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.

Nanoindentation study of the viscoelastic properties of human triple negative breast cancer tissues: Implications for mechanical biomarkers.

This paper presents the results of a combined experimental and theoretical study of the structure and viscoelastic properties of human non-tumorigenic mammary breast tissues and triple negative breast cancer (TNBC) tissues of different histological grades. A combination of immunofluorescence and confocal microscopy, and atomic force microscopy is used to study the actin cytoskeletal structures of non-tumorigenic and tumorigenic breast tissues (grade I to grade III). A combination of nanoindentation and statistical techniques is then used to measure viscoelastic properties of non-tumorigenic and human TNBC of different histological grades. A Standard Fluid Model/Anti-Zener Model II is also used to characterize the viscoelastic properties of the non-tumorigenic and tumorigenic TNBC tissues of different grades. The implications of the results are discussed for the potential application of nanoindentation and statistical deconvolution techniques to the development of mechanical biomarkers for TNBC detection/cancer diagnosis. STATEMENT OF SIGNIFICANCE: There is increasing interest in the development of mechanical biomarkers for cancer diagnosis. Here, we show that nanoindentation techniques can be used to characterize the viscoelastic properties of normal breast tissue and TNBC tissues of different histological grades. The Standard Fluid Model (Anti-Zener Model II) is used to classify the viscoelastic properties of breast tissues of different TNBC histological grades. Our results suggest that breast tissue and TNBC tissue viscoelastic properties can be used as mechanical biomarkers for the detection of TNBC at different stages.

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.

Adhesion of LHRH/EphA2 to human Triple Negative Breast Cancer tissues.

The adhesive interactions between molecular recognition units (such as specific peptides and antibodies) and antigens or other receptors on the surfaces of tumors are of great value in the design of targeted nanoparticles and drugs for the detection and treatment of specific cancers. In this paper, we present the results of a combined experimental and theoretical study of the adhesion between Luteinizing Hormone Releasing Hormone (LHRH)/Epherin type A2 (EphA2)-AFM coated tips and LHRH/EphA2 receptors that are overexpressed on the surfaces of human Triple Negative Breast Cancer (TNBC) tissues of different histological grades. Following a histochemical and immuno-histological study of human tissue extracts, the receptor overexpression, and their distributions are characterized using Immunohistochemistry (IHC), Immunofluorescence (IF), and a combination of fluorescence microscopy and confocal microscopy. The adhesion forces between LHRH or EphA2 and human TNBC breast tissues are measured using force microscopy techniques that account for the potential effects of capillary forces due to the presence of water vapor. The corresponding adhesion energies are also determined using adhesion theory. The pull off forces and adhesion energies associated with higher grades of TNBC are shown to be greater than those associated with normal/non-tumorigenic human breast tissues, which were studied as controls. The observed increase in adhesion forces and adhesion energies are also correlated with the increasing incidence of LHRH/EphA2 receptors at higher grades of TNBC. The implications of the results are discussed for the development of targeted nanostructures for the detection and treatment 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.

Tele-Operative Low-Cost Robotic Lung Ultrasound Scanning Platform for Triage of COVID-19 Patients.

Novel severe acute respiratory syndrome coronavirus 2 (COVID-19) has become a pandemic of epic proportions, and global response to prepare health systems worldwide is of utmost importance. 2-dimensional (2D) lung ultrasound (LUS) has emerged as a rapid, noninvasive imaging tool for diagnosing COVID-19 infected patients. Concerns surrounding LUS include the disparity of infected patients and healthcare providers, and importantly, the requirement for substantial physical contact between the patient and operator, increasing the risk of transmission. New variants of COVID-19 will continue to emerge; therefore, mitigation of the virus's spread is of paramount importance. A tele-operative robotic ultrasound platform capable of performing LUS in COVID-19 infected patients may be of significant benefit, especially in low- and middle-income countries. The authors address the issues mentioned above surrounding the use of LUS in COVID-19 infected patients and the potential for extension of this technology in a resource-limited environment. Additionally, first-time application, feasibility, and safety were validated in healthy subjects. Preliminary results demonstrate that our platform allows for the successful acquisition and application of robotic LUS in humans.

