Targeted drug-loaded PLGA-PCL microspheres for specific and localized treatment of triple negative breast cancer.

The paper presents the results of the experimental and analytical study of targeted drug-loaded polymer-based microspheres made from blend polymer of polylactic-co-glycolic acid and polycaprolactone (PLGA-PCL) for targeted and localized cancer drug delivery. In vitro sustained release with detailed thermodynamically driven drug release kinetics, over a period of three months using encapsulated targeted drugs (prodigiosin-EphA2 or paclitaxel-EphA2) and control drugs [Prodigiosin (PGS), and paclitaxel (PTX)] were studied. Results from in vitro study showed a sustained and localized drug release that is well-characterized by non-Fickian Korsmeyer-Peppas kinetics model over the range of temperatures of 37 °C (body temperature), 41 °C, and 44 °C (hyperthermic temperatures). The in vitro alamar blue, and flow cytometry assays in the presence of the different drug-loaded polymer formulations resulted to cell death and cytotoxicity that was evidence through cell inhibition and late apoptosis on triple negative breast cancer (TNBC) cells (MDA-MB 231). In vivo studies carried out on groups of 4-week-old athymic nude mice that were induced with subcutaneous TNBC, showed that the localized release of the EphA2-conjugated drugs was effective in complete elimination of residual tumor after local surgical resection. Finally, ex vivo histopathological analysis carried out on the euthanized mice revealed no cytotoxicity and absence of breast cancer metastases in the liver, kidney, and lungs 12 weeks after treatment. The implications of the results are then discussed for the development of encapsulated EphA2-conjugated drugs formulation in the specific targeting, localized, and sustain drug release for the elimination of local recurred TNBC tumors after surgical resection.

Self-organized mycelium biocomposites: Effects of geometry and laterite composition on compressive behavior.

This study investigates the compressive deformation and the effect of structural architecture on the compressive strength of bioprocessed mycelium biocomposites reinforced with laterite particles. In the mycelium blocks, lignocellulosic hemp hurds function as reinforcing and nutritional substrates. The mycelium acts as a supportive matrix, binding the hemp hurds and the laterite particles which are integrated for further reinforcement to improve the compressive strength of the composite. The compressive behavior of the composites is elucidated using a combined approach of experimental and theoretical studies. The deformation mechanisms are investigated via in-situ observations of the specimens under uniaxial compressive loading. The experiments show that the compressive deformation results in progressive micro-buckling in slender specimens, whereas thicker samples exhibit a soft elastic response at small strain levels followed by continuous stiffening at larger strains. Based on the experimental observations and the morphological characterization, a column buckling analysis was developed for the mycelium-hemp composites to further explain the observed deformation phenomena.

Sustained release of alpha-methylacyl-CoA racemase (AMACR) antibody-conjugated and free doxorubicin from silica nanoparticles for prostate cancer cell growth inhibition.

This article presents silica nanoparticles for the sustained release of AMACR antibody-conjugated and free doxorubicin (DOX) for the inhibition of prostate cancer cell growth. Inorganic MCM-41 silica nanoparticles were synthesized, functionalized with phenylboronic acid groups (MCM-B), and capped with dextran (MCM-B-D). The nanoparticles were then characterized using Fourier-transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, zeta potential analysis, nitrogen sorption, X-ray diffraction, and thermogravimetric analysis, before exploring their potential for drug loading and controlled drug release. This was done using a model prostate cancer drug, DOX, and a targeted prostate cancer drug, α-Methyl Acyl-CoA racemase (AMACR) antibody-conjugated DOX, which attaches specifically to AMACR proteins that are overexpressed on the surfaces of prostate cancer cells. The kinetics of sustained drug release over 30 days was then studied using zeroth order, first order, second order, Higuchi, and the Korsmeyer-Peppas models, while the thermodynamics of drug release was elucidated by determining the entropy and enthalpy changes. The flux of the released DOX was also simulated using the COMSOL Multiphysics software package. Generally, the AMACR antibody-conjugated DOX drug-loaded nanoparticles were more effective than the free DOX drug-loaded formulations in inhibiting the growth of prostate cancer cells in vitro over a 96 h period. The implications of the results are then discussed for the development of drug-eluting structures for the localized and targeted treatment of prostate cancer.

