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      Oral Treatment of Spontaneously Hypertensive Rats with Captopril-Surface Functionalized Furosemide-Loaded Multi-Wall Lipid-Core Nanocapsules


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          Multi-wall lipid-core nanocapsule (MLNC) functionalized with captopril and nanoencapsulating furosemide within the core was developed as a liquid formulation for oral administration. The nanocapsules had mean particle size below 200 nm, showing unimodal and narrow size distributions with moderate dispersity (laser diffraction and dynamic light scattering). Zeta potential was inverted from −14.3 mV [LNC-Fur(0,5)] to +18.3 mV after chitosan coating. Transmission electron microscopy and atomic force microscopy showed spherical structures corroborating the nanometric diameter of the nanocapsules. Regarding the systolic pressure, on the first day, the formulations showed antihypertensive effect and a longer effect than the respective drug solutions. When both drugs were associated, the anti-hypertensive effect was prolonged. On the fifth day, a time effect reduction was observed for all treatments, except for the nanocapsule formulation containing both drugs [Capt(0.5)-Zn(25)-MLNC-Fur(0.45)]. For diastolic pressure, only Capt(0.5)-Zn(25)-MLNC-Fur(0.45) presented a significant difference ( p < 0.05) on the first day. On the fifth day, both Capt(0.5)-MLNC-Fur(0.45) and Capt(0.5)-Zn(25)-MLNC-Fur(0.45) had an effect lasting up to 24 h. The analysis of early kidney damage marker showed a potential protection in renal function by Capt(0.5)-Zn(25)-MLNC-Fur(0.45). In conclusion, the formulation Capt(0.5)-Zn(25)-MLNC-Fur(0.45) proved to be suitable for hypertension treatment envisaging an important innovation.

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          Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile.

          We describe the development and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors. DTXL-TNP is targeted to prostate-specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors. DTXL-TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading, and drug release properties. Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half-life of about 20 hours and minimal liver accumulation. In tumor-bearing mice, DTXL-TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent-based DTXL formulation (sb-DTXL). In tumor-bearing mice, rats, and nonhuman primates, DTXL-TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL, with total DTXL plasma concentrations remaining at least 100-fold higher than sb-DTXL for more than 24 hours. Finally, initial clinical data in patients with advanced solid tumors indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL, including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb-DTXL dose typically used in the clinic.
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            Rapid quantification of malondialdehyde in plasma by high performance liquid chromatography-visible detection.

            Malondialdehyde (MDA) is one of the better-known secondary products of lipid peroxidation, and it is widely used as an indicator of cellular injury. The employment of the thiobarbituric acid reactive substances (TBARS) technique to measure MDA has received criticism over the years because of its lack of specificity. Thus, a specific and reliable method for MDA determination in plasma by high performance liquid chromatographic (HPLC)-VIS was validated; alkaline hydrolysis, n-butanol extraction steps and MDA stability were established. The plasma underwent alkaline hydrolysis, acid deproteinization, derivatization with TBA and n-butanol extraction. After this, MDA was determined at 532 nm by HPLC-VIS. The method was applied to 65-year-old subjects from a retirement home. The assay was linear from 0.28 to 6.6 microM. The reproducibility of intra-run was obtained with CV%<4% and the inter run with CV%<11%. The accuracy (bias) ranged from 2 to -4.1%, and the recovery was greater than 95%. The limit of detection (LOD) and limit of quantification (LOQ) were 0.05 and 0.17 microM, respectively. For the stability test, every sample was stored at -20 degrees C. The plasma MDA was not stable when stored after the alkaline hydrolysis step, remained stable for 30 days after TBA derivatization storage and was stable for 3 days when stored after n-butanol extraction. The elderly subjects had MDA plasma levels of 4.45+/-0.81 microM for women and 4.60+/-0.95 microM for men. The method is reproducible, accurate, stable, sensitive, and can be used in the routines in clinical laboratories. Besides, this technique presents advantages such as the complete release of protein bound MDA with the alkaline hydrolysis step, the removal of interferents with n-butanol extraction, mobile phase without phosphate buffer and rapid analytical processes and run times.
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              A brain-targeted rabies virus glycoprotein-disulfide linked PEI nanocarrier for delivery of neurogenic microRNA.

              Recent advances in efficient microRNA (miRNA) delivery techniques using brain-targeted nanoparticles offer critical information for understanding the functional role of miRNAs in vivo, and for supporting targeted gene therapy in terms of treating miRNA-associated neurological diseases. Here, we report the rabies virus glycoprotein (RVG)-labeled non-toxic SSPEI nanomaterials capable of neuron-specific miR-124a delivery to neuron in vivo. The RVG-labeled BPEI-SS (RVG-SSPEI) nanocarrier showed less toxicity in acetylcholine receptor-positive Neuro2a cells, and electrostatic interaction of RVG-SSPEI with miR-124a exhibited optimal transfection efficacy. The RVG-SSPEI polymer specifically targeted Neuro2a using cy5.5-miR-124a mixed with RVG-SSPEI. The functional action of miR-124a oligomers released from polyplexes in the cytoplasmic region was evaluated by a reporter vector containing a miR-124a -binding sequence, and showed a significantly reduced reporter signal in a dose-dependent manner. Cy5.5-miR-124a/RVG-SSPEI- injected into mice via tail veins displayed the enhanced accumulation of miR-124a in the isolated brain. Hindrance of the efficient penetration of neuronal cells by size limitation of the miR-124a/RVG-SSPEI improved with the help of mannitol through blood-brain barrier disruption. These findings indicated that the RVG peptide combined with mannitol infusion using SSPEI polymer for neuron-specific targeting in vivo is sufficient to deliver neurogenic microRNA into the brain. Copyright © 2011 Elsevier Ltd. All rights reserved.

                Author and article information

                18 January 2020
                January 2020
                : 12
                : 1
                : 80
                [1 ]Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Avenida Ipiranga 2752, Porto Alegr 90610-000, Brazil; cbmicha@ 123456hotmail.com (C.B.M.); marcelo.arbo@ 123456gmail.com (M.D.A.); adriana.pohlmann@ 123456ufrgs.br (A.R.P.)
                [2 ]Departamento de Produção e Controle de Medicamentos, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Avenida Ipiranga 2752, Porto Alegre 90610-000, Brazil
                [3 ]Laboratório de Toxicologia (LATOX), Universidade Federal do Rio Grande do Sul, Avenida Ipiranga 2752, Porto Alegre 90610-000, Brazil; lualtk@ 123456gmail.com
                [4 ]Instituto de Ciências Básicas da Saúde, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 Anexo, Porto Alegre 90035-003, Brazil; vet.andreia@ 123456gmail.com
                [5 ]Laboratório de Microscopia Avançada, Departamento de Física, Universidade Federal do Ceara, Campus do Pici, Fortaleza 60455-900, Brazil; samara.abreu@ 123456alu.ufc.br (A.S.G.A.); lucianamagal@ 123456fisica.ufc.br (L.M.R.A.)
                [6 ]Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio Grande do Sul, PBox 15003, Avenida Bento Gonçalves, 9500, Porto Alegre 91501-970, Brazil
                Author notes
                Author information
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                : 17 December 2019
                : 15 January 2020

                lipid-core nanocapsules,antihypertensive,surface-functionalization,captopril,furosemide,toxicity,oral drug delivery


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