Geary Sean M, Hu Qiaohong, Joshi Vijaya B, Bowden Ned B, Salem Aliasger K
Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, USA.
Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, USA; Guangdong Pharmaceutical University, Guangzhou, Guangdong, People's Republic of China.
J Control Release. 2015 Dec 28;220(Pt B):682-90. doi: 10.1016/j.jconrel.2015.09.002. Epub 2015 Sep 8.
The aim of the research presented here was to determine the characteristics and immunostimulatory capacity, in vivo, of antigen and adjuvant co-loaded into microparticles made from a novel diaminosulfide polymer, poly(4,4'-trimethylenedipiperdyl sulfide) (PNSN), and to assess their potential as cancer vaccine vectors. PNSN microparticles co-loaded with the antigen, ovalbumin (OVA), and adjuvant, CpG 1826, (PNSN(OVA + CpG)) were fabricated and characterized for size (1.64 μm diameter; PDI=0.62), charge (-23.1 ± 0.3), and loading efficiencies of antigen (7.32 μg/mg particles) and adjuvant (0.95 μg/mg particles). The ability of PNSN(OVA + CpG) to stimulate cellular and humoral immune responses in vivo was compared with other PNSN microparticle formulations as well as with poly(lactic-co-glycolic acid)(PLGA)-based microparticles, co-loaded with OVA and CpG (PLGA(OVA + CpG)), an adenovirus encoding OVA (Ad5-OVA), and OVA delivered with incomplete Freund's adjuvant (IFA(OVA)). In vivo OVA-specific IgG1 responses, after subcutaneous prime/boosts in mice, were similar when PNSN(OVA + CpG) and PLGA(OVA + CpG) were compared and the presence of CpG 1826 within the PNSN microparticles demonstrated significantly improved responses when compared to PNSN microparticles loaded with OVA alone (PNSN(OVA)), plus or minus soluble CpG 1826. Cellular immune responses to all particle-based vaccine formulations ranged from being negligible to modest with PNSN(OVA + CpG) generating the greatest responses, displaying significantly increased levels of OVA-specific CD8+ T lymphocytes compared to controls and IFA(OVA) treated mice. Finally, it was shown that of all vaccination formulations tested PNSN(OVA + CpG) was the most protective against subsequent challenge with an OVA-expressing tumor cell line, E.G7. Thus, microparticles made from poly(diaminosulfide)-based macromolecules possess promising potential as vaccine vectors and, as demonstrated here, may have impact as cancer vaccines in particular.
本文所呈现的研究目的是确定负载于由新型二氨基硫化物聚合物聚（4,4'-三亚甲基二哌啶基硫醚）（PNSN）制成的微粒中的抗原和佐剂在体内的特性及免疫刺激能力，并评估它们作为癌症疫苗载体的潜力。制备了共负载抗原卵清蛋白（OVA）和佐剂CpG 1826的PNSN微粒（PNSN(OVA + CpG)），并对其尺寸（直径1.64μm；多分散指数=0.62）、电荷（-23.1±0.3）以及抗原（7.32μg/mg微粒）和佐剂（0.95μg/mg微粒）的负载效率进行了表征。将PNSN(OVA + CpG)在体内刺激细胞免疫和体液免疫反应的能力与其他PNSN微粒制剂以及与共负载OVA和CpG的聚乳酸-羟基乙酸共聚物（PLGA）微粒（PLGA(OVA + CpG)）、编码OVA的腺病毒（Ad5-OVA）以及与不完全弗氏佐剂（IFA(OVA)）一起递送的OVA进行了比较。在小鼠皮下进行初次免疫/加强免疫后，比较PNSN(OVA + CpG)和PLGA(OVA + CpG)时，体内OVA特异性IgG1反应相似，并且与单独负载OVA的PNSN微粒（PNSN(OVA)）加或不加可溶性CpG 1826相比，PNSN微粒中存在CpG 1826时反应显著改善。对所有基于微粒的疫苗制剂的细胞免疫反应从可忽略不计到中等程度不等，其中PNSN(OVA + CpG)产生的反应最大，与对照组和IFA(OVA)处理的小鼠相比，OVA特异性CD8 + T淋巴细胞水平显著增加。最后，结果表明，在所有测试的疫苗制剂中，PNSN(OVA + CpG)对随后用表达OVA的肿瘤细胞系E.G7进行的攻击具有最强的保护作用。因此，由聚二氨基硫化物基大分子制成的微粒作为疫苗载体具有广阔的潜力，并且如本文所示，尤其可能对癌症疫苗产生影响。
