Doxorubicin-loaded Niosomes functionalized with gelatine and alginate as pH-responsive drug delivery system: A 3D printing approach.

Despite many efforts, breast cancer remains one of the deadliest cancers and its treatment faces challenges related to cancer drug side effects and metastasis. Combining 3D printing and nanocarriers has created new opportunities in cancer treatment. In this work, 3D-printed gelatin-alginate nanocomposites containing doxorubicin-loaded niosomes (Nio-DOX@GT-AL) were recruited as an advanced potential pH-sensitive drug delivery system. Morphology, degradation, drug release, flow cytometry, cell cytotoxicity, cell migration, caspase activity, and gene expression of nanocomposites and controls (Nio-DOX and Free-DOX) were evaluated. Results show that the obtained niosome has a spherical shape and size of 60-80 nm. Sustained drug release and biodegradability were presented by Nio-DOX@GT-AL and Nio-DOX. Cytotoxicity analysis revealed that the engineered Nio-DOX@GT-AL scaffold had 90 % cytotoxicity against breast cancer cells (MCF-7), whereas exhibited <5 % cytotoxicity against the non-tumor breast cell line (MCF-10A), which was significantly more than the antitumor effect of the control samples. Scratch-assay as an indicator cell migration demonstrated a reduction of almost 60 % of the covered surface. Gene expression could provide an explanation for the antitumor effect of engineered nanocarriers, which significantly reduced metastasis-promoting genes (Bcl2, MMP-2, and MMP-9), and significantly enhanced the expression and activity of genes that promote apoptosis (CASP-3, CASP-8, and CASP-9). Also, considerable inhibition of metastasis-associated genes (Bax and p53) was observed. Moreover, flow-cytometry data demonstrated that Nio-DOX@GT-AL decreased necrosis and enhanced apoptosis drastically. The findings of this research can confirm that employing 3D-printing and niosomal formulation can be an effective strategy in designing novel nanocarriers for efficient drug delivery applications.

3D-printing-assisted synthesis of paclitaxel-loaded niosomes functionalized by cross-linked gelatin/alginate composite: Large-scale synthesis and in-vitro anti-cancer evaluation.

Breast cancer is one of the most lethal cancers, especially in women. Despite many efforts, side effects of anti-cancer drugs and metastasis are still the main challenges in breast cancer treatment. Recently, advanced technologies such as 3D-printing and nanotechnology have created new horizons in cancer treatment. In this work, we report an advanced drug delivery system based on 3D-printed gelatin-alginate scaffolds containing paclitaxel-loaded niosomes (Nio-PTX@GT-AL). The morphology, drug release, degradation, cellular uptake, flow cytometry, cell cytotoxicity, migration, gene expression, and caspase activity of scaffolds, and control samples (Nio-PTX, and Free-PTX) were investigated. Results demonstrated that synthesized niosomes had spherical-like, in the range of 60-80 nm with desirable cellular uptake. Nio-PTX@GT-AL and Nio-PTX had a sustained drug release and were biodegradable. Cytotoxicity studies revealed that the designed Nio-PTX@GT-AL scaffold had <5 % cytotoxicity against non-tumorigenic breast cell line (MCF-10A) but showed 80 % cytotoxicity against breast cancer cells (MCF-7), which was considerably more than the anti-cancer effects of control samples. In migration evaluation (scratch-assay), approximately 70 % reduction of covered surface area was observed. The anticancer effect of the designed nanocarrier could be attributed to gene expression regulation, where a significant increase in the expression and activity of genes promoting apoptosis (CASP-3, CASP-8, and CASP-9) and inhibiting metastasis (Bax, and p53) and a remarkable decrease in metastasis-enhancing genes (Bcl2, MMP-2, and MMP-9) were observed. Also, flow cytometry results declared that Nio-PTX@GT-AL reduced necrosis and increased apoptosis considerably. The results of this study prove that employing 3D-printing and niosomal formulation is an effective approach in designing nanocarriers for efficient drug delivery applications.

Rapid generation of homogenous tumor spheroid microtissues in a scaffold-free platform for high-throughput screening of a novel combination nanomedicine.

Combination nanomedicine is a potent strategy for cancer treatment. Exploiting different mechanisms of action, a novel triple drug delivery system of 5-fluorouracil, curcumin, and piperine co-loaded human serum albumin nanoparticles (5FU-CUR-PIP-HSA-NPs) was developed via the self-assembly method for suppressing breast tumor. Both hydrophobic and hydrophilic drugs were successfully encapsulated in the HSA NPs with a high drug loading efficiency (DLE) of 10%. Successful clinical translation of nanomedicines, however, is a challenging process requiring considerable preclinical in vitro and in vivo animal tests. The aim of this study was to develop a homemade preclinical 3D culture model in the standard 96-well plates in a cost and time-effective novel approach for the rapid generation of homogenous compact tumor spheroids for disease modeling, and anticancer therapeutic/nanomedicine screening. The knowledge of drug screening can be enhanced by employing such a model in a high-throughput manner. Accordingly, to validate the formulated drug delivery system and investigate the cellular uptake and cytotoxicity effect of the nanoformulation, 3D tumor spheroids were employed. The practicality of the nanomedicine system was substantiated in different tests. The in vitro uptake of the NPs into the tight 3D tumor spheroids was facilitated by the semi-spherical shape of the NPs with a proper size and surface charge. 5FU-CUR-PIP-HSA-NPs demonstrated high potency of migration inhibition as a part of successful anti-metastatic therapy as well. The remarkable differences in 2D and 3D cytotoxicities emphasize the importance of employing 3D tumor models as an intermediate step prior to in vivo animal experiments for drug/nanomedicine screening.

