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Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy. However, its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment (ITM). Here, we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate (CaCO3) biomineralized Salmonella (Sal) as an in-situ cancer vaccine producer and systematical ITM regulator. CaCO3 can be facilely coated on the Sal surface with calcium ionophore A23187 co-loading, and such biomineralization did not affect the bioactivities of the bacteria. Upon intratumoral accumulation, the CaCO3 shell was decomposed at an acidic microenvironment to attenuate tumor acidity, accompanied by the release of Sal and Ca2+/A23187. Specifically, Sal served as a cancer vaccine producer by inducing cancer cells' immunogenic cell death (ICD) and promoting the gap junction formation between tumor cells and dendritic cells (DCs) to promote antigen presentation. Ca2+, on the other hand, was internalized into various types of immune cells with the aid of A23187 and synergized with Sal to systematically regulate the immune system, including DCs maturation, macrophages polarization, and T cells activation. As a result, such bio-vaccine achieved remarkable efficacy against both primary and metastatic tumors by eliciting potent anti-tumor immunity with full biocompatibility. This work demonstrated the potential of bioengineered bacteria as bio-active vaccines for enhanced tumor immunotherapy.
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@#In this study, different functional layer formulations and process parameters were used to prepare the levomilnacipran hydrochloride sustained-release capsules, the influence of functional layer formulation and process factors on dose dumping was studied by comparing their release curves in 40% ethanol; and the risk of dose dumping of the self-developed drug was evaluated by the similar factors of the release curve of the self-developed drug and the reference drug.The results showed that as the coating weight increased, the degree of dose dumping decreased; when the concentration of ethanol in the coating liquid solvent was less than 80%, the dose dumping increased; as the atomization pressure and maturation time increase, the dose dumping became more serious. In 0% ethanol (purified water), 5% ethanol, 20% ethanol and 40% ethanol media, the self-developed and reference preparations had the same degree of dose dumping within the specified time, and rotation speed had no significant effect on the release of metformin in vitro. In summary, formulation factors such as coating weight gain, ethanol concentration in the coating solution solvent, and process factors such as atomization pressure and curing time have a serious impact on the dose dumping of sustained-release capsules.Under the optimal functional layer formulation and process, special attention should be paid to the control of risk of self-developed dose dumping.
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The combination of chemotherapy and photodynamic therapy provides a promising approach for enhanced tumor eradication by overcoming the limitations of each individual therapeutic modality. However, tumor is pathologically featured with extreme hypoxia together with the adaptable overexpression of anti-oxidants, such as glutathione (GSH), which greatly restricts the therapeutic efficiency. Here, a combinatorial strategy was designed to simultaneously relieve tumor hypoxia by self-oxygenation and reduce intracellular GSH level to sensitize chemo-photodynamic therapy. In our system, a novel multi-functional nanosystem based on MnO
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Increasing the degree of supersaturation of drugs and maintaining their proper stability are very important in improving the oral bioavailability of poorly soluble drugs by a supersaturated drug delivery system (SDDS). In this study, we reported a complex system of Soluplus-Copovidone (Soluplus-PVPVA) loaded with the model drug silybin (SLB) that could not only maintain the stability of a supersaturated solution but also effectively promote oral absorption. The antiprecipitation effect of the polymers on SLB was observed using the solvent-shift method. In addition, the effects of the polymers on absorption were detected by cellular uptake and transport experiments. The mechanisms by which the Soluplus-PVPVA complex promotes oral absorption were explored by dynamic light scattering, transmission electron microscopy, fluorescence spectra and isothermal titration calorimetry analyses. Furthermore, a pharmacokinetic study in rats was used to demonstrate the advantages of the Soluplus-PVPVA complex. The results showed that Soluplus and PVPVA spontaneously formed complexes in aqueous solution the adsorption of PVPVA on the hydrophilic-hydrophobic interface of the Soluplus micelle, and the Soluplus-PVPVA complex significantly increased the absorption of SLB. In conclusion, the Soluplus-PVPVA complex is a potential SDDS for improving the bioavailability of hydrophobic drugs.