Cell-surface interactions on gold-coated polydimethylsiloxane nanocomposite structures: Localized laser heating on cell viability.

This article presents the results of cell-surface interactions on polydimethylsiloxane (PDMS)-based substrates coated with nanoscale gold (Au) thin films. The surfaces of PDMS and PDMS-magnetite (MNP)-based substrates were treated with UV-ozone, prior to thermal vapor deposition (sputter-coated) of thin films of titanium (Ti) onto the substrates to improve the adhesion of Au coatings. The thin layer of Ti was thermally evaporated to improve interfacial adhesion, which was enhanced by a 40-nm thick film microwrinkled/buckled wavy layer of Au, that was coated to enhance cell-surface interactions and protein absorption. Cell-surface interactions were studied on the hybrid surfaces using a combination of optical and fluorescence microscopy. Consequently, cell proliferation and surface cytotoxicity (of the sputter-coated PDMS surfaces) were elucidated by characterizing the metabolic activity in the presence of breast cancer and normal breast cells. The photothermal conversion efficiency associated with laser-materials interactions with the PDMS/PDMS-magnetite-based composites was shown to have an optimum efficiency of ~31.8%. The implications of the results are discussed for potential applications of PDMS nanocomposites in implantable biomedical devices.

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.

Actin cytoskeletal structure and the statistical variations of the mechanical properties of non-tumorigenic breast and triple-negative breast cancer cells.

This paper presents the results of a study of the actin cytoskeletal structures and the statistical variations in the actin fluorescence intensities and viscoelastic properties of non-tumorigenic breast cells and triple-negative breast cancer cells at different stages of tumor progression. The variation in the actin content of the cell cytoskeletal structures is shown to be consistent with the viscoelastic properties of the cell as it progresses from non-tumorigenic to more metastatic states. The corresponding viscoelastic properties of the nuclei and the cytoplasm (Young's moduli, viscosities, and relaxation times) of the cells are also measured using Digital Image Correlation (DIC) and shear assay techniques. These properties are shown to exhibit statistical variations that are well characterized by normal distributions. The changes in the mean properties of individual cancer cells are tested using Fisher pairwise comparisons and the analysis of variance (ANOVA). The implications of the results are then discussed for the development of shear assay techniques and mechanical biomarkers for the detection of triple-negative breast cancer at different stages of tumor progression.

Adhesion of ligand-conjugated biosynthesized magnetite nanoparticles to triple negative breast cancer cells.

This paper presents the results of an experimental study of the adhesion forces between components of model conjugated magnetite nanoparticle systems for improved selectivity in the specific targeting of triple negative breast cancer. Adhesion forces between chemically synthesized magnetite nanoparticles (CMNPs), biosynthesized magnetite nanoparticles (BMNPs), as well as their conjugated systems and triple negative breast cancer cells (MDA-MB-231) or normal breast cells (MCF 10A) are elucidated at a nanoscale. In all cases, the BMNPs had higher adhesion forces (to breast cancer cells and normal breast cells) than CMNPs. The adhesion of LHRH-conjugated BMNPs or BSA-conjugated BMNPs to cancer cells is shown to be about 6 times to that of normal breast cells. The increase in adhesion forces between luteinizing hormone-releasing hormone, LHRH- or EphA2, a breast specific antibody(BSA)-conjugated BMNPs to breast cancer cells is attributed to van der Waals interactions between the peptides/antibodies from the conjugated nanoparticles and the over-expressed receptors (revealed using immunofluorescence staining) on the surfaces of the breast cancer. The implications of the results are discussed for the selectivity and specificity of breast cancer targeting by ligand-conjugated BMNPs.