PEGylated liposomes of anastrozole for long-term treatment of breast cancer: in vitro and in vivo evaluation.

The aim of present study was to develop conventional and PEGylated (long circulating), liposomes containing anastrozole (ANS) for effective treatment of breast cancer. ANS is a third-generation non-steroidal aromatase inhibitor of the triazole class used for the treatment of advanced and late-stage breast cancer in post-menopausal women. Under such disease conditions the median duration of therapy should be prolonged until tumor regression ends (>31 months). Liposomes were prepared by the thin film hydration method by using ANS and various lipids such as soyaphosphatidyl choline, cholesterol and methoxy polyethylene glycol distearoyl ethanolamine in different concentration ratios and evaluated for physical characteristics, in vitro drug release and stability. Optimized formulations of liposome were studied for in vitro cytotoxic activity against the BT-549 and MCF-7 cell lines and in vivo behavior in Wistar rats. Preformulation studies, both Fourier transform infrared study and differential scanning calorimetry analysis showed no interaction between the drug and the excipients used in the formulations. The optimized formulations AL-07 and AL-09 liposomes showed encapsulation efficiencies in the range 65.12 ± 1.05% to 69.85 ± 3.2% with desired mean particle size distribution of 101.1 ± 5.9 and 120.2 ± 2.8 nm and zeta potentials of -43.7 ± 4.7 and -62.9 ± 3.5 mV. All the optimized formulations followed Higuchi-matrix release kinetics and when plotted in accordance with the Korsemeyer-Peppas method, the n-value 0.5 < n < 1.0 suggests an anomalous (non-Fickian) transport. Likewise, the PEGylated liposomes showed greater tumor growth inhibition on BT-549 and MCF-7 cell lines from in vitro cytotoxicity studies (p < 0.05). Pharmacokinetic study of conventional and PEGylated liposomes in Wistar rats demonstrated a 3.33- and 20.28-fold increase in AUC(0-∞) values when compared to pure drug (p < 0.001). Among the formulations, PEGylated liposomes showed encouraging results by way of their long circulation and sustained delivery properties for effective treatment of breast cancer.

Embedding a surface acoustic wave sensor and venting into a metal additively manufactured injection mould tool for targeted temperature monitoring.

Injection moulding (IM) tools with embedded sensors can significantly improve the process efficiency and quality of the fabricated parts through real-time monitoring and control of key process parameters such as temperature, pressure and injection speed. However, traditional mould tool fabrication technologies do not enable the fabrication of complex internal geometries. Complex internal geometries are necessary for technical applications such as sensor embedding and conformal cooling which yield benefits for process control and improved cycle times. With traditional fabrication techniques, only simple bore-based sensor embedding or external sensor attachment is possible. Externally attached sensors may compromise the functionality of the injection mould tool, with limitations such as the acquired data not reflecting the processes inside the part. The design freedom of additive manufacturing (AM) enables the fabrication of complex internal geometries, making it an excellent candidate for fabricating injection mould tools with such internal geometries. Therefore, embedding sensors in a desired location for targeted monitoring of critical mould tool regions is easier to achieve with AM. This research paper focuses on embedding a wireless surface acoustic wave (SAW) temperature sensor into an injection mould tool that was additively manufactured from stainless steel 316L. The laser powder bed fusion (L-PBF) "stop-and-go" approach was applied to embed the wireless SAW sensor. After embedding, the sensor demonstrated full functionality by recording real-time temperature data, which can further enhance process control. In addition, the concept of novel print-in-place venting design, applying the same L-PBF stop-and-go approach, for vent embedding was successfully implemented, enabling the IM of defectless parts at faster injection rates, whereas cavities designed and tested without venting resulted in parts with burn marks.

Development and Validation of Empirical Models to Predict Metal Additively Manufactured Part Density and Surface Roughness from Powder Characteristics.

Metal additive manufacturing (AM) processes, viz laser powder bed fusion (L-PBF), are becoming an increasingly popular manufacturing tool for a range of industries. The powder material used in L-PBF is costly, and it is rare for a single batch of powder to be used in a single L-PBF build. The un-melted powder material can be sieved and recycled for further builds, significantly increasing its utilisation. Previous studies conducted by the authors have tracked the effect of both powder recycling and powder rejuvenation processes on the powder characteristics and L-PBF part properties. This paper investigates the use of multiple linear regression to build empirical models to predict the part density and surface roughness of 316L stainless steel parts manufactured using recycled and rejuvenated powder based on the powder characteristics. The developed models built on the understanding of the effect of powder characteristics on the part properties. The developed models were found to be capable of predicting the part density and surface roughness to within ±0.02% and ±0.5 Ra, respectively. The models developed enable L-PBF operators to input powder characteristics and predict the expected part density and surface roughness.