Synergistic Effect of Self-Assembled Curcumin and Piperine Co-Loaded Human Serum Albumin Nanoparticles on Suppressing Cancer Cells.

OBJECTIVE: The combinational therapy is often considered as a desire in chemotherapy despite some limitations. This study aimed to encapsulate two natural-based drugs, curcumin (CUR), and piperine (PIP) into highly biocompatible albumin nanoparticles for anticancer applications. SIGNIFICANCE: A simultaneous exertion of CUR and PIP in a biocompatible drug delivery system with the minimum side effects and no limitations was achievable in this work for cancer treatment. METHODS: Curcumin and piperine co-loaded human serum albumin nanoparticles (CUR-PIP-HSA-NPs) were synthesized by the self-assembly method. The effectiveness of the codelivery system was evaluated physically, chemically, and pharmaceutically. Moreover, the anticancer activity of CUR-PIP-HSA-NPs was studied on MCF-7 cells by MTT assay. RESULTS: CUR-PIP-HSA-NPs showed appropriate stability with an average particle size of 154.7 ± 5.2 nm. Loading of drugs was demonstrated by Fourier transform infrared (FT-IR) and differential scanning calorimetry (DSC) analyses. The drug encapsulation efficiencies (DEEs) of CUR and PIP in NPs were 85.3% ± 1.46% and 81.7%, ± 1.67%, respectively. Furthermore, the drug loading efficiency (DLE) of CUR-PIP-HSA-NPs was 8.71% ± 0.24%. The circular dichroism (CD) examination of the NPs confirmed that the conformational structure of albumin remained unchanged during the synthesis. In addition, the cytotoxicity experiments demonstrated the high potential of CUR-PIP-HSA-NPs against breast cancer (MCF-7) cells in the presence of PIP as both bioenhancer and anticancer drug with the capability of suppressing the effect of multidrug resistance (MDR). CONCLUSIONS: The results suggest that CUR-PIP-HSA-NPs can be employed as a practical drug delivery system in cancer treatment with synergistic effects of both CUR and PIP.

A comparative and systematic approach to desolvation and self-assembly methods for synthesis of piperine-loaded human serum albumin nanoparticles.

The present work aimed to accomplish a comparative and principled study on desolvation and self-assembly methods for synthesis of piperine-loaded human serum albumin nanoparticles (PIP-HSA-NPs). Among drugs, PIP was selected as the hydrophobic model drug. The response surface methodology (RSM)-central composite design (CCD) was employed to precisely study the processes and the interactions between the factors affecting the methods. Optimization was performed to obtain the best formulations for both procedures. Both optimized PIP-HSA-NPs prepared by the two methods were stable and semi-spherical with the size less than 200 nm. The self-assembled PIP-HSA-NPs which were prepared under the optimized conditions with drug encapsulation efficiency (DEE) of 76.8% ± 0.44%, and drug loading efficiency (DLE) of 8.92% ± 0.3% had significantly higher DEE and DLE than the optimized particles obtained from the desolvation method with DEE of 34.1% ± 0.32% and DLE of 1.68 ±â€¯0.11%. The secondary structure of HSA did not change much in self-assembled PIP-HSA-NPs compared to desolvated PIP-HSA-NPs. The self-assembled PIP-HSA-NPs showed more cumulative drug release than desolvated NPs, causing them to have more cytotoxicity on MCF-7 cells at high concentrations. These findings introduce the self-assembly technique as the better chemical method to produce a practical cost-effective carrier for many hydrophobic drugs.

Correlation between Aerobic Fitness and Body Composition in Middle School Students.

BACKGROUND: Since correlations have been found between body composition and physical activity in different parts of the world, inactivity and poor physical condition likely contributes main factors in childhood obesity. This study was implemented to determine the relationship between cardiovascular fitness and body-composition in a group of Iranian middle school students. METHODS: In this descriptive study, subjects comprised of 12,946 students (10,531 girls and 2,415 boys aged 11-13 years) in the city of Isfahan. Height, weight, body-fat percent, body mass index, and cardiovascular fitness of the aforesaid students were measured by valid tests. RESULTS: This study showed that fat percentage and aerobic fitness (VO2 max) of girls were 24.73%, and 29.5 (ml/kg/min) and boys19.32% and 36.4 (ml/kg/min) respectively. Results also revealed that there was a negative significant correlation between fat percent and aerobic fitness of boys (r = -0.81), and girls (r = -0.77) respectively. CONCLUSIONS: To conclude, this study signifies that fat percentage augmentation leads to a decrease in aerobic fitness of children. Thus, fat percentage can be associated with different chronic diseases such as cardiovascular ones.