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OBJECTIVES: Daidzein (DZ), a water-insoluble isoflavone, has many beneficial effects (anti-inflammatory, antioxidant, and anticancer effects, etc.) on human health. DZ has a very low oral bioavailability related to its physicochemical properties (low solubility, intense metabolism of DZ in the intestine and liver). This study aimed to prepare and in vitro characterize the nanosuspension formulations of DZ to improve the poor solubility and efficacy of DZ. MATERIALS AND METHODS: DZ nanosuspension formulations were prepared with media milling technique using zirconium oxide beads as milling media. Pluronic F127 and polyvinylpyrrolidone (PVP) K30 (formulation A; F-A) and sodium dodecyl sulfate (SDS) (SDS + pluronic F127 + PVP K30; formulation B; F-B) were used as stabilizers. The nanosuspension formulations were evaluated for morphological properties, particle sizes, zeta potential, DZ content, saturation solubility, dissolution, and their cytotoxic effects on RG2 glioblastoma tumor cells. RESULTS: F-A and F-B formulations were nanosized (in the range of about 181-235 nm) and had negative zeta potential values before and after lyophilization. The DZ content of F-A and F-B formulations were found to be 93.68±0.78% and 89.75±0.49%, respectively. Fourier transform infrared spectroscopy analysis showed that there was no significant interaction between DZ and the excipients. Differential scanning calorimetry and X-ray diffraction analyses confirmed no change in the crystal structure of DZ in F-A and F-B formulations. CONCLUSION: In this study, the nanosuspension formulations were successfully prepared and characterized in vitro. Nanosuspension formulations increased the saturation solubility, dissolution rate, and cytotoxic effect of DZ.

Objectives Telmisartan (TLM) is an antihypertensive drug that has been shown to have antiproliferative effects on cancer cells. It has low solubility and suboptimal oral bioavailability. To investigate the potential anticancer effect of TLM on breast cancer cells, poly (D, L-lactide) (PLA) nanoparticles were formulated with the benefit of improving its solubility. Materials and methods TLM-loaded PLA nanoparticles were prepared by emulsion solvent evaporation. The effects of sonication time and polymer:drug ratio on nanoparticle size and drug encapsulation were investigated. TLM-loaded nanoparticles were tested against MCF-7 and MD-AMB-231 breast cancer cell lines for antiproliferative effects. Results Nanoparticles with mean particle size 272 nm and 79% encapsulation efficiency were obtained. Sustained release TLM nanoparticles (40% in 24 h) decreased cell viability to 45% for MCF-7 cells at 72 h, even at the lowest TLM concentration, indicating better anticancer efficiency than TLM solution. Conclusion TLM nanoparticles could be potential anticancer agents for breast cancer and deserve further studies.

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. TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [215S685] The authors would like to thank Gattefosse and IOI Chemicals for their kind supports. This research was financially supported by TUBITAK, (Research Project 215S685). WOS:000558613300003 2-s2.0-85084940581 PubMed: 32413453

Aims This study was conducted to evaluate block copolymers containing two different poly(ethyleneimine) (PEI) amounts, as new pH-sensitive micellar delivery systems for doxorubicin. Methods Micelles were prepared with block copolymers consisting of poly(2-ethyl-2-oxazoline)-co-poly(ethyleneimine) (PEtOx-co-PEI) and poly(epsilon-caprolactone) (PCL) as hydrophilic and hydrophobic blocks, respectively. Doxorubicin loading, micelle size, pH-dependent drug release, and in vitro cytotoxicity on MCF-7 cells were investigated. Results The average size of drug-loaded micelles was under 100 nm and drug loading was between 10.7% and 48.3% (w/w). pH-sensitive drug release was more pronounced (84.7% and 68.9% (w/w) of drug was released at pH 5.0 and pH 7.4, respectively) for the micelles of the copolymer with the lowest PEI amount. The cell viability of doxorubicin-loaded micelles which were prepared by the copolymer with the lowest PEI amount was 28-33% at 72 h. Conclusions PEtOx-co-PEI-b-PCL micelles of this copolymer were found to be stable and effective pH-sensitive nano-sized carriers for doxorubicin delivery. TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [213M728] This study was supported by TUBITAK Grant 213M728. WOS:000547724300001 2-s2.0-85087898563 PubMed: 32627670

Purpose: The aim of this study was to design naproxen sodium (NS)-containing, biomimetic, porous poly(lactide-co-glycolide) (PLGA) scaffolds for regeneration of damaged corneal epithelium. Methods:...

The in-vitro cytotoxicity, in-vitro permeability and in-vivo pharmacokinetics of a BCS Class-II drug - rufinamide - in a 3DP tablet formulation were evaluated. The cytotoxicity of the 3DP tablet formulation was evaluated with an MTT test; in-vitro permeability was evaluated with a Caco-2 cell culture study; and in-vivo pharmacokinetics were evaluated in Wistar albino male rats. The pharmacokinetic studies were performed following a two -sequence and single-period design approach. The highest Caco-2 permeability was obtained with the 3DP tablet formulation; and the highest cell viability was achieved with the 3DP tablet in both the Hep G2 and Caco-2 cell lines. In the in-vivo pharmacokinetic study, AUC and Cmax values were higher in the 3DP tablet formulation than in the Inovelon (R) film tablet at a 40 mg/kg dose. Thanks to the increased solubility of the active substance, higher in-vitro permeability and in-vivo absorption were achieved with the 3DP tablet formulation, and with lower cytotoxicity. Based on these promising findings, the 3DP tablet formulation can be considered an effective lower-dose treatment than commercial preparations.

WOS: 000480162500001, PubMed ID: 31342792, Objective: The aim of the study was to formulate, cyclodextrin (CD)-polyanhydride (PA) nanoparticles (CPNs) with rosuvastatin calcium (RCa) in order to enhance the poor oral bioavailability. Methods: CPNs containing RCa/CD complexes were prepared by a modified solvent displacement method and morphological analyses, particle size (PS), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE), DSC, FT-IR, XRD, H-1-NMR analyses were performed. In vitro release properties, release kinetics, cytotoxicity, in vitro permeability and pharmacokinetic studies were also studied. The stability of the formulations were evaluated during the storage period of 3 months. Results: The physicochemical studies showed that the RCa/CD complexes were well incorporated into CPNs resulted in nanosized particles (215.22 and 189.13 nm) with homogenous size distribution (PDI: 0.203 and 0.182) with relatively high incorporation capacity (76.11 and 68.18%) for the CPN1 and CPN2 formulations respectively. Sustained release of RCa from CPNs were achieved. The cytotoxicity values showed that the safety of the formulations. According to permeability studies, pure RCa had lowest permeability data (3.08 x 10(-7) cm.s(-1) P-app value) while CPNs gained higher permeability data (1.36 x 10(-5) and 1.12 x 10(-5) cm.s(-1) P-app values) for the CPN1 and CPN2 formulations respectively. CPN2 formulation was selected for pharmacokinetic studies and analyses results demonstrated that approximately 8-fold relative oral bioavailability enhancement compared to the pure RCa was achieved. Conclusion: Considering the analyses results of the study, CPNs can be regarded as suitable, safe, functional oral delivery systems for RCa with enhanced oral bioavailability., Anadolu University Scientific Research Project Foundation [1404S289], This study was supported by Anadolu University Scientific Research Project Foundation [No. 1404S289].

