A novel combination for the treatment of small cell lung cancer: Active targeted irinotecan and stattic co-loaded PLGA nanoparticles.

Polymeric nanoparticles are widely used drug delivery systems for cancer treatment due to their properties such as ease of passing through biological membranes, opportunity to modify drug release, specifically targeting drugs to diseased areas, and potential of reducing side effects. Here, we formulated irinotecan and Stattic co-loaded PLGA nanoparticles targeted to small cell lung cancer. Nanoparticles were successfully conjugated with CD56 antibody with a conjugation efficiency of 84.39 ± 1.01%, and characterization of formulated nanoparticles was conducted with in-vitro and in-vivo studies. Formulated particles had sizes in the range of 130-180 nm with PDI values smaller than 0.3. Encapsulation and active targeting of irinotecan and Stattic resulted in increased cytotoxicity and anti-cancer efficiency in-vitro. Furthermore, it was shown with ex-vivo biodistribution studies that conjugated nanoparticles were successfully targeted to CD56-expressing SCLC cells and distributed mainly to tumor tissue and lungs. Compliant with our hypothesis and literature, the STAT3 pathway was successfully inhibited with Stattic solution and Stattic loaded nanoparticles. Additionally, intravenous injection of conjugated co-loaded nanoparticles resulted in decreased side effects and better anti-tumor activity than individual solutions of drugs in SCLC tumor-bearing mice. These results may indicate a new treatment option for clinically aggressive small cell lung cancer.

Effects of Particle Geometry for PLGA-Based Nanoparticles: Preparation and In Vitro/In Vivo Evaluation.

The physicochemical properties (size, shape, zeta potential, porosity, elasticity, etc.) of nanocarriers influence their biological behavior directly, which may result in alterations of the therapeutic outcome. Understanding the effect of shape on the cellular interaction and biodistribution of intravenously injected particles could have fundamental importance for the rational design of drug delivery systems. In the present study, spherical, rod and elliptical disk-shaped PLGA nanoparticles were developed for examining systematically their behavior in vitro and in vivo. An important finding is that the release of the encapsulated human serum albumin (HSA) was significantly higher in spherical particles compared to rod and elliptical disks, indicating that the shape can make a difference. Safety studies showed that the toxicity of PLGA nanoparticles is not shape dependent in the studied concentration range. This study has pioneering findings on comparing spherical, rod and elliptical disk-shaped PLGA nanoparticles in terms of particle size, particle size distribution, colloidal stability, morphology, drug encapsulation, drug release, safety of nanoparticles, cellular uptake and biodistribution. Nude mice bearing non-small cell lung cancer were treated with 3 differently shaped nanoparticles, and the accumulation of nanoparticles in tumor tissue and other organs was not statistically different (p > 0.05). It was found that PLGA nanoparticles with 1.00, 4.0 ± 0.5, 7.5 ± 0.5 aspect ratios did not differ on total tumor accumulation in non-small cell lung cancer.

Design of Besifloxacin HCl-Loaded Nanostructured Lipid Carriers: In Vitro and Ex Vivo Evaluation.

Objective: In the treatment of severe cases of bacterial keratitis, conventional eye drops containing antibiotics should be applied daily and very frequently. The aim of this study is to develop low-dose high-effect formulations with the prepared nanostructured lipid carrier (NLC) formulations to reduce antibiotic resistance and increase patient compliance. Methods: NLC formulations were loaded with besifloxacin HCl (BHL) and the besifloxacin HCl: sulfobutyl ether beta-cyclodextrin (SBE-CD) complex. Positive charge was gained with chitosan, and corneal permeation and resolubility were increased with SBE-CD. In vitro characterization studies, permeability studies, and cytotoxicity and ex vivo transport studies were carried out. Results: In this study, it was found that SBE-CD increased BHL's solubility by 8-fold based on phase solubility studies. The optimized NLCs were small in size (13.63-16.09 nm) with a low polydispersity index (0.107-0.181) and adequate BHL drug loading efficiency. In vitro release studies showed that formulations were released approximately for 8 h and at levels over the minimum inhibitory concentration of Pseudomonas aeruginosa and Staphylococcus aureus. NLC formulations had a better corneal permeation rate than the marketed product during 6 h of ex vivo studies. Conclusions: According to in vitro and ex vivo data, it was determined that the most favorable NLC formulation was the formulation containing BHL/SBE-CD that was covered with chitosan. It has the highest drug loading capacity and one of the highest ex vivo corneal passage levels, along with desired drug release. The formulation containing BHL/SBE-CD and chitosan can be a potential alternative for the treatment of bacterial keratitis.

