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DNA immunotherapy with polyphosphoester microspheres and nanospheres.

机译：用聚磷酸酯微球和纳米球进行DNA免疫治疗。

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The immune response to DNA vaccines can be modified and enhanced by the surrounding cytokine milieu so delivery of the appropriate cytokines by biodegradable polymeric controlled-release systems may be beneficial. The physical size of the administered DNA-containing systems is critical for uptake by the appropriate tissues and for processing by cells. A polyphosphoester polymer was chosen due to its attractive degradation and physicochemical properties. Parameters that affect the size of controlled-release biodegradable microspheres and nanospheres were examined, and spheres in defined size ranges were produced.; These spheres were administered into mice by two routes: the muscle and the bladder. Intramuscular administration of bolus plasmid LacZ (pLacZ) elicited an antibody response, which was no different than when recombinant IFN-γ protein (rIFN-γ) was co-injected as bolus or encapsulated in microspheres. Additionally, microsphere-encapsulated LacZ co-injected with bolus rIFN-γ did not produce an antibody response. In contrast, when DNA was either coencapsulated or coinjected with encapsulated rIFN-γ, the antibody response was significantly enhanced, especially the TH2 response. These findings may lead to the use of cytokines as specific adjuvants in a much different manner than they are presently used, since the effects of a particular cytokine may be based upon the kinetics of administration.; Bladder administration of polyphosphoester nanospheres containing DNA resulted in bladder uptake and trafficking to the lymphatics and transport to the lymph node interior, which was not seen with larger sizes of the same spheres (microspheres). Furthermore, nanospheres of a different polymer, polystyrene, did not enter the lymph node. For polyphosphoester nanospheres, gene expression was noted in the lymph nodes, and immune responses such as an antibody response and spleen enlargement were observed. These results illustrate the interesting potential of the bladder delivery route in immunization and the startling dependence of tissue trafficking on particulate composition.; In summary, coadministration of antigen-encoding DNA with microencapsulated cytokine protein (rIFN-γ) or nanoencapsulated cytokine genes (pGM-CSF) via the intramuscular and bladder routes of delivery, respectively, were found to enhance the immune responses to the DNA vaccine. Thus, the encapsulation of genes and cytokine proteins into biodegradable spheres may customize the immune responses to gene-based immunotherapies.
机译：可以通过周围的细胞因子环境来修饰和增强对DNA疫苗的免疫反应，因此通过可生物降解的聚合物控释系统递送适当的细胞因子可能是有益的。所施用的含DNA的系统的物理尺寸对于适当的组织摄取和细胞加工至关重要。选择聚磷酸酯聚合物是由于其有吸引力的降解和理化性质。检查了影响可控释的可生物降解微球和纳米球尺寸的参数，并生产了定义尺寸范围的球。这些球体通过两种途径向小鼠给药：肌肉和膀胱。推注质粒LacZ（pLacZ）的肌内给药引起抗体应答，这与推注推注或封装在微球中的重组IFN-γ蛋白（rIFN-γ）相同。另外，与大剂量rIFN-γ共注射的微球包囊的LacZ不会产生抗体应答。相反，当将DNA与rIFN-γ共包封或共包封时，抗体反应显着增强，尤其是T H 2反应。这些发现可能导致以与目前使用的细胞因子大不相同的方式将细胞因子用作特定的佐剂，因为特定细胞因子的作用可能取决于给药的动力学。对含有DNA的多磷酸酯纳米球进行膀胱给药会导致膀胱摄取，向淋巴管的运输和向淋巴结内部的运输，这在较大尺寸的相同球体（微球体）中是看不到的。此外，另一种聚合物聚苯乙烯的纳米球没有进入淋巴结。对于聚磷酸酯纳米球，在淋巴结中注意到基因表达，并且观察到免疫应答，例如抗体应答和脾肿大。这些结果说明了在免疫中膀胱输送途径的潜在潜力以及组织运输对颗粒成分的惊人依赖性。总之，发现分别通过肌内和膀胱递送途径将编码抗原的DNA与微囊化的细胞因子蛋白（rIFN-γ）或纳米囊化的细胞因子基因（pGM-CSF）共同施用可增强对DNA疫苗的免疫应答。因此，将基因和细胞因子蛋白封装到可生物降解的球体中可以定制对基于基因的免疫疗法的免疫反应。

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