Furosemide is a widely used diuretic drug for the treatment of edema associated with heart, liver cirrhosis, renal diseases and hypertension. It is a Class IV drug with low aqueous solubility and low permeability according to Biopharmaceutics Classification System (BCS). Furosemide was chosen as a model drug to examine the effect of polymeric precipitation inhibitors (PPIs) on the supersaturation and solubility. Solubility and concentration change of furosemide as a function of time at pH 1.2 and 6.8 were determined to show the effects of PPIs on furosemide solubility. The 24 h equilibrium solubility of furosemide was 0.017 +/- 0.004 and 3.62 +/- 0.201 mg/mL at pH 1.2 and pH 6.8 buffer solutions, respectively. PPI type and concentration (0.05%, 0.25%) did not increase furosemide solubility at pH 1.2. However, both hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidoneK17 (PVPK17) at two concentrations increased furosemide solubility at pH 1.2 and 6.8. In addition, viscosity of solutions was in the range of 2.2-3.7 centipoise, and it was not influenced by PPIs concentrations. Our results showed that designing supersaturated formulations using PPIs can be useful and promising to enhance solubility of furosemide. WOS:000629451200011 2-s2.0-85103506237

Here we present self-assembled polymeric micelles as potential delivery systems for therapeutic agents with highly tunable properties. The major goal of this study is to design breast and prostate cancer specific targeting peptide modified PEtOx-co-PEI-b-PCL block copolymer based micelles as a targetable carrier system in cancer treatment. For this, a series of micelles based on poly(2-ethyl-2-oxazoline)-co-polyethyleneimine-block-poly(epsilon-caprolactone) [P(EtOx-co-EI)-b-PCL] copolymers with two different proportions of PEI (30% and 60% hydrolysis degrees of PEtOx) were successfully prepared. The block copolymers were synthesized using a combination of living cationic ring-opening polymerization and a copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction. Then, peptide 18 and peptide 563 were conjugated to P(EtOx-co-EI)-b-PCL through a thiol-ene click-type reaction to obtain the desired tumor-targeting. The structural properties of the copolymers were confirmed by H-1 NMR, FT-IR, UV-Vis spectrometry and GPC. Peptide and non-peptide-conjugated micelles with particle sizes between 82 +/- 0.6 and 170 +/- 10.7 nm were obtained by self-assembly with two different chain lengths of PEI blocks. The micelles containing the 60% PEI block showed increased zeta potential values. The cytotoxicity of the copolymers was evaluated under in vitro conditions. Overall, our results indicate that the micelles prepared with peptide-conjugated block copolymers can be used as potential nanocarriers for targeted therapeutic delivery systems. Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [213M725] The authors would like to thank the Scientific and Technological Research Council of Turkey (TUBITAK) for financial support with grant number 213M725. WOS:000678167300001 2-s2.0-85113149945

This study was conducted to evaluate block copolymers containing two different poly(ethyleneimine) (PEI) amounts, as new pH-sensitive micellar delivery systems for doxorubicin.Micelles were prepared with block copolymers consisting of poly(2-ethyl-2-oxazoline)-The average size of drug-loaded micelles was under 100 nm and drug loading was between 10.7% and 48.3% (w/w). pH-sensitive drug release was more pronounced (84.7% and 68.9% (w/w) of drug was released at pH 5.0 and pH 7.4, respectively) for the micelles of the copolymer with the lowest PEI amount. The cell viability of doxorubicin-loaded micelles which were prepared by the copolymer with the lowest PEI amount was 28-33% at 72 h.PEtOx

0000-0002-2782-3280 0000-0002-7617-8433 0000-0003-4865-2377 0000-0003-3892-2775 0000-0002-2576-3085 0000-0002-1627-3834 0000-0002-2793-6533 PubMed: 30032650 WOS:000460141900025 A new efficient, non-viral gene delivery cationic polymeric micellar system was developed by partial hydrolysis of poly(2-ethyl-2-oxazoline) (PEtOx) with two different hydrolysis percentages of PEtOx (30% and 60%) to reduce the disadvantages of the PEI. These self-assemble amphiphilic cationic micelles prepared from poly(2-ethyl-2-oxazoline)(30%)-co-poly(ethyleneimine)-block-poly(epsilon-caprolactone) (PEtOx(30%)-co-PEI-b-PCL) (PPP30) and poly(2-ethyl-2-oxazoline) (60%)-co-poly(ethyleneimine)-block-poly(epsilon-caprolactone) (PEtOx(60%)-co-PEI-b-PCL) (PPP60) block copolymers were successfully condensed with pEGFP-C3 plasmid DNA via electrostatic interactions to form micelle/DNA complexes with desirable particle sizes. All formulations showed low critical micelle concentration (CMC) values that means highly stable in serum containing medium. Polymeric micelles were also evaluated for their stability in the presence of serum and nuclease as well as cytotoxicity and transfection efficiency. All our results proved that our novel polymeric micellar system prepared by PPP60 block copolymer offer to be an efficient promising carrier for gene delivery applications. Moreover, these findings contribute to design and development of novel gene vectors with tunable and functionality features and also to reduce the cytotoxicity of PEI by partial hydrolysis of PEtOx an alternative synthesis method to produce linear PEI. [GRAPHICS] . TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [213M728] This work was supported by the TUBITAK under Grant number 213M728.