Novel Drug Delivery Systems to Improve the Treatment of Keratitis.

Keratitis is a disease characterized by inflammation of the cornea caused by different pathogens. It can cause serious visual morbidity if not treated quickly. Depending on the pathogen causing keratitis, eye drops containing antibacterial, antifungal, or antiviral agents such as besiloxacin, moxifloxacin, ofloxacin, voriconazol, econazole, fluconazole, and acyclovir are used, and these drops need to be applied frequently due to their low bioavailability. Studies are carried out on formulations with extended residence time in the cornea and increased permeability. These formulations include various new drug delivery systems such as inserts, nanoparticles, liposomes, niosomes, cubosomes, microemulsions, in situ gels, contact lenses, nanostructured lipid carriers, carbon quantum dots, and microneedles. Ex vivo and in vivo studies with these formulations have shown that the residence time of the active substances in the cornea is prolonged, and their ocular bioavailability is increased. In addition, in vivo studies have shown that these formulations successfully treat keratitis. However, it has been observed that fluoroquinolones are used in most of the studies; similar drug delivery systems are generally preferred for antifungal drugs, and studies for viral and acanthameba keratitis are limited. There is a need for new studies on different types of keratitis and different drug active substances. At the same time, proving the efficacy of drug delivery systems, which give promising results in in vivo animal models, with clinical studies is of great importance for progress in the treatment of keratitis.

Mixed micelles formulation for carvedilol delivery: In-vitro characterization and in-vivo evaluation.

Carvedilol (CAR) is a widely studied, beta and alpha-1 blocker, antihypertensive drug due to its poor water solubility and low oral bioavailability (25-35%). The aim of this work is to improve poor water solubility and the pharmacokinetic parameters of carvedilol by using an optimized and self-assembly prepared micelle formulation. Optimized micelle formulation composed of Pluronic® F127, D-α-tocopheryl polyethylene glycol 1000 succinate, L-cysteine HCl in a ratio of 4:3:3. Micellar size, polydispersity index, zeta potential, morphology, critical micelle concentration, thermal behaviors, in-vitro dissolution of micelles and pharmacokinetic parameters in rats were characterized in this study. Carvedilol aqueous solubility increased (up to 271-fold) as a result of its encapsulation within a mixed micelle formulation. The measured micellar sizes of blank and carvedilol loaded mixed micelles are lower than 30 nm with size distributions of 26.69 ±â€¯2.93 nm and 24.16 ±â€¯4.89 nm, respectively. Transmission electron microscopy revealed that the micelles were spherically shaped. There is a significant enhancement of carvedilol dissolution compared to commercially available tablet formulation (f2 < 50). The in-vivo test demonstrated that the t1/2 and AUC0-∞ values of micelles were approximately 10.89- and 2.65-fold greater than that of the commercial tablets, respectively. Based on our study, bring such applications into being may provide effective new drugs for treatment armamentarium of cardiovascular diseases and hypertension in near future.

Antibody-mediated drug delivery.

