RESUMEN
BACKGROUND: The significant morbidity and mortality resulted from the infection of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) call for urgent development of effective and safe vaccines. We report the immunogenicity and safety of an inactivated SARS-CoV-2 vaccine, KCONVAC, in healthy adults. METHODS: Phase 1 and phase 2 randomized, double-blind, and placebo-controlled trials of KCONVAC were conducted in healthy Chinese adults aged 18 to 59 years. The participants in the phase 1 trial were randomized to receive two doses, one each on Days 0 and 14, of either KCONVAC (5 or 10 µg/dose) or placebo. The participants in the phase 2 trial were randomized to receive either KCONVAC (at 5 or 10 µg/dose) or placebo on Days 0 and 14 (0/14 regimen) or Days 0 and 28 (0/28 regimen). In the phase 1 trial, the primary safety endpoint was the proportion of participants experiencing adverse reactions/events within 28 days following the administration of each dose. In the phase 2 trial, the primary immunogenicity endpoints were neutralization antibody seroconversion and titer and anti-receptor-binding domain immunoglobulin G seroconversion at 28 days after the second dose. RESULTS: In the phase 1 trial, 60 participants were enrolled and received at least one dose of 5-µg vaccine (nâ=â24), 10-µg vaccine (nâ=â24), or placebo (nâ=â12). In the phase 2 trial, 500 participants were enrolled and received at least one dose of 5-µg vaccine (nâ=â100 for 0/14 or 0/28 regimens), 10-µg vaccine (nâ=â100 for each regimen), or placebo (nâ=â50 for each regimen). In the phase 1 trial, 13 (54%), 11 (46%), and seven (7/12) participants reported at least one adverse event (AE) after receiving 5-, 10-µg vaccine, or placebo, respectively. In the phase 2 trial, 16 (16%), 19 (19%), and nine (18%) 0/14-regimen participants reported at least one AE after receiving 5-, 10-µg vaccine, or placebo, respectively. Similar AE incidences were observed in the three 0/28-regimen treatment groups. No AEs with an intensity of grade 3+ were reported, expect for one vaccine-unrelated serious AE (foot fracture) reported in the phase 1 trial. KCONVAC induced significant antibody responses; 0/28 regimen showed a higher immune responses than that did 0/14 regimen after receiving two vaccine doses. CONCLUSIONS: Both doses of KCONVAC are well tolerated and able to induce robust immune responses in healthy adults. These results support testing 5-µg vaccine in the 0/28 regimen in an upcoming phase 3 efficacy trial. TRIAL REGISTRATION: http://www.chictr.org.cn/index.aspx (No. ChiCTR2000038804, http://www.chictr.org.cn/showproj.aspx?proj=62350; No. ChiCTR2000039462, http://www.chictr.org.cn/showproj.aspx?proj=63353).
Asunto(s)
COVID-19 , SARS-CoV-2 , Adulto , Vacunas contra la COVID-19 , Método Doble Ciego , Humanos , Vacunas de Productos Inactivados/efectos adversosRESUMEN
BACKGROUND: The tumor-targeting ability and pH-sensitive properties of intelligent drug delivery systems are crucial for effective drug delivery and anti-tumor therapy. METHODS: In this study, sHA-DOX/HA-GA mixed micelles were designed with the following properties: sulfated hyaluronic acid (sHA) was synthesized to block cell migration by inhibiting HAase; sHA-DOX conjugates were synthesized via pH-sensitive hydrazone bond to realize DOX-sensitive release. The introduction of HA-GA conjugate could improve active-targeting ability and cellular uptake. RESULTS: The results showed that the mixed micelles possessed a nearly spherical shape, nanoscale particle size (217.70±0.89 nm), narrow size distribution (PDI=0.07±0.04), negative zeta potential (-31.87±0.61 mV) and pH-dependent DOX release. In addition, the sHA-DOX/HA-GA micelles exhibited concentration-dependent cytotoxicities against liver carcinoma cells (HepG2) and HeLa cells, and were shown to be effectively taken up by HepG2 cells by confocal microscopy analysis. Furthermore, the in vivo anti-tumor study showed that mixed micelles had a superior anti-tumor effect compared to that of free DOX. Further evidence obtained from the hematoxylin-eosin staining and immunohistochemistry analysis also demonstrated that sHA-DOX/HA-GA exhibited stronger tumor inhibition and lower systemic toxicity than free DOX. CONCLUSION: The sHA-DOX/HA-GA mixed micelles could be a potential drug delivery system for anti-hepatoma therapy.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Ácido Hialurónico/química , Neoplasias Hepáticas/tratamiento farmacológico , Hígado/patología , Micelas , Sulfatos/química , Carcinoma Hepatocelular/patología , Movimiento Celular/efectos de los fármacos , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Liberación de Fármacos , Endocitosis , Células HeLa , Células Hep G2 , Humanos , Concentración de Iones de Hidrógeno , Hígado/efectos de los fármacos , Neoplasias Hepáticas/patología , Tamaño de la Partícula , Polímeros/química , Distribución Tisular/efectos de los fármacosRESUMEN
BACKGROUND: Recent efforts have been focused on combining two or more therapeutic approaches with different mechanisms to enhance antitumor therapy. Moreover, nanosize drug-delivery systems for codelivering two drugs with proapoptotic and antiangiogenic activities have exhibited great potential in efficient treatment of cancers. METHODS: Glycyrrhetinic acid (GA)-modified liposomes (GA LPs) for liver-targeted codelivery of curcumin (Cur) and combretastatin A4 phosphate (CA4P) were prepared and characterized. In vitro cellular uptake, cytotoxicity, cell migration, in vivo biodistribution, antitumor activity, and histopathological studies were performed. RESULTS: Compared with unmodified LPs (Cur-CA4P LPs), Cur-CA4P/GA LPs were taken up effectively by human hepatocellular carcinoma cells (BEL-7402) and showed higher cytotoxicity than free drugs. In vivo real-time near-infrared fluorescence-imaging results indicated that GA-targeted LPs increased accumulation in the tumor region. Moreover, Cur-CA4P/GA LPs showed stronger inhibition of tumor proliferation than Cur, Cur + CA4P, and Cur-CA4P LPs in vivo antitumor studies, which was also verified by H&E staining. CONCLUSION: GA-modified LPs can serve as a promising nanocarrier for liver-targeted co-delivery of antitumor drugs against hepatocellular carcinoma.