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Aim To investigate the effect of SM-1 on seven main cytochrome P450(CYP450)in human liver microsomes.Methods Substrate or SM-1 was incubated with human liver microsomes for 30 min in vitro,and divided into control group and experimental group.The effects of SM-1 on the main phase I metabolic enzymes in human liver microsomes was detected by HPLC.Phenacetin,bupropion,paclitaxel,tolbutamide,omeprazole,dextromethorphan,testosterone were investigated as probe drugs.Results Inhibition rate of SM-1 on the classical substrate of human liver microsomal CYP was 0.05%,3.37%,0.08%,2.07%,4.20%,-0.15%and 10.84%,respectively.Conclusions SM-1 may have inhibitory effect on CYP3A4.Attention should be paid to the interaction of clinical drug induced by CYP enzyme inhibition.
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Shenfu Injection (SFI) is a well-defined Chinese herbal formulation that is obtained from red ginseng and processed aconite root. The main active constituents in SFI are ginsenosides and aconitum alkaloids. In this work, ginsenosides (ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rc) and aconitum alkaloids (benzoylmesaconine and fuziline) were used as the index components to explore the pharmacokinetic behavior of SFI. A selective and sensitive HPLC-MS/MS method was developed for the quantification of ginsenosides and aconitum alkaloids in dog plasma and was used to characterize the pharmacokinetics of the five index components after intravenous drip of three different dosages of SFI in beagle dogs. The pharmacokinetic properties of the index components were linear over the dose range of 2-8 mL/kg.
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Aim To study absorption characteristics of SM-1 , a novel anti-tumor agent , to provide a research basis for the druggability evaluation of SM-1 and formu-lation design. Methods Caco-2 cell monolayer model and in situ single-pass intestinal perfusion rat model were used to study the absorption characteristics of SM-1 , and the absorption of SM-1 in vivo was evaluated through absolute bioavailability study in rats. Results The results of cell monolayer model showed that cu-mulative absorption and efflux of SM-1 increased line-arly with concentration ( 10 ~40 mg · L-1 ) . There were no significant differences in Papp with different concentrations ( P>0. 05 ) . SM-1 was absorbed mainly through passive diffusion. The intestinal perfusion re-sults showed that Ka and Pef of SM-1 had no significant differences ( P > 0. 05 ) , when the concentrations ranged from 25 to 100 mg · L-1 . SM-1 entered the systemic circulation mainly via on passive diffusion, indicating it is a compound with high permeability. The absorption of SM-1 in duodenum was superior to other intestinal segments ( P 0. 05 ) . The absolute bioavailability of SM-1 in rats was 29. 3%. Conclusion The membrane perme-ability of SM-1 is high and it can be absorbed by intes-tine well. The absorption mechanism of SM-1 is pas-sive diffusion, and it possibly escapes from the efflux transporter protein. The absolute bioavailability of SM-1 in rats is low.
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Molecular imaging technology, an advanced research area of imaging, can provide real-time, non-invasive image information of the target site in molecular level. The key of the molecular imaging technology is molecular probe. Aptamers are short oligonucleotides with high affinity and specificity to the target molecules. The targeting ability, stability and safety of aptamers are superior to traditional antibodies so that aptamers show prosperous usages in targeting drug delivery and disease diagnostics. Therefore, aptamers are considered to be an extremely ideal probes, which can guide quantum dots, magnetic nanoparticles and ultrasound contrast agents on the targets and realize optical, magnetic resonance, ultrasonic multimodal and multifunctional imaging. All of the advantages can further promote the application of molecular imaging in disease treatment and diagnosis. In this paper, we review recent developments in the application of aptamers as molecular probes in major branches of molecular imaging.
Subject(s)
Animals , Humans , Aptamers, Nucleotide , Contrast Media , Molecular Imaging , Methods , Molecular Probes , SELEX Aptamer TechniqueABSTRACT
We studied the correlation of sustained-release tablet of naftopidil between the in vitro release and the in vivo absorption in the dog. The release rate (X) of naftopidil sustained-release tablet in artificial gastric fluid was determined and the naftopidil concentration in plasma was determined after a single oral dose of 100 mg naftopidil (tablet or sustained-release tablet) in the dog. The absorbed fraction(F) and in vivo absorption rate (A) of the NAF sustained-release tablet in the dog at different time were calculated by W-N method and deconvolution method, respectively. Then the regression equations between F or A and X of the corresponding time point were obtained: F=2. 1533X - 27. 636(r = 0.9927) and A=2.3452X - 25.474(r= 0.9938). W-N method and deconvolution method both indicated that the correlation between the in vitro release and the in vivo absorption in the dog of the NAF sustained-release tablet was good.
