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Triple-negative breast cancer (TNBC) is more aggressive and difficult to treat using conventional bulk chemotherapy that is often associated with increased toxicity and side effects. In this study, we encapsulated targeted drugs [A bacteria-synthesized anticancer drug (prodigiosin) and paclitaxel] using single solvent evaporation technique with a blend of FDA-approved poly lactic-co-glycolic acid-polyethylene glycol (PLGA_PEG) polymer microspheres. These drugs were functionalized with Luteinizing Hormone-Releasing hormone (LHRH) ligands whose receptors are shown to overexpressed on surfaces of TNBC. The physicochemical, structural, morphological and thermal properties of the drug-loaded microspheres were then characterized using Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), Dynamic Light Scattering (DLS), Nuclear Magnetic Resonance Spectroscopy (NMR), Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC). Results obtained from in vitro kinetics drug release at human body temperature (37 °C) and hyperthermic temperatures (41 and 44 °C) reveal a non-Fickian sustained drug release that is well-characterized by Korsmeyer-Peppas model with thermodynamically non-spontaneous release of drug. Clearly, the in vitro and in vivo drug release from conjugated drug-loaded microspheres (PLGA-PEG_PGS-LHRH, PLGA-PEG_PTX-LHRH) is shown to result in greater reductions of cell/tissue viability in the treatment of TNBC. The in vivo animal studies also showed that all the drug-loaded PLGA-PEG microspheres for the localized and targeted treatment of TNBC did not caused any noticeable toxicity and thus significantly extended the survival of the treated mice post tumor resection. The implications of this work are discussed for developing targeted drug systems to treat and prevent local recurred triple negative breast tumors after surgical resection.

Bulk chemotherapy and drug release strategies for cancer treatment have been associated with lack of specificity and high drug concentrations that often result in toxic side effects. This work presents the results of an experimental study of cancer drugs (prodigiosin or paclitaxel) conjugated to Luteinizing Hormone-Releasing Hormone (LHRH) for the specific targeting and treatment of triple negative breast cancer (TNBC). Injections of LHRH-conjugated drugs (LHRH-prodigiosin or LHRH-paclitaxel) into groups of 4-week-old athymic female nude mice (induced with subcutaneous triple negative xenograft breast tumors) were found to specifically target, eliminate or shrink tumors at early, mid and late stages without any apparent cytotoxicity, as revealed by in vivo toxicity and ex vivo histopathological tests. Our results show that overexpressed LHRH receptors serve as binding sites on the breast cancer cells/ tumor and the LHRH-conjugated drugs inhibited the growth of breast cells/tumor in in vitro and in vivo experiments. The inhibitions are attributed to the respective adhesive interactions between LHRH molecular recognition units on the prodigiosin (PGS) and paclitaxel (PTX) drugs and overexpressed LHRH receptors on the breast cancer cells and tumors. The implications of the results are discussed for the development of ligand-conjugated drugs for the specific targeting and treatment of TNBC. Breast cancer is the most commonly diagnosed cancer and the second most frequent cause of death in women 1. In general, breast tumors are intrinsically heterogeneous in nature, making them difficult to detect and treat 2. Approximately, 75-80% of breast cancers are hormone receptor-positive 2,3. Also, these overexpressed receptors are usually estrogen and/or progesterone receptors 2,3. However, Triple Negative Breast Cancer (TNBC) (which represents approximately 10-17% of all breast cancers) does not express estrogen receptors (ER), or progesterone receptors (PR), or the human epidermal growth factor receptor 2 gene (HER2) 4-8. In addition, TNBCs also exhibit distinctive clinical features 7,8 and are more common in younger patients 6 and African American/African women 9. TNBC is an aggressive and immunopathology subtype of breast cancer that usually does not respond to drugs that target ER, PR and HER2 6. Furthermore, since the most common and conventional breast cancer diagnosis and treatment techniques tend to focus and target ER, PR and HER2, it is often difficult to detect 10 and treat 11 TNBCs with conventional targeted hormonal therapy and chemotherapy. The challenges associated with TNBCs

This article presents the results of the combined effects of RGD (arginine-glycineaspartate) 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.

In this study, we explore the development of controlled PLGA-CS-PEG microspheres, which are used to encapsulate model anticancer drugs (prodigiosin (PGS) or paclitaxel (PTX)) for controlled breast cancer treatment. The PLGA microspheres are blended with hydrophilic polymers (chitosan and polyethylene glycol) in the presence of polyvinyl alcohol (PVA) that were synthesized via a water-oil-water (W/O/W) solvent evaporation technique. Chitosan (CS) and polyethylene glycol (PEG) were used as surface-modifying additives to improve the biocompatibility and reduce the adsorption of plasma proteins onto the microsphere surfaces. These PLGA-CS-PEG microspheres are loaded with varying concentrations (5 and 8 mg/mL) of PGS or PTX, respectively. Scanning electron microscopy (SEM) revealed the morphological properties while Fourier transform infrared spectroscopy (FTIR) was used to elucidate the functional groups of drug-loaded PLGA-CS-PEG microparticles. A thirty-day, in vitro, encapsulated drug (PGS or PTX) release was carried out at 37 °C, which corresponds to human body temperature, and at 41 °C and 44 °C, which correspond to hyperthermic temperatures. The thermodynamics and kinetics of in vitro drug release were also elucidated using a combination of mathematical models and the experimental results. The exponents of the Korsmeyer–Peppas model showed that the kinetics of drug release was well characterized by anomalous non-Fickian drug release. Endothermic and nonspontaneous processes are also associated with the thermodynamics of drug release. Finally, the controlled in vitro release of cancer drugs (PGS and PTX) is shown to decrease the viability of MDA-MB-231 cells. The implications of the results are discussed for the development of drug-encapsulated PLGA-CS-PEG microparticles for the controlled release of cancer drugs in treatment of triple negative breast cancer.