Furosemide, a widely used loop diuretic, has a low aqueous solubility, and low permeability. Nanosuspensions have been widely used to increase the solubility of poorly soluble drugs. The aim of this study was to develop and characterize furosemide containing nanosuspensions. Furosemide nanosuspensions with Tween 80, were prepared using high pressure homogenization method using ultrasonic probe or ultra turrax, ball milling method, and combination of these methods. The physicochemical properties of furosemide, physical mixture and nanosuspensions were evaluated by FT-IR, DSC and X-ray analyses. Particle size, polydispersity index, zeta potential, solubility and permeability of nanosuspensions were also determined. FT-IR analysis revealed that characteristic peaks of furosemide were seen in all formulations. X-ray analysis indicated that crystalline structure of furosemide was preserved in nanosuspensions. The particle size of furosemide decreased significantly (p

Azole antifungals are potent inhibitors of fungal lanosterol 14 alpha demethylase (CYP51) and have been used for eradication of systemic candidiasis clinically. Herein we report the design synthesis and biological evaluation of a series of 1-phenyl/1-(4-chlorophenyl)-2-(1H-imidazol-1-yl) ethanol esters. Many of these derivatives showed fungal growth inhibition at very low concentrations. Minimal inhibition concentration (MIC) value of 15 was 0.125 mu g/mL against Candida albicans. Additionally some of our compounds such as 19 (MIC: 0.25 mu g/mL) were potent against resistant C. glabrata a fungal strain less susceptible to some first-line antifungal drugs. We confirmed their antifungal efficacy by antibiofilm test and their safety against human monocytes by cytotoxicity assay. To rationalize their mechanism of action we performed computational analysis utilizing molecular docking and dynamics simulations on the C. albicans and C. glabrata CYP51 (CACYP51 and CGCYP51) homology models we built. Leu130 and T131 emerged as possible key residues for inhibition of CGCYP51 by 19. (C) 2017 Elsevier Masson SAS. All rights reserved.

bjectives: Telmisartan (TLM) is an antihypertensive drug that has been shown to have antiproliferative effects on cancer cells. It has low solubility and suboptimal oral bioavailability. To investigate the potential anticancer effect of TLM on breast cancer cells, poly (D, L-lactide) (PLA) nanoparticles were formulated with the benefit of improving its solubility.Materials and Methods: TLM-loaded PLA nanoparticles were prepared by emulsion solvent evaporation. The effects of sonication time and polymer:drug ratio on nanoparticle size and drug encapsulation were investigated. TLM-loaded nanoparticles were tested against MCF-7 and MDA-MB-231 breast cancer cell lines for antiproliferative effects.Results: Nanoparticles with mean particle size 272 nm and 79% encapsulation efficiency were obtained. Sustained release TLM nanoparticles (40% in 24 h) decreased cell viability to 45% for MCF-7 cells at 72 h, even at the lowest TLM concentration, indicating better anticancer efficiency than TLM solution.Conclusion: TLM nanoparticles could be potential anticancer agents for breast cancer and deserve further studies. Amaç: Telmisartan (TLM), kanser hücreleri üzerinde antiproliferatif etkisi olduğu gösterilmiş antihipertansif bir ilaçtır. Düşük çözünürlüğe, suboptimal oral biyoyararlanıma sahiptir. TLM’nin meme kanseri hücreleri üzerindeki potansiyel antikanser etkisini araştırmak için, TLM’nin çözünürlüğünü iyileştiren poli (D, L-laktid) PLA nanopartikülleri formüle edilmiştir.Gereç ve Yöntemler: TLM yüklü PLA nanopartikülleri emülsiyon hazırlama-çözücü buharlaştırma yöntemiyle hazırlanmıştır. Sonikasyon süresi ve polimer: ilaç oranının nanopartikül büyüklüğü ve ilaç enkapsülasyonu üzerindeki etkisi araştırılmıştır. TLM yüklü nanopartiküllerin, antiproliferatif etkileri MCF-7 ve MDA-MB-231 meme kanseri hücre hatları kullanılarak test edilmiştir.Bulgular: Ortalama partikül büyüklüğü 272 nm ve %79 enkapsülasyon etkinliğine sahip nanopartiküller elde edilmiştir. Sürekli salım gösteren TLM nanopartikülleri (24 saatte %40) MCF-7 hücrelerinde, TLM çözeltisinden daha iyi antikanser aktivite göstererek, en düşük TLM konsantrasyonunda bile hücre canlılığını 72 saatte %45’e düşürmüştür.Sonuç: TLM nanopartiküllerinin, meme kanseri için potansiyel antikanser ajanlar olabileceği ve daha ileri çalışmalarda araştırılmaya değer olduğu sonucuna varılmıştır. WOS:000585327200006 2-s2.0-85094607914 PubMed: 33177929

OBJECTIVES: Telmisartan (TLM) is an antihypertensive drug that has been shown to have antiproliferative effects on cancer cells. It has low solubility and suboptimal oral bioavailability. To investigate the potential anticancer effect of TLM on breast cancer cells, poly (D, L-lactide) (PLA) nanoparticles were formulated with the benefit of improving its solubility. MATERIALS AND METHODS: TLM-loaded PLA nanoparticles were prepared by emulsion solvent evaporation. The effects of sonication time and polymer:drug ratio on nanoparticle size and drug encapsulation were investigated. TLM-loaded nanoparticles were tested against MCF-7 and MD-AMB-231 breast cancer cell lines for antiproliferative effects. RESULTS: Nanoparticles with mean particle size 272 nm and 79% encapsulation efficiency were obtained. Sustained release TLM nanoparticles (40% in 24 h) decreased cell viability to 45% for MCF-7 cells at 72 h, even at the lowest TLM concentration, indicating better anticancer efficiency than TLM solution. CONCLUSION: TLM nanoparticles could be potential anticancer agents for breast cancer and deserve further studies.

Ozdemir, Ayse Nurten/0000-0003-3228-6579; Vural, Imran/0000-0002-1627-3834, WOS: 000457344000054, A multiple unit oral floating drug delivery system of itraconazole was developed to prolong gastric residence time, target stomach mucosa and increase drug bioavailability. To prepare non-effervescent floating microspheres/beads, ionotropic gelation method was used. Since the solubility of itraconazole is low at pH 1.2, it was attempted to increase the solubility by preparing inclusion complexes using randomly methylated beta-cyclodextrin and with polyvinylpyrrolidone cross linked and starch. in this study, the effects of formulation parameters like, concentration and types of polymer, crosslinking agent and the excipients, the floating ability, surface characteristics and drug release profiles were investigated. Optimum formulation (NG17) was used for Caco-2 cell culture studies. in permeability studies, at pH 5, 6 and 7.4, the formulation NG17 at pH 5, which is the pH of the proximal region of small intestine (absorption window of itraconazole), showed the highest permeability value which is 5.88x10(-6) cm/s. NG17 was also used for in vivo imaging studies. It was conducted in rabbits by using gamma scintigraphy and obtained that NG17 floated for 6.5 h in the stomach. As a result, it was found that, with non-effervescent floating bead formulations, the bioavailability of itraconazole can be improved.

