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Alan IS Morais, 1,* Xichi Wang, 2–4,* Ewerton G Vieira, 1 Bartolomeu C Viana, 1, 5 Edson C Silva-Filho, 1 Josy A Osajima, 1 Samson Afewerki, 3, 4 Marcus AF Corat, 6 Heurison S Silva, 5 Fernanda R Marciano, 5 Guillermo U Ruiz-Esparza, 3, 4 Thiago D Stocco, 6, 7 Mirian MM de Paula, 6 Anderson O Lobo 1 1LIMAV-Interdisciplinary Laboratory for Advanced Materials, Materials Science and Engineering Graduate Program, UFPI-Federal University of Piauí, Teresina, PI CEP 64049-550, Brazil; 2Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People’s Republic of China; 3Division of Engineering in Medicine, Department of Medicine, Harvard Medical School, Brigham & Women´s Hospital, Cambridge, MA 02139, USA; 4Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, MIT, Cambridge, MA 02139, USA; 5Department of Physics, UFPI-Federal University of Piauí, Teresina, PI CEP 64049-550, Brazil; 6Multidisciplinary Center for Biological Research, University of Campinas (UNICAMP), Campinas 13083-877, Brazil; 7Faculty of Physiotherapy, Santo Amaro University, São Paulo 04829-300, Brazil*These authors contributed equally to this workCorrespondence: Anderson O Lobo Email lobo@ufpi.edu.brBackground: The facile preparation of oxygen-generating microparticles (M) consisting of Polycaprolactone (PCL), Pluronic F-127, and calcium peroxide (CPO) (PCL-F-CPO-M) fabricated through an electrospraying process is disclosed. The biological study confirmed the positive impact from the oxygen-generating microparticles on the cell growth with high viability. The presented technology could work as a prominent tool for various tissue engineering and biomedical applications.Methods: The oxygen-generated microparticles fabricated through electrospraying processes were thoroughly characterization through various methods such as X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR) analysis, and scanning electron microscopy (SEM)/SEM-Energy Dispersive Spectroscopy (EDS) analysis.Results: The analyses confirmed the presence of the various components and the porous structure of the microparticles. Spherical shape with spongy characteristic microparticles were obtained with negative charge surface (ζ = – 16.9) and a size of 17.00 ± 0.34 μm. Furthermore, the biological study performed on rat chondrocytes demonstrated good cell viability and the positive impact of increasing the amount of CPO in the PCL-F-CPO-M.Conclusion: This technological platform could work as an important tool for tissue engineering due to the ability of the microparticles to release oxygen in a sustained manner for up to 7 days with high cell viability.Keywords: oxygen-generating-microparticles, electrospraying, tissue engineering, calcium peroxide, cartilage

Guillermo U Ruiz-Esparza,1,3 Jose H Flores-Arredondo,2 Victor Segura-Ibarra,3 Guillermo Torre-Amione,2,3 Mauro Ferrari,1 Elvin Blanco,1,* Rita E Serda1,3,* 1Methodist Hospital Research Institute, 2Methodist DeBakey Heart and Vascular Center, Methodist Hospital, Houston, TX, USA; 3Escuela de Medicina y Ciencias de la Salud, Instituto Tecnológico y de Estudios Superiores de Monterrey, Cátedra de Cardiología y Medicina Vascular, Monterrey, Mexico *Senior authors Abstract: Heart disease remains the major cause of death in males and females, emphasizing the need for novel strategies to improve patient treatment and survival. A therapeutic approach, still in its infancy, is the development of site-specific drug-delivery systems. Nanoparticle-based delivery systems, such as liposomes, have evolved into robust platforms for site-specific delivery of therapeutics. In this review, the clinical impact of cardiovascular disease and the pathophysiology of different subsets of the disease are described. Potential pathological targets for therapy are introduced, and promising advances in nanotherapeutic cardiovascular applications involving liposomal platforms are presented. Keywords: liposomes, cardiovascular disease, therapeutics, nanoparticles, nanomedicine

Background: The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) (PI3k/Akt/mTOR) pathway is dysregulated in certain breast cancers. Ongoing clinical trials aim to therapeutically exploit this pathway through administration of rapamycin (RAP), an mTOR inhibitor, in combination with paclitaxel (PTX). However, actual drug synergy in clinical settings may not be fully realized due to disparate pharmacokinetic parameters of individual drug formulations, wherein drugs or their effects may never be present in the tumor at the same time. Our objective was to generate a nanoparticle platform capable of site-specifically delivering precise amounts of rapamycin and paclitaxel to breast tumors with hopes of increasing synergistic targeting of the PI3k/Akt/mTOR pathway. Materials and Methods: Drug-containing nanoparticles composed of amphiphilic block copolymers of pegylated poly (∈-caprolactone) (PEG-PCL, MW = 5k-5k) were fabricated and nanoparticle size and drug loading efficiency was determined. In vitro growth inhibition of nanoparticle formulations of varying ratios was evaluated in MCF-7 and MDA-MB-468 breast cancer cells via sulforhodamine B assays, after which median-effect plot analyses and combination index calculations were conducted. Antitumor efficacy studies were performed in female nude mice bearing MDA-MB-468 tumors, in which nanoparticles were administered intravenously twice a week for the duration of three weeks. Biodistribution of drug-containing nanoparticles in extracted tumors were examined, as well as reverse phase protein array (RPPA) analysis to gain insights into site-specific synergy. Results: Nanoparticles were spherical, with an average diameter of 9 nm. Both rapamycin and paclitaxel loaded favorably, allowing for customization of different ratios within nanoparticles. Combination indices demonstrated that a 3:1 ratio of RAP:PTX had the most synergy in MDA-MB-468 breast cancer cells in vitro, a synergy found to be preserved in vivo. Significant tumor regression (> 1.5 fold reduction from initial tumor volume) was observed in vivo upon administration of 3:1 RAP:PTX (15:5 mg/kg) nanoparticles. The precise ratio of rapamycin and paclitaxel (3:1) was found maintained in tumors 24 h after administration, an effect not achievable with free drug formulations. RPPA analysis demonstrated effective blocking of mTOR and Akt 24 h after administration of nanoparticles, key events in drug synergy. Discussion: Site-specific delivery of synergistic agents in precisely-controlled drug ratios, possible through their incorporation into nanoparticles, was shown to be highly efficacious against breast tumors. Findings demonstrate the ability to deliver specific drug ratios to tumors, potentially precluding the need to administer maximal doses of both agents in order to achieve synergy, lessening patient side-effects. This study demonstrates the potential for prediction of in vivo therapeutic outcomes from in vitro synergistic findings. Nanoparticle delivery of drugs may also yield enhanced understanding of mechanisms of synergy between molecular-targeted drugs and traditional chemotherapeutics in vivo, resulting in novel and more efficacious treatment regimens. [ABSTRACT FROM AUTHOR]