Résumé
Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance. Herein, a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms. A disulfide bond-linked bispecific prodrug of NLG919 and JQ1 (namely NJ) was synthesized and self-assembled into a prodrug nanoparticle, which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ. Upon tumor accumulation via passive tumor targeting, the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug. NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond. JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1. In contrast, NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment, which thus restores robust antitumor immune responses. Photodynamic therapy (PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells. The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.
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Drug delivery systems (DDS) are defined as methods by which drugs are delivered to desired tissues, organs, cells and subcellular organs for drug release and absorption through a variety of drug carriers. Its usual purpose to improve the pharmacological activities of therapeutic drugs and to overcome problems such as limited solubility, drug aggregation, low bioavailability, poor biodistribution, lack of selectivity, or to reduce the side effects of therapeutic drugs. During 2015-2018, significant progress in the research on drug delivery systems has been achieved along with advances in related fields, such as pharmaceutical sciences, material sciences and biomedical sciences. This review provides a concise overview of current progress in this research area through its focus on the delivery strategies, construction techniques and specific examples. It is a valuable reference for pharmaceutical scientists who want to learn more about the design of drug delivery systems.
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Objective To evaluate the effect of setup errors on the 2D image projection and image registration, and then propose an improved registration method based on mutual information. Methods An anthropomorphic head phantom was used to simulate the rotational and translational setup errors. The geometric disparities were reflected by the changes of mutual information. Known setup errors were intentionally introduced to twenty cases divided into two groups demarcated by 3 mm translation error and 3° rotation error: ten cases with larger errors and ten with smaller errors. Then the anterior-posterior and lateral portal images were captured by the electronic portal imaging device ( EPID ) , based on which the setup errors were calculated using two mutual information registration method respectively: the vender provided one, and the improved method as proposed. The calculated errors were compared with the actual setup errors to evaluate robustness of the method. Results For the ten cases with smaller setup errors, the average translational registration disparities using the conventional method were 0. 3, 0. 4, and 0. 3 mm in x, y and z directions respectively. The rotational disagreements were 0. 4° in both x and z directions. The average time consumption was 28. 7 s. The corresponding discrepancies analyzed using the improved method were 0. 3, 0. 4, 0. 3 mm, 0. 5° and 0. 4°, respectively. On average, 31. 1 s was needed for registration. For the ten cases with larger setup errors, the mean disparities of the conventional method were 0. 9, 0. 7, 0. 8 mm, 0. 9° and 0. 8°, 29. 9 s taken on average. The corresponding result of the improved method was 0. 5, 0. 4, 0. 5 mm, 0. 6° and 0. 5°, 33. 2 s taken on average. Conclusions Regarding smaller setup errors, the two methods showed little difference and both had good performance in imageregistration accuracy. For larger setup errors, however, the improved mutual information registration method exhibited significantly higher accuracy than the conventional method, at cost of clinically acceptable registration time.
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Objective To evaluate the effect of setup errors on the 2D image projection and image registration, and then propose an improved registration method based on mutual information. Methods An anthropomorphic head phantom was used to simulate the rotational and translational setup errors. The geometric disparities were reflected by the changes of mutual information. Known setup errors were intentionally introduced to twenty cases divided into two groups demarcated by 3 mm translation error and 3° rotation error: ten cases with larger errors and ten with smaller errors. Then the anterior-posterior and lateral portal images were captured by the electronic portal imaging device ( EPID ) , based on which the setup errors were calculated using two mutual information registration method respectively: the vender provided one, and the improved method as proposed. The calculated errors were compared with the actual setup errors to evaluate robustness of the method. Results For the ten cases with smaller setup errors, the average translational registration disparities using the conventional method were 0. 3, 0. 4, and 0. 3 mm in x, y and z directions respectively. The rotational disagreements were 0. 4° in both x and z directions. The average time consumption was 28. 7 s. The corresponding discrepancies analyzed using the improved method were 0. 3, 0. 4, 0. 3 mm, 0. 5° and 0. 4°, respectively. On average, 31. 1 s was needed for registration. For the ten cases with larger setup errors, the mean disparities of the conventional method were 0. 9, 0. 7, 0. 8 mm, 0. 9° and 0. 8°, 29. 9 s taken on average. The corresponding result of the improved method was 0. 5, 0. 4, 0. 5 mm, 0. 6° and 0. 5°, 33. 2 s taken on average. Conclusions Regarding smaller setup errors, the two methods showed little difference and both had good performance in imageregistration accuracy. For larger setup errors, however, the improved mutual information registration method exhibited significantly higher accuracy than the conventional method, at cost of clinically acceptable registration time.