The aim of this study was to prepare pullulan-based orally disintegrating films (ODFs) containing amlodipine besylate, an anti-hypertensive drug, by the solvent casting method. For this purpose, nine different ODF formulations (F1-F9) were prepared by using different plasticizers (glycerol, sorbitol, propylene glycol) and different superdisintegrants (croscarmellose sodium, sodium starch glycolate, crospovidone). FD&C Green and aspartame were used as coloring agent and sweetener, respectively. According to the results of preformulation studies, the optimum ODF (F9) was determined and various characterization studies such as uniformity of mass, film thickness, surface pH of films, and mechanical properties (such as elongation at break, tensile strength, Young's modulus, and folding endurance), moisture content, disintegration time, uniformity of content and dissolution test, X-ray, DSC, SEM and short term stability analysis were performed on this formulation. Cytotoxicity and permeability studies for the F9 formulation were performed on the human epithelial colorectal adenocarcinoma (Caco-2) cell line. The formulation F9 had appropriate morphological and mechanical properties and disintegrated within 51.3 s according to the petri dish method, and 28.8 s according to the drop method. Dissolution studies revealed that 78.1 % of amlodipine besylate was dissolved in 20 min from F9 formulation. Cell culture studies showed that the formulation had no significant toxic effect on the Caco-2 cells. Also, there was no significant difference between the Caco-2 permeabilities of amlodipine besylate powder and amlodipine besylate ODFs. As a result of all these studies, we suggest to use the pullulan based amlodipine besylate ODFs to enhance ease of administration and patient compliance.

LyP-1, a nine-amino-acid tumor homing peptide, selectively binds to its cognate receptor, p32. Overexpression of p32 in certain tumors should allow use of LyP-1 as a targeting agent for the delivery of therapeutic or diagnostic agents. Peptide conjugates are developed for enhanced pre-targeting of MDA-MB-231 breast cancer cells with peptide-antibody bispecific complexes and targeting with multiple-drug/-fluorophore-conjugated nano-polymers. LyP-1-anti-DTPA bispecific antibody complexes (LyP-1-bsAbCx) were generated by conjugation of anti-DTPA antibody and LyP-1. LyP-1–doxorubicin (Dox), Dox-DTPA-succinyl-polylysine (Dox-DSPL), Dox-DSPL-LyP-1, DTPA-Dox-poly glutamic acid (D-Dox-PGA) or DTPA-rhodamine conjugated polylysine (DSPL-RITC) were prepared. In vitro therapeutic efficacy and targeting by immunofluorescence in MDA-MB-231 breast cancer cells were assessed with Dox-LyP-1. Immunofluorescence visualization of cancer cells was evaluated after pretargeting with LyP-1-bsAbCx and targeting with DSPL-RITC. Cytotoxicity of Dox-LyP-1 conjugates was significantly greater than free doxorubicin (p

Malignant gliomas are highly lethal. Delivering chemotherapeutic drugs to the brain in sufficient concentration is the major limitation in their treatment due to the blood-brain barrier (BBB). Drug delivery systems may overcome this limitation and can improve the transportation through the BBB. Paclitaxel is an antimicrotubule agent with effective anticancer activity but limited BBB permeability. R-Flurbiprofen is a nonsteroidal antienflammatory drug and has potential anticancer activity. Accordingly, we designed an approach combining R-flurbiprofen and paclitaxel and positively-charged chitosan-modified poly-lactide-co-glycolic acid (PLGA) nanoparticles (NPs) and to transport them to glioma tissue. NPs were characterized and, cytotoxicity and cellular uptake studies were carried out in vitro. The in vivo efficacy of the combination and formulations were evaluated using a rat RG2 glioma tumor model. Polyethylene glycol (PEG) modified and chitosan-coated PLGA NPs demonstrated efficient cytotoxic activity and were internalized by the tumor cells in RG2 cell culture. In vivo studies showed that the chitosan-coated and PEGylated NPs loaded with paclitaxel and R-flurbiprofen exhibited significantly higher therapeutic activity against glioma. In conclusion, PLGA NPs can efficiently carry their payloads to glioma tissue and the combined use of anticancer and anti-inflammatory drugs may exert additional anti-tumor activity.

Nasal delivery is an emerging strategy to prevent both local and systemic diseases. The aim of this study was to develop a promising and innovative therapeutic system for the nasal delivery system of liposomes. Ovalbumin(OVA) was used as a model compound in this study. For this purpose we have developed OVA containing gel formulations using chitosan(2% w/v) and Carbopol® 974P(0.25% w/v). The developed gels have appropriate pH and viscosity for mucosal administration. We have also developed OVA containing liposome formulation for nasal administration. The developed liposomes have negative zeta potential(-5.33 mV ± 2.019), 200-250 nm particle size and 73% entrapment efficiency. To improve the mucosal retention time, liposome was dispersed in chitosan gel(lipogel). It was shown that developed formulations do not show cell toxicity, by cell viability near 100% on Calu-3 cells which is a model cell line of the respiratory mucosa. Sodium dodecyl sulfate polyacrylamide gel electrophoresis(SDS-PAGE) results of the formulations also showed that the antigen OVA maintained its integrity except liposome in chitosan gel formulation. We have also evaluated mucoadhesive and mechanical properties of the formulations on sheep nasal mucosa. Results from this study indicate that carbopol gel and lipogel formulations may be effective as nasal delivery systems.

In terms of ocular drug delivery, biodegradable implant systems have several advantages including the ability to provide constant drug concentration at the target site, no necessity for surgical removal, and minimum systemic side effects. Cyclosporin A (CsA) is a neutral, hydrophobic, cyclic peptide of amino acids that frequently used for dry eye disease treatment. The aim of this study was to develop a nanoparticle-loaded implant system for sustained-release CsA delivery following subconjunctival implantation. Poly(lactide-co-glycolide) (85:15) or poly-epsilon-caprolactone (PCL) were used to prepare two different nanoparticle formulations. These nanoparticles loaded into PCL or poly(lactide-co-caprolactone) implant formulations were prepared by two different methods, which were molding and electrospinning. Size and zeta potential of nanoparticles were determined and the morphology of the formulations were investigated by scanning electron microscopy. CsA-loading efficiencies were calculated and the in vitro degradation and in vitro release studies were performed. MTT test was also performed using L929 fibroblast cells to evaluate the cytotoxicity of the formulations. PCL-PCL-NP-I formulation was implanted to Swiss Albino mice with induced dry eye syndrome to evaluate the efficacy. In vitro release studies showed that the release from the formulations continues between 30 and 60 days, and the cell viability was found to be 77.4%-99.0%. In vivo studies showed that healing is significantly faster in the presence of the selected implant formulation. Results indicated that nanodecorated implants are promising ocular carriers for controlled-release CsA application. (c) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1709-1720, 2015