Asunto(s)
Antineoplásicos/farmacología , Curcumina/administración & dosificación , Curcumina/farmacología , Sistemas de Liberación de Medicamentos , Hígado/metabolismo , Estilbenos/administración & dosificación , Estilbenos/farmacología , Animales , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Ácido Glicirretínico/síntesis química , Ácido Glicirretínico/química , Humanos , Liposomas , Hígado/efectos de los fármacos , Masculino , Ratones Endogámicos BALB C , Tamaño de la Partícula , Fosfatidiletanolaminas/síntesis química , Fosfatidiletanolaminas/química , Polietilenglicoles/síntesis química , Polietilenglicoles/química , Espectroscopía de Protones por Resonancia MagnéticaRESUMEN
The tumor targetability and stimulus responsivity of drug delivery systems are crucial in cancer diagnosis and treatment. In this study, hepatoma-targeting mixed micelles composed of a hyaluronic acid-glycyrrhetinic acid conjugate and a hyaluronic acid-l-histidine conjugate (HA-GA/HA-His) were prepared through ultrasonic dispersion. The formation and characterization of the mixed micelles were confirmed via ¹H-NMR, particle size, and ζ potential measurements. The in vitro cellular uptake of the micelles was evaluated using human liver carcinoma (HepG2) cells. The antitumor effect of doxorubicin (DOX)-loaded micelles was investigated in vitro and in vivo. Results indicated that the DOX-loaded HA-GA/HA-His micelles showed a pH-dependent controlled release and were remarkably absorbed by HepG2 cells. Compared with free DOX, the DOX-loaded HA-GA/HA-His micelles showed a higher cytotoxicity to HepG2 cells. Moreover, the micelles effectively inhibited tumor growth in H22 cell-bearing mice. These results suggest that the HA-GA/HA-His mixed micelles are a good candidate for drug delivery in the prevention and treatment of hepatocarcinoma.
Asunto(s)
Antibióticos Antineoplásicos/química , Doxorrubicina/química , Portadores de Fármacos/química , Ácido Hialurónico/química , Micelas , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Femenino , Células Hep G2 , Histidina/química , Humanos , Concentración de Iones de Hidrógeno , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Espectroscopía de Resonancia Magnética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microscopía Electrónica de Transmisión , Tamaño de la Partícula , Trasplante HeterólogoRESUMEN
Histidine-hyaluronic acid (His-HA) conjugates were synthesized using hyaluronic acid (HA) as a hydrophilic segment and histidine (His) as hydrophobic segment by 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (EDC) mediated coupling reactions. The structural characteristics of the His-HA conjugates were investigated using (1)H NMR. His-HA nanoparticles (HH-NPs) were prepared based on His-HA conjugates, and the characteristics of HH-NPs were investigated using dynamic light scattering, transmission electron microscopy (TEM), scanning electron microscopy (SEM), and fluorescence spectroscopy. The particles were between 342 and 732 nm in size, depending on the degree of substitution (DS) of the His. TEM and SEM images indicated that the morphology of HH-NPs was spherical in shape. The critical aggregation concentrations of HH-NPs ranged from 0.034 to 0.125 mg/ml, which decreased with an increase in the DS of the His. Images of fluorescence microscopy indicate that HH-NPs were taken up by the cancer cell line (MCF-7), and significantly decreased by competition inhibition of free HA. From the cytotoxicity test, it was found that DOX-loaded HH-NPs exhibited similar dose and time-dependent cytotoxicity against MCF-7 cells with free DOX.