316L Stainless Steel Powders for Additive Manufacturing: Relationships of Powder Rheology, Size, Size Distribution to Part Properties.

Laser-Powder Bed Fusion (L-PBF) of metallic parts is a highly multivariate process. An understanding of powder feedstock properties is critical to ensure part quality. In this paper, a detailed examination of two commercial stainless steel 316L powders produced using the gas atomization process is presented. In particular, the effects of the powder properties (particle size and shape) on the powder rheology were examined. The results presented suggest that the powder properties strongly influence the powder rheology and are important factors in the selection of suitable powder for use in an additive manufacturing (AM) process. Both of the powders exhibited a strong correlation between the particle size and shape parameters and the powder rheology. Optical microscope images of melt pools of parts printed using the powders in an L-PBF machine are presented, which demonstrated further the significance of the powder morphology parameters on resulting part microstructures.

A novel long-acting biodegradable depot formulation of anastrozole for breast cancer therapy.

The purpose of the present study was to fabricate PLGA 50:50 and PLA microspheres for controlled delivery of anastrozole. The microspheres were prepared by oil-in-water (o/w) emulsion/solvent evaporation technique and evaluated for particle size and encapsulation. The optimised formulations were studied for solid state characterization, in vitro release and pharmacokinetic studies. The maximum encapsulation efficiency for PLGA 50:50 and PLA microspheres with 40:1 polymer - drug ratio was observed to be 78.4±2.5 and 87.7±2.6%. The solid state characterization confirmed dispersion of drug at the molecular level in the polymeric matrix. Microspheres were spherical in shape with a very smooth surface texture. Drug release was found to be in a sustained fashion, releasing constantly up to 720h (30days) for PLGA and 60days for PLA microspheres. The pharmacokinetic study data revealed that the intramuscular administration of PLA microspheres showed improved pharmacokinetic profile as compared to PLGA microspheres, and therefore this formulation can be considered as the best optimised formulation with sustained exposure of the drug in vivo compared to other microspheres. From experimental results, PLA microspheres demonstrate the feasibility of employing biodegradable depot polymeric microspheres of anastrozole for long-term treatment of breast cancer.

Nanomedicine of anastrozole for breast cancer: Physicochemical evaluation, in vitro cytotoxicity on BT-549 and MCF-7 cell lines and preclinical study on rat model.

AIM: Formulation and evaluation of anastrozole, an anti-cancer drug loaded in different biodegradable polymeric nanoparticles. MATERIALS AND METHODS: Different carrier systems such as poly(lactide-co-glycolide) (PLGA 50:50), poly(lactic-acid) (PLA) and poly(ε-caprolactone) (PCL) are used to prepare nanoparticles by simple emulsion technique. The surfactants polyvinyl alcohol and sodium deoxycholate were studied for their use as stabilizing agents at varying concentrations. The formulations were studied for their particle size, zeta potential, entrapment efficiency and solid state characteristics, and also were tested for their in vitro cytotoxicity and in vivo behavior in rats. KEY FINDINGS: The entrapment ranged from 35 to 85%, depending on the drug-polymer ratio used. Particle size ranged from 100 to 350nm with optimal zeta potential. Accordingly, discrete spherical nanoparticles with smooth surface were obtained as evidence from Field Emission Scanning Electron Microscopy (FESEM) study. The solid state characteristics revealed dispersion of drug at the molecular level in the polymeric matrix of nanoparticles. A non-Fickian transport with initial burst release followed by slow release was observed with nanoparticles. The remarkable decrease in cell viability at various time points was observed for PLGA nanoparticles compared to other polymer matrices. The AUC(0→∞) of PLGA, PLA and PCL nanoparticles were found to be 4.77, 19.31 and 19.81 fold higher than (p<0.05) anastrozole in solution, respectively. Also, pharmacokinetics study revealed the long time circulation of anastrozole loaded polymeric nanoparticles. SIGNIFICANCE: The results suggest that developed nanoparticles could be used successfully for effective management of breast cancer chemotherapy.