This study aimed to design and characterize an inhalable dry powder of ciprofloxacin or levofloxacin combined with the mucolytics acetylcysteine and dornase alfa for the management of pulmonary infections in patients with cystic fibrosis.Ball milling, homogenization in isopropyl alcohol and spray drying processes were used to prepare dry powders for inhalation. Physico-chemical characteristics of the dry powders were assessed via thermogravimetric analysis, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry and scanning electron microscopy. The particle size distribution, dissolution rate and permeability across Calu-3 cell monolayers were analyzed. The aerodynamic parameters of dry powders were determined using the Andersen cascade impactor (ACI).After the micronization process, the particle sizes of the raw materials significantly decreased. X-ray and DSC results indicated that although ciprofloxacin showed no changes in its crystal structure, the structure of levofloxacin became amorphous after the micronization process. FT-IR spectra exhibited the characteristic peaks for ciprofloxacin and levofloxacin in all formulations. The dissolution rates of micro-homogenized and spray-dried ciprofloxacin were higher than that of untreated ciprofloxacin. ACI results showed that all formulations had a mass median aerodynamic diameter less than 5 μm; however, levofloxacin microparticles showed higher respirability than ciprofloxacin powders did. The permeability of levofloxacin was higher than those of the ciprofloxacin formulations.Together, our study showed that these methods could suitably characterize antibiotic and mucolytic-containing dry powder inhalers.

Introduction: Orally disintegrating tablets (ODTs) provide an important treatment option for pediatric, geriatric and psychiatric patients. In our previous study, we have performed the initial studies for the formulation development and characterization of new ODT formulations containing a bitter taste drug, mirtazapine, coated with 6% (w/w) Eudragit® E-100 (first group of formulations, FGF) without taste evaluation. In present study, coating ratio of the drug was increased to 8% (w/w) (second group of formulations, SGF) to examine the effect of increased coating ratio of drug on in vitro characterization of the formulations including in vitro taste masking study. Materials and methods: Coacervation technique using Eudragit® E-100 was employed to obtain taste-masked mirtazapine granules. FGF and SGF were compared to original product (Remeron SolTab, an antidepressant drug which produced by pellet technology) in terms of in vitro permeability, in vitro taste masking efficiency which was performed by dissolution studies in salivary medium and dissolution stability. Also, the other tablet characteristics (such as diameter, thickness) of SGF were examined. Results and discussion: The disintegration time of the SGF were found as A1 ® E-100), but all of the formulations dissolved under 30 seconds and friability values were less than 1%. In vitro taste masking efficiency studies demonstrated that C2 formulation (in FGF) had the most similar dissolution profile to Remeron SolTab. Conclusions: According to these findings, B2 or C2 (with citric acid or sodium bicarbonate, respectively, with 6% Eudragit® E-100) formulations could be promising alternatives to Remeron SolTab.

Objectives We aimed to develop lipid–polyethylene glycol (PEG)–polymer hybrid nanoparticles, which have high affinity to tumour tissue with active ingredient, a new generation antineoplastic drug, farnesylthiosalicylic acid (FTA) for treatment of glioblastoma. Method Farnesylthiosalicylic acid-loaded poly(lactic-co-glycolic acid)-1,2 distearoyl-glycerol-3-phospho-ethanolamine-N [methoxy (PEG)-2000] ammonium salt (PLGA-DSPE-PEG) with or without 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) hybrid nanoparticles has been prepared and evaluated for in-vitro characterization. Cytotoxicity of FTA-loaded nanoparticles along with its efficacy on rat glioma-2 (RG2) cells was also evaluated both in vitro (in comparison with non-malignant cell line, L929) and in vivo. Key findings Scanning electron microscopy studies showed that all formulations prepared had smooth surface and spherical in shape. FTA and FTA-loaded nanoparticles have cytotoxic activity against RG2 glioma cell lines in cell culture studies, which further increases with addition of DOTAP. Magnetic resonance imaging and histopathologic evaluation on RG2 tumour cells in rat glioma model (49 female Wistar rats, 250–300 g) comparing intravenous and intratumoral injections of the drug have been performed and FTA-loaded nanoparticles reduced tumour size significantly in in-vivo studies, with higher efficiency of intratumoral administration than intravenous route. Conclusion Farnesylthiosalicylic acid-loaded PLGA-DSPE-PEG-DOTAP hybrid nanoparticles are proven to be effective against glioblastoma in both in-vitro and in-vivo experiments.

Endothelial cells form a barrier between the blood and the central nervous system, namely the blood-brain barrier (BBB). Cellular components of the BBB, as well as tight junctions and paracellular barrier characterizations, are described in this chapter. Furthermore, in vitro BBB models are classified as 2D models (monoculture and coculture), 3D, dynamic, and microfluidic models and further explained in detail. The components of the neurovascular unit and their role in obtaining special BBB properties in vitro are outlined, and methods that mimic the dynamic nature of an in vivo microenvironment are discussed. Promising approaches, such as stem cells and microfluidics, for future modeling of the BBB are also mentioned throughout this chapter. As a result it has been concluded that for drug discovery and delivery studies, which target the central nervous system, in vitro BBB models are very useful. © 2017 Elsevier Inc. All rights reserved.

New drug delivery systems are highly needed in research and clinical area to effectively treat gliomas by reaching a high antineoplastic drug concentration at the target site without damaging healthy tissues. Intranasal (IN) administration, an alternative route for non-invasive drug delivery to the brain, bypasses the blood-brainbarrier (BBB) and eliminates systemic side effects. This study evaluated the antitumor efficacy of farnesylthiosalicylic acid (FTA) loaded (lipid-cationic) lipid-PEG-PLGA hybrid nanoparticles (HNPs) after IN application in rats. FTA loaded HNPs were prepared, characterized and evaluated for cytotoxicity. Rat glioma 2 (RG2) cells were implanted unilaterally into the right striatum of female Wistar rats. 10 days later, glioma bearing rats received either no treatment, or 5 repeated doses of 500 mu M freshly prepared FTA loaded HNPs via IN or intravenous (IV) application. Pre-treatment and post-treatment tumor sizes were determined with MRI. After a treatment period of 5 days, IN applied FTA loaded HNPs achieved a significant decrease of 55.7% in tumor area, equal to IV applied FTA loaded HNPs. Herewith, we showed the potential utility of IN application of FTA loaded HNPs as a non-invasive approach in glioblastoma treatment.