Passive and active targeted nanoparticulate delivery systems show promise to compensate for lacking properties of conventional therapy such as side effects, insufficient efficiency and accumulation of the drug at target site, poor pharmacokinetic properties etc. For active targeting, physically or covalently conjugated ligands, including monoclonal antibodies and their fragments, are consistently used and researched for targeting delivery systems or drugs to their target site. Currently, there are several FDA approved actively targeted antibody-drug conjugates, whereas no active targeted delivery system is in clinical use at present. However, efforts to successfully formulate actively targeted delivery systems continue. The scope of this review will be the use of monoclonal antibodies and their fragments as targeting ligands. General information about targeted delivery and antibodies will be given at the first half of the review. As for the second half, fragmentation of antibodies and conjugation approaches will be explained. Monoclonal antibodies and their fragments as targeting ligands and approaches for conjugating these ligands to nanoparticulate delivery systems and drugs will be the main focus of this review, polyclonal antibodies will not be included.

Development and evaluation of polymeric micelle containing tablet formulation for poorly water-soluble drug: tamoxifen citrate.

Poor aqueous solubility is one of the key reasons for slow dissolution rate and poor intestinal absorption and finally that causes low therapeutic efficacy of many existing drugs. Tamoxifen citrate (TMX) (BCS Class II drug) with low water solubility has poor oral bioavailability in the range of 20%-30%, therefore, high doses are required for treatment with TMX. Self-assemblage of amphiphilic polymers leads to the formation of polymeric micelles which makes them unique nano-carriers with excellent biocompatibility, low toxicity, enhanced blood circulation time, and solubilization of poorly water-soluble drugs. In this study poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) triblock copolymer, which has been approved by FDA for oral application was used to benefit its micellar solubilization effect. Self-assembled micelles were prepared for the delivery of TMX and this way TMX solubility was increased approximately 60 times. TMX-treated cells showed 38.06 ± 1.5% viability at 50 µM concentration for 24 h; 66.71 ± 11.6% viability at 25 µM concentration for 48 h, at the same conditions TMX-loaded micelles exhibited 24.994 ± 0.25% and 43.36 ± 4.37% cell viability, respectively (p < 0.05). These results showed that the encapsulation of TMX into PEG-PPG-PEG micelles facilitated the cellular uptake, which led to an increased cytotoxicity in MCF-7 cancer cells. Tablet formulation containing lyophilized TMX-loaded micelles was showed an improved dissolution than commercial TMX tablet (Tamoxifen® TEVA). It can be reasonably expected that the obtained drug dissolution rate and increased cytotoxicity to tumor cells will result in an increase of TMX bioavailability and tolerability associated with an important dose reduction and decreased side effects.

Development of besifloxacin HCl loaded nanofibrous ocular inserts for the treatment of bacterial keratitis: In vitro, ex vivo and in vivo evaluation.

Novel drug delivery systems have emerged to treat bacterial keratitis, an acute infection of the cornea. In this study, besifloxacin HCl loaded insert formulations were designed and investigated in vitro, ex vivo and in vivo for the treatment of bacterial keratitis. Besifloxacin HCl (BH) or BH-hydroxypropyl-beta-cyclodextrin (HP-ß-CD) complex containing poly(caprolactone)/polyethylene glycol (PLC/PEG) fibrous inserts were prepared with an electrospinning method. These fibrous inserts were coated with mucoadhesive polymers such as sodium alginate (SA) or thiolated sodium alginate (TSA). Developed inserts compared to commercially available drug and it was found that coating of the insert surfaces with SA and TSA, increases bioadhesion of the formulations. Insert formulations showed a burst release in the first 2 days followed by a slow-release profile. Ex vivo transport studies showed that HP-ß-CD possessed a drug delivery level close to the commercial drug. Both TSA coated inserts as well as inserts containing HP-ß-CD-drug complex were effectively reducing bacterial keratitis in rabbit eyes upon single-dose application compared to multiple dosing with the commercial drug. Consequently, TSA coated inserts as well as the inserts containing HP-ß-CD-drug complex, may be potential alternatives to conventional market product by reducing the application frequency in the clinic leading to increased patient compliance.