Triptorelin-functionalized PEG-coated biosynthesized gold nanoparticles: Effects of receptor-ligand interactions on adhesion to triple negative breast cancer cells.

This paper presents the results of an experimental and computational study of the adhesion of triptorelin-conjugated PEG-coated biosynthesized gold nanoparticles (GNP-PEG-TRP) to triple-negative breast cancer (TNBC) cells. The adhesion is studied at the nanoscale using a combination of atomic force microscopy (AFM) experiments and molecular dynamics (MD) simulations. The AFM measurements showed that the triptorelin-functionalized gold nanoparticles (GNP-TRP and GNP-PEG-TRP) have higher adhesion to triple-negative breast cancer cells (TNBC) than non-tumorigenic breast cells. The increased adhesion of GNP-TRP and GNP-PEG-TRP to TNBC is also attributed to the overexpression of LHRH receptors on the surfaces of both TNBC. Finally, the molecular dynamics model reveals insights into the effects of receptor density, molecular configuration, and receptor-ligand docking characteristics on the interactions of triptorelin-functionalized PEG-coated gold nanoparticles with TNBC. A three to nine-fold increase in the adhesion is predicted between triptorelin-functionalized PEG-coated gold nanoparticles and TNBC cells. The implications of the results are then discussed for the specific targeting of TNBC.

Laser-induced heating of polydimethylsiloxane-magnetite nanocomposites for hyperthermic inhibition of triple-negative breast cancer cell proliferation.

This paper presents the results of an experimental and computational study of the effects of laser-induced heating provided by magnetite nanocomposite structures that are being developed for the localized hyperthermic treatment of triple-negative breast cancer. Magnetite nanoparticle-reinforced polydimethylsiloxane (PDMS) nanocomposites were fabricated with weight percentages of 1%, 5%, and 10% magnetite nanoparticles. The nanocomposites were exposed to incident Near Infrared (NIR) laser beams with well-controlled powers. The laser-induced heating is explored in: (i) heating liquid media (deionized water and cell growth media [Leibovitz L15+]) to characterize the photothermal properties of the nanocomposites, (ii) in vitro experiments that explore the effects of localized heating on triple-negative breast cancer cells, and (iii) experiments in which the laser beams penetrate through chicken tissue to heat up nanocomposite samples embedded at different depths beneath the chicken skin. The resulting plasmonic laser-induced heating is explained using composite theories and heat transport models. The results show that the laser/nanocomposite interactions decrease the viability of triple-negative breast cancer cells (MDA-MB-231) at temperatures in the hyperthermia domain between 41 and 44°C. Laser irradiation did not cause any observed physical damage to the chicken tissue. The potential in vivo performance of the PDMS nanocomposites was also investigated using computational finite element models of the effects of laser/magnetite nanocomposite interactions on the temperatures and thermal doses experienced by tissues that surround the nanocomposite devices. The implications of the results are then discussed for the development of implantable nanocomposite devices for localized treatment of triple-negative breast cancer tissue via hyperthermia.

In vitro studies of Annona muricata L. extract-loaded electrospun scaffolds for localized treatment of breast cancer.