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Objective To investigate the radiosensitization effects of the combination treatment of clioquinol (CQ) and zinc on human cervical cell line HeLa in vitro.Methods Cells were divided into the 4 groups:controls,drug,radiation,and combined drug and radiation group.Cytotoxic effect of CQ and zinc on cell viability was determined by CCK-8 assay.Radiosensitization effect of CQ and zinc on HeLa cells was detected by colongenic assay,and the single-hit multi-target model was used to stimulate the doseresponse curve of survival and to calculate radiosensitization parameters.The cell cycle and apoptosis of HeLa cells were analyzed with flow cytometry.Luciferase reporter assay was used to study NF-κB activity of HeLa cells.Results The combination of CQ and zinc inhibited cell growth in a dose-dependent manner (F =188.00,P ＜ 0.01).The mean lethal dose was 3.16 and 2.04 Gy for radiation group and combined drug and radiation group,respectively,and hence the SER was 1.55.Compared with the radiation group,the ratio of G2-phase cells in the combined drug and radiation group decreased(t =10.39,P ＜ 0.05),the apoptosis rate increased at 24 h post-irradiation (t =5.64,P ＜ 0.01),and the NF-κB activity decreased (t =21.42,P ＜ 0.05).Compared to the control group,the NF-κB activity increased in the radiation group(t=6.23,P＜0.05),but decreased in the drug group(t =12.48,P＜0.05).Conclusions The combination of CQ and zinc could increase the radiosensitivity of HeLa cells by decreasing the ratio of G2-phase cells,increasing apoptosis and the inhibiting of NF-κB activity.
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Objective To investigate the therapeutic effects and toxic effects of radiochemotherapy versus chemotherapy alone in patients with advanced gastric cancer after gastrectomy.Methods A total of 183 patients with stage Ⅱ-Ⅳ (M0) gastric cancer,who received treatment after gastrectomy from 2004 to 2010,were included in the study.Of the 183 patients,64 received radiochemotherapy after gastrectomy,and 119 received chemotherapy alone after gastrectomy.The survival rates and hematological and gastrointestinal toxic effects were compared between the two groups;survival difference was also analyzed after the patients were stratified by TNM stage,number of metastatic lymph nodes,and extent of lymph node dissection (D0,D1,and D2).The Kaplan-Meier method was used for calculating survival rates,and the log-rank test was used for survival difference analysis and univariate prognostic analysis;the chi-square test was used for comparing toxic effects between the two groups.Results The follow-up rate was 87.8％ ;72 patients were followed up for at least 3 years,and 29 patients for at least 5 years.The 1-,3-,and 5-year survival rates for the radiochemotherapy group were 86％,62％,and 55％,respectively,as compared with 77％,53％,and 43％ for the chemotherapy group (P =0.079).There were no significant differences in grade 3-4 hematological and gastrointestinal toxic effects between the two groups (P =0.363 and 0.617).The univariate analysis showed that radiochemotherapy had a significantly better survival benefit than chemotherapy alone in patients with stage ⅢB-Ⅳ (M0) gastric cancer,patients who underwent D0 lymph node dissection,and patients with more than 6 metastatic lymph nodes (P =0.022,0.025,and 0.021).Conclusions Compared with chemotherapy alone,radiochemotherapy tends to improve survival in patients with gastric cancer after gastrectomy,and its toxic effects are tolerable.The patients with stage ⅢB-Ⅳ (M0) gastric cancer,patients who undergo D0 lymph node dissection,and patients with more than 6 metastatic lymph nodes can benefit from radiochemotherapy.
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Objective To detect the selective inhibitory effects of irradiation plus adenovirusmediated horseradish peroxidase ( HRP)/indole-3-acetic acid (IAA) suicide gene system using tumorspecific and radio-inducible chimeric promoter on human hepatocellular carcinoma subcutaneously xenografted in nude mouse.MethodsRecombinant replicated-deficient adenovirus vector containing HRP gene and chimeric human telomerase reverse transcriptase (hTERT) promoter carrying 6 radioinducible CArG elements was constructed.A human subcutaneous transplanting hepatocellular carcinoma (MHCC97 cell line) model was treated with -γ-ray irradiation plus intra-tumor injections of adenoviral vector and intra-peritoneal injections of prodrug IAA.The change of tumor volume and tumor growth inhibiting rate,the survival time of nude mice,as well as histopathology of xenograft tumor and normal tissues were evaluated.Results Thirty one days after the treatment,the relative tumor volumes in the negative,adenovirus therapy,irradiation,and combination groups were 49.23 ± 4.55,27.71 :± 7.74,28.53 + 10.48 and 11.58 ± 3.23,respectively.There was a significantly statistical difference among them (F = 16.288,P ＜0.01 ).The inhibition effect in the combination group was strongest as compared with that in other groups,and its inhibition ratio was 76.5%.The survival period extended to 43 d in the combination group,which showed a significantly difference with that in the control group(x2 = 18.307 ,P ＜0.01 ).The area of tumors necrosis in the combination group was larger than that in the other groups,and the normal tissues showed no treatment-related toxic effect in all groups.However,multiple hepatocellular carcinoma metastases were observed in the liver in the control group,there were a few metastases in the monotherapy groups and no metastasis in the combination group.Conclusions Adenovirus-mediated suicide gene therapy plus radiotherapy dramatically could inhibit tumor growth and prolong median survival time.It might provide a promising therapeutic modality for hepatocellular carcinoma therapy.