Design of ocular drug delivery platforms and in vitro - in vivo evaluation of riboflavin to the cornea by non-interventional (epi-on) technique for keratoconus treatment.

AIM: Keratoconus is a common and progressive eye disease characterized by thinning and tapering of the cornea. This degenerative eye disease is currently treated in the clinic with an interventional technique ("epi-off") that can cause serious side effects as a result of the surgical procedure. The aim of this project is to design innovative formulations for the development of a riboflavin-containing medicinal product to develop a non-invasive ("epi-on") keratoconus treatment as an alternative to current treatment modalities. METHODS: Nanostructured lipid carriers (NLCs) were successfully loaded with either riboflavin base of riboflavin-5-phosphate sodium and designed with either Stearylamine (positive charge) or Trancutol P (permeation enhancer). In vitro characterization studies, cytotoxicity and permeability studies were performed. Selected formulations and commercial preparations were applied and compared in ex-vivo corneal drug accumulation and transition studies. Furthermore, in vivo studies were performed to assess drug accumulation in the rat cornea and the corneal stability after NLC treatment was investigated via a biomechanical study on isolated rabbit corneas. RESULTS: Both in vitro and ex-vivo as well as in vivo data showed that from the prepared NLC formulations, the most effective formulation was riboflavin-5-phosphate sodium containing NLC with Transcutol P as permeation enhancer. It possessed the highest drug loading content, low accumulation in the cornea but high permeability through the cornea as well as the highest functional performance in corneal crosslinking. CONCLUSION: Topical application of riboflavin-5-phosphate sodium loaded NLC systems designed with permeation enhancer Transcutol P may act as a potential alternative for non-invasive keratoconus treatments.

Aggregation of chitosan nanoparticles in cell culture: Reasons and resolutions.

Nanoparticles are promising drug delivery systems which are flexible for targeting specific tissues to reduce therapeutic doses and minimize side effects. Nanoparticles should be maintained with high stability and uniformity; however, aggregation is a major challenge which commonly impairs stability and efficacy of nanocarriers. In this study, we revisited the factors that influence the stability of chitosan (Protasan™ UP CL113) nanoparticles prepared with ionotropic gelation, widely recognized to be prone to aggregation, and proposed a model to overcome the negative influence of aggregation while testing in vitro efficacy. Decrease in pH due to cell proliferation, 37 °C cell culture temperature, serum in culture media, and incubation time were considered as factors causing chitosan nanoparticles' aggregation which deteriorates cell culture assay readouts, increases optical density values and leads to false-positive results. Size and stability studies were not sufficient to avoid misleading results in cell culture. The chitosan nanoparticle aggregation was almost inevitable under standard culture conditions; nevertheless, the removal of nanoparticles before aggregation but after an incubation period long enough for efficient cellular uptake was determined as a feasible and inexpensive method for testing the in vitro efficacy of polymeric nanoformulations. This approach was used with blank and gemcitabine-loaded chitosan nanoparticles on pancreatic cancer cells and proved to be useful for reliable cytotoxicity results.

Current Advances in Nanopharmaceuticals.

Nanotechnology is one of the hot topics not only in pharmaceutical industry, but also in many others that are currently existing in our daily lives. Since the last two decades, many nanotechnology based drugs have been introduced in the market providing new and optimized treatment perspectives. In addition to that, local regulatory authorities also meet new challenging issues regarding the development process of the nanopharmaceuticals. It is a clear fact that the novelty of nanopharmaceuticals also include a more precise clarification process on the efficacy and safety of the formulations for the benefit of public health. Therefore, current scientific improvements as well as current regulatory perspectives are reflected in this review.

Tumor-Induced Myeloid Cells Are Reduced by Gemcitabine-Loaded PAMAM Dendrimers Decorated with Anti-Flt1 Antibody.