This paper presents in vitro studies of the sustained release of Annona muricata leaf extracts (AME) from hybrid electrospun fibers for breast cancer treatment. Electrospun hybrid scaffolds were fabricated from crude AME extracts, poly(lactic-co-glycolic acid)/gelatin (PLGA/Ge) and pluronic F127. The physicochemical properties of the AME extract and scaffolds were studied. The antiproliferative effects of the scaffolds were also assessed on breast cancer (MCF-7 and MDA-MB-231) and non-tumorigenic breast (MCF10A) cell lines. Scanning electron microscope micrographs revealed a random network of micro- and submicron fibers. In vitro drug release profiles, governed by quasi-Fickian diffusion at pH 7.4 and non-Fickian super case II at pH 6.7, showed initial burst AME release from the PLGA/Ge-AME and PLGA/Ge-F127/AME fibers at pH 7.4, and burst release from PLGA/Ge-F127/AME (not observed from PLGA/Ge-AME) at pH 6.7. Then, a slower, sustained release of the remaining AME from the fibers, attributed to the onset of degradation of the PLGA/Ge backbone, was observed for the next 72 hr. The cumulative release of AME was 89.33 ± 0.73% (PLGA/Ge-AME) and 51.17 ± 7.96% (PLGA/Ge-F127/AME) at pH 7.4, and 9.27 ± 2.3% and 73.5 ± 4.5%, respectively, at pH 6.7. Pluronic F127 addition increased the drug loading capacity and prolonged the sustained AME release from the fibers. The released AME significantly inhibited the in vitro growth of the breast cancer cells more than the non-tumorigenic cells, due to the induction of apoptosis, providing evidence for using pluronic F127-containing electrospun fibers for sustained and localized AME delivery to breast cancer cells.

Mechanical stimulation improves osteogenesis and the mechanical properties of osteoblast-laden RGD-functionalized polycaprolactone/hydroxyapatite scaffolds.

This article presents the results of the combined effects of RGD (arginine-glycine-aspartate) functionalization and mechanical stimulation on osteogenesis that could lead to the development of implantable robust tissue-engineered mineralized constructs. Porous polycaprolactone/hydroxyapatite (PCL/HA) scaffolds are functionalized with RGD-C (arginine-glycine-aspartate-cysteine) peptide. The effects of RGD functionalization are then explored on human fetal osteoblast cell adhesion, proliferation, osteogenic differentiation (alkaline phosphatase activity), extracellular matrix (ECM) production, and mineralization over 28 days. The effects of RGD functionalization followed by mechanical stimulation with a cyclic fluid shear stress of 3.93 mPa in a perfusion bioreactor are also elucidated. The tensile properties (Young's moduli and ultimate tensile strengths) of the cell-laden scaffolds are measured at different stages of cell culture to understand how the mechanical properties of the tissue-engineered structures evolve. RGD functionalization is shown to promote initial cell adhesion, proliferation, alkaline phosphatase (ALP) activity, and ECM production. However, it does not significantly affect mineralization and tensile properties. Mechanical stimulation after RGD functionalization is shown to further improve the ALP activity, ECM production, mineralization, and tensile properties, but not cell proliferation. The results suggest that combined RGD functionalization and mechanical stimulation of cell-laden PCL/HA scaffolds can be used to accelerate the regeneration of robust bioengineered bone structures.

Electrospun oriented gelatin-hydroxyapatite fiber scaffolds for bone tissue engineering.

Tissue engineering of human fetal osteoblast cells was investigated on gelatin-hydroxyapatite (HA), crosslinked, electrospun oriented fiber scaffolds at the different HA concentrations of 0, 10, 20, and 25 wt % in the dry fibers and different fiber diameter, pore size and porosity of scaffolds. Rheological tests and proton nuclear magnetic resonance spectroscopy were conducted for all solutions used for electrospinning. It was found that 25 wt % HA-gelatin scaffolds electrospun at 20 kV led to the greatest cell attachment, cell proliferation and extracellular matrix (ECM) production while fiber orientation improved the mechanical properties, where crosslinked electrospun 25 wt % HA-gelatin fiber scaffolds yielded a Young's modulus in the range of 0.5-0.9 GPa and a tensile strength in the range of 4-10 MPa in the fiber direction for an applied voltage of 20-30 kV, respectively, in the electrospinning of scaffolds. Biological characterization of cell seeded scaffolds yielded the rate of cell growth and ECM (collagen and calcium) production by the cells as a function of time; it included cell seeding efficiency tests, alamar blue cell proliferation assay, alkaline phosphate (ALP) assay, collagen assay, calcium colorimetric assay, fluorescence microscopy for live and dead cells, and scanning electron microscopy for cell culture from 1 to 18 days. After 18 days, cells seeded and grown on the 25 wt % HA-gelatin scaffold, electrospun at 20 kV, reached production of collagen at 370 µg/L and calcium production at 0.8 mM. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1911-1926, 2017.