therefore, EMLs can be a promising novel nanoplatform for circumventing AG oral delivery obstacles and provide targeted delivery to the lymphatic system at a lower dose with fewer side effects.

Novel rhein integrate transphytosomes as non-invasive local therapy for osteoarthritis to ameliorate cartilage deterioration in MIA-arthritic rats.

Rhein (RH), a natural chondroprotective agent, suffers from poor systemic availability (20-25%) after oral administration concomitant to side effects on the gastrointestinal tract and liver. We present a new approach for non-invasive local targeted delivery of rhein to ameliorate cartilage deterioration employing cartilage-homing phospholipids nanocarriers. This is the first work to elaborate RH loaded transphytosome (RH-T-PHY) as novel nanovesicular systems for transdermal drug delivery based on an advantageous hybrid between phytosomes and transfersomes or bilosomes. Here, we developed transphytosomes through incorporating various edge activators (EAs) such as Tween 80, Span 80 and sodium deoxycholate into the lipid bilayer of RH phytosomes to affix the flexibility. RH-T-PHY with high flexibility and entrapment efficacy showed the highest significant skin permeation compared to conventional phytosomes. Additionally, RH-T-PHY have a magnificent potential in maintaining high chondroprotective activity as demonstrated by enhanced repair, regeneration of chondrocytes and GAG formation in MIA-induced osteoarthritis (OA) rat model. Besides, histological examination of vital organs revealed the formulation safety. Confocal laser microscopy images revealed the highest drug availability in the articular cartilage of RH-T-PHY treated group. Conclusively, novel RH-T-PHY can serve as a promising alternative means for delivery of chondroprotective drugs for effective non-invasive local therapy of OA.

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.

Novel rhein-phospholipid complex targeting skin diseases: development, in vitro, ex vivo, and in vivo studies.

Rhein (RH), an anthraquinone derivative, has proven to be a promising molecule for treating several skin disorders thanks to its pleiotropic pharmacological activities like antimicrobial, antifungal, antioxidant, and anticancer. However, RH's low water and oil solubility and poor skin permeability halted its topical delivery. This is the first work to investigate the expediency of tailoring a rhein-phospholipid complex (RH-PLC) to improve RH challenging physicochemical and skin permeability properties. The phospholipid complex was prepared by employing different methods and different RH/PL molar ratios. RH-PLC was successfully developed at a stoichiometric ratio of 1:1 using a novel pH-dependent method where at a certain pH, it exhibits the highest complexation efficiency (95%). RH-PLC formation was confirmed using FTIR, DSC, and XRPD analysis. RH-PLC showed a significant increase in water and n-octanol solubility. RH-PLC was self-assembled upon dispersion into water forming nano-sized particles (196.6 ± 1.6 nm) with high negatively charged surface (- 29.7 ± 2.45 mV). RH-PLC exhibited a significant 3.3- and 2.46-fold increase in ex vivo and in vivo skin permeability when compared with RH suspension, respectively. Confocal microscopy study confirmed the ability of RH-PLC to penetrate deeply into rat skin. Besides, skin irritation test on healthy rats indicated compatibility and safety of RH-PLC. Conclusively, phospholipid complex might be a suitable approach to improve permeability of RH and other promising abandoned poor-permeable drugs. The proposed RH-PLC is expected to be a major progressive step toward the development of a topical RH formulation. Graphical abstract.

Oleosomes Encapsulating Sildenafil Citrate as Potential Topical Nanotherapy for Palmar Plantar Erythrodysesthesia with High Ex vivo Permeation and Deposition.