While reshaping their microenvironment, tumors are also capable of influencing systemic processes including myeloid cell production. Therefore, the tumor-induced myeloid cells, such as myeloid-derived suppressor cells (MDSCs), which are characterized with pro-cancer properties, became another target in order to increase the success of the therapy. This study evaluated the capacity of a novel dendrimeric drug delivery platform to eliminate tumor-induced myeloid cells. As described in a previous study by our research group, the anti-Flt1 antibody-conjugated polyethylene glycol (PEG)-cored poly(amidoamine) (PAMAM) dendrimers improved the efficacy of gemcitabine against pancreatic cancer. Here, the biodistribution studies showed that these dendrimeric structures accumulated in the compartments that became rich in myeloid cells in the pancreatic tumor-bearing mice. When gemcitabine was loaded into the dendrimer complexes, the number of myeloid cells was significantly reduced while the percentage distribution of granulocytic and monocytic myeloid cells was not always significantly altered. The CD11b+Ly6G-Ly6C+ monocytes were more severely affected by the treatments than CD11b+Ly6G+Ly6C+ granulocytes. Immune infiltration levels in the tumor tissue were also altered. Myeloid cells in the spleen and F4/80+ macrophages of the liver were protected. The compartments, such as the liver and the bone marrow, which are known to have high vascular endothelial growth factor (VEGF)-Flt1 pathway activity, were particularly targeted by gemcitabine when delivered through anti-Flt1 antibody-conjugated PAMAM dendrimers. In conclusion, chemotherapeutic agents complexed with dendrimers not only improve anticancer efficacy, but they also assist in the elimination of the tumor-induced myeloid cells.

Design and in vitro evaluation of tenofovir-loaded vaginal gels for the prevention of HIV infections.

Infection with the human immunodeficiency virus (HIV) is affecting women disproportionally with increasing incidence rates over the last decades. Tenofovir is one of the most commonly used antiretroviral agents, which belongs to the nucleoside/nucleotide reverse transcriptase inhibitor family, for the prevention of HIV acquisition. In scope of this study, a thermogelling system containing tenofovir-loaded chitosan nanoparticles for the controlled release of tenofovir was developed and characterized. The in vitro release studies have shown that the burst release effect was decreased to 27% with f-TFV CS NPs-Gel. Gelation temperature of developed formulation was found as 26.6 ± 0.2 °C, which provides ease of administration while gelation occurs after the administration to the vagina. The work of adhesion values was used as parameters for comparison of mucoadhesive performance and the mucoadhesion of f-TFV CS NPs-Gel was found as 0.516 ± 0.136 N.s at 37 °C. The biocompatibility of blank formulations was evaluated by cell viability studies using L929 cells, in which Gel + CS NPs formulation was found to be safe with 82.4% and 90.2% cell viability for 1:16 and 1:32 dilutions, respectively. In conclusion, an improved tenofovir containing vaginal gel formulation was successfully developed and evaluated for preventing HIV transmission.

Novel advances in targeted drug delivery.

Developing a new drug molecule is not only time-consuming and expensive, but also mostly a failing process. However, improving bioavailability, targetability, efficacy or safety of old drugs could be more effective way to use them in clinic. For these purposes, so many strategies including individualising drug therapy, nanoparticle-based drug delivery systems, drug conjugates, therapeutic drug monitoring, stimuli-sensitive targeted therapy are investigated intensely. Depending on the desired application or targeted site, nanoparticles can be administrated as orally, locally, topically and systemically. Currently, the Food and Drug Administration and the European Medicines Agency approved nanoparticles are mostly aimed to treat cancer. Although some of these formulations were approved by Food and Drug Administration and/or European Medicines Agency to use in clinic, most of them have fell down to pass either pre-clinical or clinical trials. To have high approval rate, failure reasons need to be better understand.

Preparation and in vitro evaluation of 5-fluorouracil-loaded PCL nanoparticles for colon cancer treatment.