Theranostic liposomes carry both the therapeutic active ingredients and the contrast agent into one delivery system. Codelivery of imaging contrast agent and chemotherapeutic drugs can provide real-time validation of the targeting strategy, resulting in an another step forward for individual-based therapy. The aim of this study was the incorporation of different drugs used in the diagnosis and treatment of tumors into one delivery system to develop nanosized, polyethylene glycol (PEG)-coated, different charged theranostic liposomes. Different charged liposomes consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or Phospholipon(®) 90G (PL 90G; Phospholipid GmbH, Cologne, Germany), cholesterol, poly(ethylene glycol)2000/phosphatidyl ethanolamine (PEG(2000)-PE), stearylamine (SA) or dicetyl phosphate (DCP), and diethylenetriamine pentaacetate/PE (DTPA-PE) as bilayer ingredients and 5-florouracil (5-FU) as active substance were prepared by the film technique. Characterization, 5-FU in vitro release, cytotoxicity, and physical stability studies were performed. Particle size of all liposomes was 100-150 nm. Difference was not noted between encapsulation efficiency (EE%) of neutral DPPC and PL 90G liposomes containing 5-FU. EE% of charged DPPC liposomes was higher than that of charged PL 90G liposomes. PL 90G containing liposomes had a higher phospholipid amount than the same formulation of DPPC liposomes. DPPC containing different charged liposomes were selected for cytotoxicity studies. Different charged DPPC liposomes had the same antitumoral activity with the free 5-FU solution on MCF-7 cell lines. Liposome dispersions were more stable from the point of particle-size change and 5-FU leakage during storage at refrigerated temperature. The results of this study are very encouraging for the development of theranostic liposome formulations as a targeted delivery system for drugs, such as 5-FU, used both in therapy and imaging.

Objective Ocular diseases affecting retina, such as diabetic retinopathy (DR), age-related macular degeneration (AMD) and glaucoma are the major causes of blindness, and their treatment is still a challenge due to the special structure of the eye. The purpose of this study was to prepare a sustained release DEX conjugate formulation with enhanced ocular permeation using poly(amidoamine) (PAMAM) dendrimers and to evaluate the effects of conjugation on DEX release and ocular residence time. Methods PAMAM G3.5 and PAMAM G4.5 dendrimers were used to prepare DEX conjugates, and conjugation was confirmed using 1H-NMR. Formulations were evaluated in terms of drug release in the presence of ocular enzymes and cytotoxicity on ARPE19 cell lines. Fluorotron analysis was performed and ocular pharmacokinetic properties of DEX–PAMAM conjugates were studied in Sprague Dawley rats following intravitreal and subconjunctival applications. Key Findings The results indicated that DEX–PAMAM conjugates were able to enhance ocular permeability and ocular tissue levels of DEX following subconjunctival injection, and results were encouraging when compared to the literature that has reported DEX getting cleared from vitreous in 3 h. Conclusion Current studies are focused on formulation improvement to enhance hydrolysis and clearance time.

Context: Lipid-polymer hybrid nanoparticles (LPNPs) are polymeric nanoparticles enveloped by lipid layers, which have emerged as a potent therapeutic nanocarrier alternative to liposomes and polymeric nanoparticles. Objective: The aim of this work was to develop, characterize and evaluate LPNPs to deliver a model protein, lysozyme. Materials and methods: Lysozyme-loaded LPNPs were prepared by using the modified w/o/w double-emulsion-solvent-evaporation method. Poly-?-caprolactone (PCL) was used as polymeric core material and tripalmitin:lechitin mixture was used to form a lipid shell around the LPNPs. LPNPs were evaluated for particle size distribution, zeta potential, morphology, encapsulation efficiency, in vitro drug release, stability and cytotoxicity. Results: The DLS measurement results showed that the particle size of LPNPs ranged from 58.04 ± 1.95 nm to 2009.00 ± 0.52 nm. The AFM and TEM images of LPNPs demonstrate that LPNPs are spherical in shape. The protein-loading capacity of LPNPs ranged from 5.81% to 60.32%, depending on the formulation parameters. LPNPs displayed a biphasic drug release pattern with a burst release within 1 h, followed by sustained release afterward. Colloidal stability results of LPNPs in different media showed that particle size and zeta potential values of particles did not change significantly in all media except of FBS 100% for 120 h. Finally, the results of a cellular uptake study showed that LPNPs were significantly taken up by 83.3% in L929 cells. Conclusion: We concluded that the LPNPs prepared with PCL as polymeric core material and tripalmitin:lechitin mixture as lipid shell should be a promising choice for protein delivery. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

The aim of the present study was to develop and characterize metformin HCl-loaded nanoparticle formulations. Nanoparticles were prepared by the nanoprecipitation method using both a single polymer (Eudragit(®)RSPO) and a polymer mixture (Eudragit/PLGA). The mean particle size ranged from 268.8 to 288 nm and the nanoparticle surface was positively charged (9.72 to 10.1 mV). The highest encapsulation efficiency was observed when Eudragit®RSPO was used. All formulations showed highly reproducible drug release profiles and the in vitro drug release in phosphate buffer (pH = 6.8) ranged from 92 to 100% in 12 h. These results suggest that Eudragit(®)RSPO or Eudragit/PLGA nanoparticles might represent a promising sustained-release oral formulation for metformin HCl, reducing the necessity of repeated administrations of high doses to maintain effective plasma concentrations, and thus, increasing patient compliance and reducing the incidence of side-effects.

Furosemide loaded chitosan coated liposomes were prepared by the evaporation-sonication method to improve pharmaceutical characteristics of drug. Formulations were characterized in terms of particle size, zeta potential, cell viability and permeability on Caco-2 cells. Cytotoxic effect was evaluated by using MTT test. The encapsulation efficiency, zeta potential and particle size of liposomes were increased when they were coated with chitosan. An eight fold increase on Furosemide permeability was obtained for coated liposomes when compared to uncoated formulations. In addition, Cytotoxicity of chitosan coated liposomes was decreased towards Caco-2 cell line. Obtained results suggest that prepared formulations have potential to be used as carriers of poorly soluble drugs and they may improve their bioavailability after oral administration.

The objective of this study was to improve poor aqueous solubility and dissolution properties of anticancer drug rapamycin through formation of inclusion complexes with natural and modified cyclodextrins. Of the cyclodextrins tested, ?-cyclodextrin and hydroxypropyl-?- cyclodextrin did not complex with rapamycin. However, complexes of rapamycin with ß-cyclodextrin, methyl-ß-cyclodextrin and hydroxypropyl-ß- cyclodextrin were prepared and characterized by techniques such as Fourier Transform infrared spectroscopy, differential scanning calorimetry, phase solubility analysis and in vitro dissolution studies. According to the characterization data for the complexes, rapamycin water solubility was highly enhanced by all three ß-cyclodextrins with methyl-ß-cyclodextrin complex resulting in particularly higher solubility enhancement. FTIR spectra and DSC thermograms supported the formation of inclusion complexes. The complexes showed highly improved dissolution rate in water. Complexation with cyclodextrin derivatives such as methyl-ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin can provide promising alternatives for the formulation of rapamycin. © 2010 Springer Science+Business Media B.V.

