PurposeThe blood brain barrier compromises glioblastoma chemotherapy. However high blood concentrations of lipophilic, alkylating drugs result in brain uptake, but cause myelosuppression. We hypothesised that nanoparticles could achieve therapeutic brain concentrations without dose-limiting myelosuppression.MethodsMice were dosed with either intravenous lomustine Molecular Envelope Technology (MET) nanoparticles (13 mg kg−1) or ethanolic lomustine (6.5 mg kg−1) and tissues analysed. Efficacy was assessed in an orthotopic U-87 MG glioblastoma model, following intravenous MET lomustine (daily 13 mg kg−1) or ethanolic lomustine (daily 1.2 mg kg−1 - the highest repeated dose possible). Myelosuppression and MET particle macrophage uptake were also investigated.ResultsThe MET formulation resulted in modest brain targeting (brain/ bone AUC0-4h ratios for MET and ethanolic lomustine = 0.90 and 0.53 respectively and brain/ liver AUC0-4h ratios for MET and ethanolic lomustine = 0.24 and 0.15 respectively). The MET formulation significantly increased mice (U-87 MG tumours) survival times; with MET lomustine, ethanolic lomustine and untreated mean survival times of 33.2, 22.5 and 21.3 days respectively and there were no material treatment-related differences in blood and femoral cell counts. Macrophage uptake is slower for MET nanoparticles than for liposomes.ConclusionsParticulate drug formulations improved brain tumour therapy without major bone marrow toxicity.

Andrographolide is a potential chemopreventive and chemotherapeutic agent that suffers from poor aqueous solubility. Encapsulation in poly(lactide-co-glycolide) (PLGA) nanoparticles can overcome solubility issues and enable sustained release of the drug, resulting in improved therapeutic efficacy. In this study, andrographolide was encapsulated in PLGA nanoparticles via emulsion solvent evaporation technique. Effect of various formulation parameters including polymer composition, polymer molecular weight, polymer to drug ratio, surfactant concentration and the organic solvent used on nanoparticle properties were investigated. A selected formulation was used to determine the effect of encapsulation in nanoparticles on andrographolide’s in vitro anticancer efficacy. Nanoparticles formulated using a polymer with 85:15 lactide to glycolide ratio and ethyl acetate as the organic solvent were found to be optimal based on average hydrodynamic particle size (135 ± 4 nm) and drug loading (2.6 ± 0.6%w/w). This formulation demonstrated sustained release of andrographolide over 48 h and demonstrated significantly greater in vitro anticancer efficacy compared to free drug in a metastatic breast cancer cell line. These results suggest that additional, more in-depth efficacy studies are warranted for the nanoparticle formulation of andrographolide.

Background: In this study, the chronic wound healing ability of PLA-based electrospun nanofibers loaded with hyaluronic acid, valsartan, and ascorbic acid is explored. PLA-based scaffolds were fabricated by electrospinning, followed by loading the scaffolds with different concentrations of hyaluronic acid, valsartan, and ascorbic acid hydrogels. The produced formulations were characterized by scanning electron microscopy imaging (SEM), tensile strength testing, Fourier-transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). An in vitro drug release study was conducted to monitor the release of valsartan from the different formulations. This was followed by exploring the wound healing effects of the scaffolds in alloxan-induced diabetic rats and comparing the wound healing effects with positive and negative controls. Results: The average diameter of the fibers was in the range of 300 to 490 nm with high porosity in the range of 63.90 to 79.44%, offering a large surface area-to-volume ratio, enhanced drug solubility, oxygen permeability, and fluid uptake. The presence of valsartan significantly impacted on the re-epithelization rate. Percentage reepithelization rate was 31.2% ± 1.77% in the absence of treatment. Histologic section of tissue showed skin with underlying loose fibro-collagenous stroma (dermis) containing sebaceous glands and hair follicles for animals treated with VA, VB, VC, and VD. All the scaffolds reduced the number of inflammatory cell infiltrates at the wound site compared to the no treatment and conventionally treated groups. Conventional antibiotic treatment and VD (electrospun biomimetic scaffolds containing ascorbic acid) had % re-epithelization rates of 59.45% ± 1.69% and 62.01% ± 1.68% which were significantly lower than the PLA/HA-valsartan hydrogel scaffolds with VB having the highest % re-epithelization rate of 85.5% ± 1.7% (Figure 4B & 5C). Conclusion: This study explored the use of biomimetic polylactic acid-based electrospun fiber and HA-valsartan hydrogel scaffold incorporating topical angiotensin receptor blockers to successfully accelerate wound healing. The novel PLA-based electrospun fibers loaded with hyaluronic acid-valsartan hydrogels were stable and possessed proven diabetic wound healing property. This was as a result of the known biomimetic effect of the fibers and increased re-epithelization facilitated by the hydrogels containing valsartan.

ÖZAmaç: İstatistiksel olarak tasarlanmış deney ile birlikte Yüzey cevap grafiği metodolojisinin çok değişkenli prosesleri optimize etmede çok yararlı olduğu bulunmuştur. Bu çalışmanın amacı, iki bağımsız değişken olan permeabilite arttırıcılar/antioksidanlar (Transcutol ve Tetracarpidium conophorum EETC'nin etanolik ekstraktı) ve karıştırma oranının gentamisin hidrojelin akı ve permeasyonu üzerine olan etkisini değerlendirmektir. Gereç ve Yöntemler: Gentamisin hidrojelin formüle edilmesi için bir serbest radikal başlangıç polimerizasyon modifikasyonu kullanıldı. Permeabilite arttırıcı Transcutol: EETC (X1), Karıştırma hızı (X2) bağımsız değişkenlerinin etkisini araştırmak için bağımlı değişkenler Akı (Y1) ve 12 saatten sonra etken maddenin ex-vivo permeasyon miktarı açısından değerlendirilen 14 formülasyon serisi ile 32 faktöryel santral kompozit tasarım (CCD) kullanıldı. Introduction:Response surface methodology coupled with statistically designed experiment has been found to be very useful in optimising multivariable processes. The aim of this study is to evaluate the influence of two independent variables, a ratio of permeation enhancers/antioxidants (Transcutol and ethanolic extract of Tetracarpidium conophorum EETC) and stirring rate, on the flux and permeation of gentamicin hydrogel. Methods: A modification of free radical initial polymerization was utilized to formulate the gentamicin hydrogel. A 3² factorial central composite design was then utilized to investigate the effect of independent variables of permeation enhancer Transcutol: EETC (X1), Stirring speed (X2) via 14 formulation batches which were evaluated for dependent variables Flux (Y1) and amount of drug permeated after 12 hours (Y2) ex vivo. Results:The results of analysis of variance carried out to determine the fit of the models revealed that the models were statistically significant (p < 0.05) and did not show lack of fit (R2 > 0.80). The regression equation generated for flux was Y1 = 19.35 -25.82X1 -0.044X2 + 0.0097X1X2 + 11.86X21 and for cumulative permeation of gentamicin in 12 hours Y2= 315.50 -189.67X1 + 0.28X2 -1.29X1X2 + 123.55X21. The validity of the statistical models used for predicting flux and drug permeation was confirmed by carrying out three confirmation experimental runs at the identified optimum conditions. The results showed that there was no significant difference between the experimental results and those predicted by the statistical models. Discussion And Conclusion: The excellent correlation between the predicted and measured values shows the validity of statistical models (R2= 0.95). Utilization of antioxidant and permeation enhancer has been used for the first time to investigate the influence on dependent variables. Optimization of gentamicin hydrogel using central composite statistical design is valid for prediction of drug permeation and flux utilizing variables in formulation.

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