Nanoparticles loaded with 5-fluorouracil (5-FU) for colon cancer therapies were prepared using the solvent evaporation technique, which involved lyophilization by freeze-drying. Formulations produced a substantially high encapsulation efficiency of approximately 93%. A positive correlation was seen when increasing polycaprolactone (PCL) and/or PVA concentrations and the size of nanoparticles produced. Increasing PCL concentration had a considerable influence on PDI while increasing PVA concentration had a lesser effect. All nanoparticles possessed a negative zeta potential, particularly in formulations with low polymer and polymer emulsifier concentrations. The formulation with the lowest PCL and PVA concentration was characterized by the most optimal properties; which accounts for the desirable delayed release profile of the active drug in dissolution testing indicating an improved targeting capability and enhanced bioavailability at the action site. Cytotoxicity studies showed that 5-FU loaded PCL nanoparticles had higher antiproliferative effect than free 5-FU on Caco-2 cell line (p < 0.05). The encouraging results obtained offer reasons for optimism regarding the future of 5-FU nanoparticles as a promising drug delivery system which could be further improved by including either enteric coating or encapsulating the nanoparticles onto microparticles to overcome unanticipated degradation.

Design and evaluation of gamma-sterilized vancomycin hydrochloride-loaded poly(ɛ-caprolactone) microspheres for the treatment of biofilm-based medical device-related osteomyelitis.

CONTEXT: There is a great necessity to find and use accomplished terminal sterilization technique for industrial manufacturing, research and development studies. Gamma (γ)-sterilization has been commonly employed for wide range of products as indicated by the pharmacopoeias. However, carefully examination should be performed prior to administration since γ-radiation can cause changes in drug and polymer excipients. No information is available in literature about γ-sterilization effects on vancomycin HCl-loaded poly (ɛ-caprolactone) (PCL) microspheres. OBJECTIVE: Formulations were developed using a different preparation approach for the treatment of medical device-related osteomyelitis, and γ-sterilization effects on the physicochemical characterization of the formulations were examined. METHODS: Water-in-oil-in-water (w/o/w) emulsion technique using polyvinyl alcohol (PVA) in inner and outer phase was applied to prepare formulations. Physicochemical properties of the formulations were investigated before and after γ-sterilization and the antibacterial activity against Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis) were measured. RESULTS: The particle size of the nonsterilized formulations were between 58 and 134 µm. 60% or 20% of vancomycin HCl were released from 42.500 Mn or 70.000-90.000 Mn PCL microspheres, respectively, in 24 h. No difference was observed in the particle size, drug-loading efficiency, morphology, in vitro release and antimicrobial activity of the formulations after γ-sterilization (p > 0.05).

Effective targeting of gemcitabine to pancreatic cancer through PEG-cored Flt-1 antibody-conjugated dendrimers.

Tumor-targeted delivery of anticancer drugs using dendrimers has been recognized as a promising strategy to increase efficiency and reduce adverse effects of chemotherapy. Herein, we developed a dendrimer-based drug delivery system targeting Flt-1 (a receptor for vascular endothelial growth factors (VEGF)) receptor to improve therapeutic efficacy of gemcitabine in pancreatic cancer. Synthesized polyethylene glycol (PEG)-cored PAMAM dendrimers, which bear anionic carboxylic acid groups on the surface were modified with PEG chains, which were then conjugated with Flt-1 antibody. Following structural and chemical characterization studies, gemcitabine HCl-dendrimer inclusion complexes were successfully prepared. These complexes were efficiently engulfed by Flt-1 expressing pancreatic cancer cells, which enhanced the cytotoxicity of gemcitabine. Moreover, pancreatic tumors established in mice were highly targeted by PEG-cored Flt-1 antibody-conjugated dendrimers and increased accumulation of these gemcitabine-loaded complexes exhibited satisfactory in vivo anti-cancer efficacy. In conclusion, dendrimer-based targeted delivery of chemotherapeutics may serve as a promising approach for the treatment of malignancies such as pancreatic cancer that do not benefit from conventional chemotherapy.