Exemestane (EXE) is an irreversible aromatase inactivator used for the treatment of advanced postmenopausal breast cancer. EXE is orally active but its bioavailability is about 5% due to its low solubility in water and the extensive first pass effect. It is known that cyclodextrin (CD) complexation enhances solubility and oral bioavailability of poorly soluble drugs. Thus, it was aimed to design and develop cyclodextrin complexes in powder and tablet forms containing EXE to improve aqueous solubility and in vitro permeability. In this study, inclusion complexes of EXE were prepared with three different CD derivatives (methyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin) and by two different preparation methods (kneading and colyophilization) and the complexes were characterized with H-1 NMR, FT-IR, SEM, X-ray and DSC analyses. Both inclusion complexes and tablet formulations prepared using EXE:CD inclusion complexes showed significant improvement in the dissolution profile of this oral antiestrogen drug. Furthermore, Caco-2 cell permeation studies revealed that apparent permeability constant for EXE was increased by 3-fold via cyclodextrin complexation. In conclusion, complexation of EXE with cyclodextrin derivatives, randomly methylated-beta-cyclodextrin in particular, results in a more efficient tablet formulation with improved dissolution and better permeation suggesting an enhancement in oral bioavailability of the drug. (C) 2010 Elsevier B.V. All rights reserved.

Rapamycin (Sirolimus) is a macrolide lactone with antifungal, immunosuppressant, and antiproliferative actions. The mechanism of rapamycin action involves the inhibition of mTOR and subsequent cytostasis. Rapamycin also prevents angiogenesis in tumors and can prevent cancer cells' resistance to other chemotherapeutic agents. However, very poor water solubility, bioavailability, only slight solubility in acceptable parenteral excipients, chemical instability, and major sequestration (95%) of free rapamycin into the erythrocytes have prevented its development as an anticancer drug. To address these problems, it was attempted to develop liposomal rapamycin delivery systems in this study. Conventional and pegylated liposomes were prepared with various lipid and cholesterol ratios. They were then characterized; these liposomes contained 0.68-0.90 mg of rapamycin per milliliter of liposome suspension. Having suitable particle size, these liposomes successfully retained the entrapped drug. Both types of liposomes were found to be effective; however, conventional liposomes showed better antiproliferative activity against MCF-7 cells than pegylated liposomes. But, pegylated liposome showed better stability than conventional liposomes. In conclusion, the enhanced permeability and retention effercts of tumors should provide the opportunity for pegylated liposomal rapamycin to be applied as an intravenous drug-delivery system for targeted delivery to cancer cells, avoiding the major sequestration of free rapamycin into the erythrocytes.

Current treatment options for diabetic retinopathy (DR) have side effects because of invasive application and topical application does not generally result in therapeutic levels in the target tissue. Therefore, improving the drug delivery to retina, following topical administration, might be a solution to DR treatment problems. The purpose of this study was to investigate the complexation effects of poly(amidoamine) (PAMAM) dendrimers on ocular absorption of dexamethasone (DEX). Using different PAMAM generations, complex formulations were prepared and characterized. Formulations were evaluated in terms of cytotoxicity and cell permeability, as well as ex vivo transport across ocular tissues. The ocular pharmacokinetic properties of DEX formulations were studied in Sprague-Dawley rats following topical and subconjunctival applications, to evaluate the effect of PAMAM on retinal delivery of DEX. Methyl-thiazol-tetrazolium (MTT) assay indicated that all groups resulted in cell viability comparable to DEX solution (87.5%), with the cell viability being the lowest for G3 complex at 73.5%. Transport study results showed that dendrimer complexation increases DEX transport across both cornea and sclera tissues. The results of in vivo studies were also indicated that especially anionic DEX-PAMAM complex formulations have reached higher DEX concentrations in ocular tissues compared with plain DEX suspension. (c) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3814-3823, 2015

Treatment of central nervous system (CNS) diseases with potentially useful pharmaceuticals is prevented by the blood-brain barrier (BBB). The BBB is a unique protective barrier in the body. It is formed by epithelial-like tight junctions, which are expressed by the brain capillary endothelial cells. Although most molecules are potentially active in the CNS, they cannot readily enter the brain because of their properties. Antisense oligonucleotides (ODNs) have a great potential as neuropharmaceuticals; however, the large size and polar nature of nucleic acid drugs prevent these molecules from bypassing the BBB and readily entering the CNS following systemic administration. One approach to improve both the pharmacokinetics and the pharmacodynamics of ODNs involves the use of sustained-release polymer formulations, such as poly(lactide-co-glycolide) (PLGA) nanoparticulate systems. In this study, nanospheres were prepared by the emulsification diffusion technique and characterized in terms of particle size, surface morphology, encapsulation efficiency, in vitro release profiles and ODN stability. The nanospheres produced were spherical with homogenous size distribution. Nanospheres were prepared with different encapsulation efficiency. Release profiles of formulations were also evaluated. The results show that formulations with different ODN content exhibited different release profiles. Moreover, the chemical integrity of ODN during the processes was conserved. These results demonstrate that a stable ODN formulation could be prepared utilizing PLGA nanospheres as a potential delivery system for the treatment of CNS diseases.

Nanospheres and nanocapsules of beta-CDC6, amphiphilic beta-cyclodextrin modified on the secondary face with 6C aliphatic esters, were prepared with nanoprecipitation technique directly from inclusion complexes of tamoxifen citrate and beta-CDC6 (1:1 molar ratio). Blank and loaded nanospheres and nanocapsules were characterized by particle size distribution, zeta potential, drug loading and in vitro drug release. Particle sizes were between 250 and 300 nm for different formulations of nanospheres and nanocapsules. Zeta potential which was around -18 mV for blank particles was reported to be between +12 and +15 mV for tamoxifen-loaded particles. Average entrapped drug quantity was found to be around 150 mug/mL for particles prepared from inclusion complexes and this is double the loading value for conventionally prepared particles. Pre-loaded formulations showed a significantly slower release profile extended up to 6 h while formulations loaded conventionally displayed rapid and complete release within an hour. Cytotoxic efficacy of tamoxifen citrate loaded nanospheres and nanocapsules was determined against MCF-7 cells and tamoxifen citrate incorporated in amphiphilic beta-cyclodextrin nanoparticles was found to be cytotoxic and effective against this cell line.