Palmar plantar erythrodysesthesia (PPE) is a commonly reported skin toxicity of chemotherapeutic agents that significantly affects patients' quality of life. PPE is described as inflammation, swelling, and even cracks and ulcers in the skin of palms and soles of the feet. Conventional treatment includes topical creams, analgesics, or corticosteroids. However, serious cases are not responding to these medications. PPE has been reported to cause drug cessation or dose reduction if not properly treated. Sildenafil citrate (SC) has a well-documented activity in wound healing through improving blood supply to the affected area. However, SC has poor physicochemical properties limiting its transdermal permeation and deposition. This research endeavored to elaborate novel vesicular system with natural components, phospholipids and oleic acid, loaded with sildenafil citrate for topical management of PPE. Sildenafil-loaded oleosomes were prepared using modified ethanol injection method. Optimized oleosomes had nanometric particle size (157.6 nm), negative zeta potential (- 85.2 mv), and high entrapment efficiency (95.56%). Ex vivo studies on human skin revealed that oleosomes displayed 2.3-folds higher permeation and 4.5-folds more deposition through the human skin compared to drug suspension. Results endorsed SC oleosomes as suitable topical treatment of PPE providing ameliorated sildenafil permeability in addition to acting as a reservoir for gradual release of the drug. Graphical abstract.

High efficacy, rapid onset nanobiolosomes of sildenafil as a topical therapy for erectile dysfunction in aged rats.

Developing topical sildenafil for local treatment of erectile dysfunction has been of great interest in pharmaceutical research. Sildenafil citrate (SC) exhibited a well-documented success for treatment of several types of erectile dysfunction. However, its oral use is limited by serious adverse effects, poor bioavailability, delayed onset, and drug-drug interactions. This work is the first to design and assess sildenafil-loaded bilosomes for topical local treatment of erectile dysfunction. Different sildenafil-loaded bilosomes were prepared and characterized. Permeability of selected formulations was conducted through full-thickness human skin. Optimized bilosomes integrating sodium tauroglycocholate (STGC) showed spherical shape with good particle size (133 nm), high zeta potential (-53.6 mV) and high entrapment efficiency (87.45%). Ex-vivo permeability study revealed that about 39% of the applied dose permeated within 15 min. Furthermore, in-vivo appraisal of therapeutic efficacy was performed using aged male Sprague-Dawley rats. After single application of 2 mg/kg sildenafil loaded in STGC-bilosomes, behavioral and biochemical evaluation was carried out. Behavioral assessment recorded an increased rats' potency manifested as 2 folds increase in intromission frequency and intromission ratio compared to untreated group. That was accompanied by significant increase in cGMP concentration in corpora cavernosa (P < 0.0001) confirming increased potency. In conclusion, STGC-bilosomes could provide topical treatment of impotence with 20% of the oral dose and fast onset of action (10 min).

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.

Current strategies for different paclitaxel-loaded Nano-delivery Systems towards therapeutic applications for ovarian carcinoma: A review article.

Ovarian carcinoma (OC) is one of the leading causes of death among gynecologic malignancies all over the world. It is characterized by high mortality rate because of the lack of early diagnosis. The first-line chemotherapeutic regimen for late stage epithelial ovarian cancer is paclitaxel in combination to carboplatin. However, in most of cases, relapse occurs within six months despite the initial success of this chemotherapeutic combination. A lot of challenges have been encountered with the conventional delivery of paclitaxel in addition to the occurrence of severe off-target toxicity. One major problem is poor paclitaxel solubility which was improved by addition of Cremophor EL that unfortunately resulted in hypersensitivity side effects. Another obstacle is the multi drug resistance which is the main cause of OC recurrence. Accordingly, incorporation of paclitaxel, solely or in combination to other drugs, in nanocarrier systems has grabbed attention of many researchers to circumvent all these hurdles. The current review is the first article that provides a comprehensive overview on multi-faceted implementations of paclitaxel loaded nanoplatforms to solve delivery obstacles of paclitaxel in management of ovarian carcinoma. Moreover, challenges in physicochemical properties, biological activity and targeted delivery of PTX were depicted with corresponding solutions using nanotechnology. Different categories of nanocarriers employed were collected included lipid, protein, polymeric, solid nanoemulsion and hybrid systems. Future perspectives including imperative research considerations in ovarian cancer therapy were proposed as well.