Cytotoxicity and biodistribution studies on PEGylated EDA and PEG cored PAMAM dendrimers.

Starting from Ethylenediamine (EDA) or poly(ethylene glycol) tetra amine (4-arm-PEG) cores, two different peripheral methylester (-COOCH3) or amine (-NH2) PAMAM dendrimers have been synthesized. In the growth phase of dendrimers, two important building blocks, methyl acrylate for the half generation and EDA for the full generations, have been used. In order to improve the yield and decrease the time for the aminolysis step, a microwave-assisted technique was applied. Both of these dendrimers with different cores were grown up to 4.5 generations where surface modification, i.e. PEGylation, with 10% Poly(ethylene glycol) bis(amine) was performed. In order to increase the solubility of dendrimers, esteric surfaces were converted to carboxylic acid groups. Accordingly, the dendrimers were soluble in water or in water-methanol mixture which enabled their purification by liquid-phase polymer-based retention in each step. Finally, the resulting products that were characterized with (NMR and FTIR) spectroscopy were evaluated in vitro and in vivo. The analytical grade dendrimers were not cytotoxic to mouse fibroblasts and their biodistribution was mainly determined in the site of injection (peritoneum), liver and kidneys.

5-Fluorouracil-loaded PLA/PLGA PEG-PPG-PEG polymeric nanoparticles: formulation, in vitro characterization and cell culture studies.

In this study, 5-FU, a potent anticancer drug, is planned to be delivered via a new and promising drug delivery system, nanoparticles formed with hydrophobic core polymer and triblock copolymers; Poly(DL-lactic acid), Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymer (PLA/PEG-PPG-PEG) and Poly(D,L-lactide-co-glycolide)/Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymer (PLGA/PEG-PPG-PEG) nanoparticles. Particle size range of nanoparticles was found to be between 145 and 198 nm, which would promote the passive targeting of the nanoparticles to tumor cells based on the enhanced permeability and retention (EPR) effect. SEM images revealed all nanoparticles formulations to be spherical and without pores. Zeta potential, yield value and encapsulation efficiencies of 5-FU-loaded nanoparticles were within the range of -11.1 and -13.7 mV, 72.7-87.7% and 83.6-93.9%, respectively. Cumulative release of 5-FU was observed between 90% and 94.4% in all nanoparticle formulations by the end of 72 h, and fitness of release profiles to Higuchi model indicated matrix-controlled diffusion of the 5-FU from polymeric nanoparticles. Cell viability values of the cells treated with 5-FU-loaded nanoparticles were obtained as low as 47% and 52% with tetrazolium dye assay, suggesting that delivery of 5-FU via amphiphilic triblock copolymer nanoparticles would be a promising delivery system because of the EPR effect.

Cytotoxicity and in vitro characterization studies of synthesized Jeffamine-cored PAMAM dendrimers.

The objective of this study is to make comprehensive cytotoxicity evaluation and in vitro characterization of Jeffamine-cored polyamidoamine (PAMAM) dendrimers on L929 cell lines for oral drug delivery purposes. Ester-, amine- and carboxylic acid-terminated PAMAMs were investigated for their cytotoxicity on L929 cells at different generations and concentrations. Cationic surface charge caused highest cytotoxicity on L929 cells, while ester-terminated PAMAMs showed generation- and concentration-dependent toxicity. Anionic dendrimers were determined as the lowest cytotoxic group, and highest generation number presented lowest cellular toxicity. Encapsulation studies were performed with anionic PAMAMs at 2.5, 3.5 and 4.5 generations and different concentrations. Increasing generation number provides greater loaded naproxen amounts and larger particle size. Moreover, formulations provide controlled release at simulated terminal ileum conditions. Consequently, Jeffamine-cored carboxylic acid-terminated PAMAMs can be a promising option for oral drug delivery of poorly water-soluble drugs.