This study describes the preparation and evaluation of mitoxantrone (MTZ)-loaded chitosan, bovine serum albumin (BSA) and poly(D,L-lactide-co-glycolide) (PLGA) microsphere formulations in vitro and investigation of the in vitro bioactivity of the released drug (for BSA microspheres) or that obtained by extraction from microspheres (microencapsulated drug) on the rat glioma (RG2) cells. The prepared microspheres were tested for the particle size, drug loading, surface morphology and release characteristics. Then, RG2 cells were used for evaluating the cytotoxicity of MTZ (the original drug or that microencapsulated or released from the microspheres) by methyl-thiazol-tetrazolium (MTT) assay. Chitosan and PLGA microsphere formulations exhibiting particle size from 7.7 to 59.8 μm, encapsulation efficiency from 8.2 to 55.5% were prepared. They were spherical in shape, had a smooth surface and homogenous distribution. For the release samples of MTZ-containing BSA microspheres, the cell death ratios were over 50% for all formulations. With regard to MTZ obtained by extraction from drug-loaded chitosan and PLGA microspheres the cell death ratios were between 57.1-68.5% and 74.3%, respectively. It was concluded that BSA, chitosan and PLGA microspheres-delivered MTZ has significant cytotoxic effect on RG2 glioma cells.

In the present study, the preparation and characterization of bovine serum albumin (BSA) microspheres and the evaluation of the in vitro cytotoxicity of these microspheres on acute promyelocytic leukaemia (HL-60) cells were described. Mitoxantrone (MTZ)-incorporated microspheres were evaluated for particle size, drug loading, release characteristics and surface morphology. The biological effect of MTZ released from BSA microspheres was determined on an in vitro cultured HL-60 cell line, showing that, after encapsulation, MTZ still retains cytotoxic activity. For this purpose, methyl-thiazol-tetrazolium (MTT) assay was used to evaluate the in vitro cytotoxicity of MTZ-loaded microspheres. Particle size of BSA microspheres was determined between 17.61-20.38 microm and they were smooth and spherical in shape. Encapsulation efficiency of the drug-loaded microspheres was between 22.26-60.50%. For MTZ-containing microspheres, the cell death ratios were greater than 80% for all formulations. This study demonstrate that BSA microspheres were well suited for the controlled release of MTZ and were promising for anti-cancer chemotherapy.

This article describes the preparation and characterization of anticancer drug-loaded poly(lactide-co-glycolide) (PLGA) microparticles. PLGA microparticles loaded with doxorubicin HCl (DOX) were prepared via o/w emulsion solvent evaporation. The release characteristics, encapsulation efficiency, size, and morphology of the PLGA microparticles were also determined. A cytotoxicity test was performed by using Glioma RG2 cancer cells to investigate the cytotoxicity of DOX-loaded PLGA microparticles. The DOX-loaded PLGA microparticles had an average diameter of 500 \pm 9 nm. The DOX encapsulation efficiency and drug loading were 22.75% and 0.78%, respectively. DOX-loaded PLGA microparticles displayed a significant cytotoxicity toward the RG2 cells as compared to the unloaded PLGA

The aims of this study were to develop and characterize paclitaxel nanoparticles, to identify and control critical sources of variability in the process, and to understand the impact of formulation and process parameters on the critical quality attributes (CQAs) using a quality-by-design (QbD) approach. For this, a risk assessment study was performed with various formulation and process parameters to determine their impact on CQAs of nanoparticles, which were determined to be average particle size, zeta potential, and encapsulation efficiency. Potential risk factors were identified using an Ishikawa diagram and screened by Plackett–Burman design and finally nanoparticles were optimized using Box–Behnken design. The optimized formulation was further characterized by Fourier transform infrared spectroscopy, X-ray diffractometry, differential scanning calorimetry, scanning electron microscopy, atomic force microscopy, and gas chromatography. It was observed that paclitaxel transformed from crystalline state to amorphous state while totally encapsulating into the nanoparticles. The nanoparticles were spherical, smooth, and homogenous with no dichloromethane residue. In vitro cytotoxicity test showed that the developed nanoparticles are more efficient than free paclitaxel in terms of antitumor activity (more than 25%). In conclusion, this study demonstrated that understanding formulation and process parameters with the philosophy of QbD is useful for the optimization of complex drug delivery systems. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3748–3761, 2013

The hallmark of cell death is the development of cell membrane lesions. Such lesions in the myocardium are usually associated with acute myocardial infarction. Minimizing myocardial necrosis by thrombolytic reperfusion therapy constitutes the only major treatment to date. We envisioned a method to seal these membrane lesions using immunoliposomes as a novel adjunctive approach. An antigen to intracellular cytoskeletal myosin in hypoxic embryonic cardiocytes is used as an anchoring site, and a specific antibody on immunoliposomes as the anchor to plug and to seal the membrane lesions. H9C2 cells were used because they are cardiocytes and are propagated in tissue culture and their viability may be assessed by various methods. Viability assessed by [3H]thymidine uptake in hypoxic cardiocyte cultures (n = 6 each) treated with antimyosin-immunoliposomes (3.26 +/- 0.483 x 10(6) c.p.m.) was similar to that of normoxic cells (3.68 +/- 0.328 x 10(6) c.p.m.), but was greater than those of untreated hypoxic cells (0.115 +/- 0.155 x 10(6) c.p.m.) or hypoxic cells treated with plain liposomes (1.140 +/- 0.577 x 10(6) c.p.m.). These results were reconfirmed by trypan blue exclusion and by fluorescent, confocal and transmission electron microscopy. They indicated that cell death in hypoxic cardiocytes can be prevented by targeted cell membrane sealing. This concept of cell salvage should be applicable in the prevention of cell death in different biological systems.

The over-expression of the P-glycoprotein (P-gp) in cancer cells is one of the main reasons of the acquired Multidrug Resistance (MDR). Combined treatment of MDR cancer cells with P-gp inhibitors and chemotherapeutic agents could result in reversal of resistance in P-gp-expressing cells. In this study, paclitaxel (PTX) was co-encapsulated in actively targeted (anticancer mAb 2C5-modified) polymeric lipid-core PEG-PE-based micelles with Cyclosporine A (CycA), which is one of the most effective first generation P-gp inhibitors. Cell culture studies performed using MDCKII (parental and MDR1) cell lines to investigate the potential MDR reversal effect of the formulations. The average size of both empty and loaded PEG(2000)-PE/Vitamin E mixed micelles was found between 10 and 25 nm. Zeta potentials of the formulations were found between -7 and -35 mV. The percentage of PTX in the micelles was found higher than 3% for both formulations and cumulative PTX release of about 70% was demonstrated. P-gp inhibition with CycA caused an increase in the cytotoxicity of PTX. Dual-loaded micelles demonstrated significantly higher cytotoxicity in the resistant MDCKII-MDR1 cells than micelles loaded with PTX alone. Micelle modification with mAb 2C5 results in the highest cytotoxicity against resistant cells, with or without P-gp modulator, probably because of better internalization bypassing the P-gp mechanism. Our results suggest that micelles delivering a combination of P-gp modulator and anticancer drug or micelles loaded with only PTX, but targeted with mAb 2C5 represent a promising approach to overcome drug resistance in cancer cells.