Subject(s)
Animals , Dogs , Biological Availability , Delayed-Action Preparations , Naphthalenes , Chemistry , Pharmacokinetics , Piperazines , Chemistry , Pharmacokinetics , Solubility , TabletsABSTRACT
AIM To prepare naftopidil bioadhesive sustained-release capsule and study their pharmacokinetics and relative bioavailability in the dog. METHODS Bioadhesive polymers such as hydroxypropyl methylcellulse (HPMC) and Carbopol 934 (CP 934) were used in capsule prescriptions. Naftopidil capsule and two formulations of bioadhesive sustained-release capsules (I and II) were given to five healthy male dogs in a cross-over test. The naftopidil concentrations in plasma were determined by a newly developed HPLC method and the pharmacokinetic parameters as well as the relative bioavailability were measured. RESULTS The C0→∞, Cmax and Tmax of naftopidil capsule was (3728±573) h*ng*mL-1, (697±94) ng*mL-1 and (1.2±0.5) h. These parameters of bioadhesive sustained-release capsule I and II, respectively, were (5518±391) h*ng*mL-1 and (5636±427) h*ng*mL-1; (468±61) ng*mL-1 and (512±72) ng*mL-1; both (4.0±0.7) h. Results from statistics showed that there were significant difference between bioadhesive formulations and the non-bioadhesive one in C0→∞, Cmax and Tmax. The bioadhesive formulations and the non-bioadhesive one were not bioequivalent, the relative bioavailability of the two bioadhesive sustained-release capsules were respectively 150%±14% and 154%±23% when compared with the non-bioadhesive capsule. CONCLUSION It is much improving bioavailability of naftopidil by using bioadhesion.
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OBJECTIVE:To study the in vitro-in vivo correlation of sustained-release naftopidil capsule,review the rationality of the designed dissolution conditions METHODS:Artificial gastric juice was selected as the dissolution medium,the dissolution rate of the two naftopidil sustained-release capsules were studied;the 3p97 pharmacokinetic program was used to characterize the in vivo course of the sustained-release capsules after giving dogs a oral single dose of 200mg,after this,the percentage absorbed at different time were calculated The input functions were obtained by using deconvolution technique Then the correlation coefficients of the calibration graph by plotting the dissolution rate to the percentage absorbed or the input functions were calculated The in vitro-in vivo correlations of sustained-release naftopidil capsules were studied by comparing the correlation coefficients calculated to the critical correlation coefficients RESULTS:The correlation coefficients calculated by the two methods were both more than the critical coefficients,the in vitro-in vivo correlations of the two sustained-release naftopidil capsules were good CONCLUSION:The two methods mentioned in this paper to study the in vitro-in vivo correlation were simple and reliable,the results of this study were very useful in the rapid formulation screening,the designing of rational dissolution rate conditions,and the providing theory basic of evaluation of the naftopidil sustained-release capsules
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OBJECTIVE:To screen the formulations of bioadhesive danazol suppository,and to study its drug release in vitro.METHODS:Hydroxypropyl methylcellulse(HPMC),polyethylene glycol(PEG)6000and PEG600were employed in the bioadhesive sustained-release formulation.Suppositories were prepared and the correlation between drug release rate from suppositories and the ratio of HPMC to PEGs used in the formulae was studied.RESULTS:HPMC retarded drug release,and drug gradually released in the12-hours period when the ratio of HPMC to PEGs was1∶6.5;the law of drug release was conformed to weibull models and mono-exponential models.CONCLUSION:HPMC,PEG6000and PEG600were suitable to the formulation of bioadhesive danazol suppositories,and HPMC could slow down the drug release from the this preparation;the best ratio of HPMC to PEGs was1∶6.5.