Ghaffarian Rasa, Herrero Edgar Pérez, Oh Hyuntaek, Raghavan Srinivasa R, Muro Silvia
Fischell Department of Bioengineering, 2330 Jeong H. Kim Engineering Building, University of Maryland, College Park, MD 20742, USA.
Institute for Bioscience and Biotechnology Research, 5115 Plant Sciences Building, University of Maryland, College Park, MD 20742, USA.
Adv Funct Mater. 2016 May 24;26(20):3382-3393. doi: 10.1002/adfm.201600084. Epub 2016 Apr 23.
When administered intravenously, active targeting of drug nanocarriers (NCs) improves biodistribution and endocytosis. Targeting may also improve oral delivery of NCs to treat gastrointestinal (GI) pathologies or for systemic absoption. However, GI instability of targeting moieties compromises this strategy. We explored whether encapsulation of antibody-coated NCs in microcapsules would protect against gastric degradation, providing NCs release and targeting in intestinal conditions. We used nanoparticles coated with antibodies against intercellular adhesion molecule-1 (anti-ICAM) or non-specific IgG. NCs (~160-nm) were encapsulated in ~180-μm microcapsules with an alginate core, in the absence or presence of a chitosan shell. We found >95% NC encapsulation within microcapsules and <10% NC release from microcapsules in storage. There was minimal NC release at gastric pH (<10%) and burst release at intestinal pH (75-85%), slightly attenuated by chitosan. Encapsulated NCs afforded increased protection against degradation (3-4 fold) and increased cell targeting (8-20 fold) after release vs. non-encapsulated NCs. Mouse oral gavage showed that microencapsulation provided 38-65% greater protection of anti-ICAM NCs in the GI tract, 40% lower gastric retention, and 4-9-fold enhanced intestinal biodistribution vs. non-encapsulated NCs. Therefore, microencapsulation of antibody-targeted NCs may enable active targeting strategies to be effective in the context of oral drug delivery.
静脉给药时，药物纳米载体（NCs）的主动靶向可改善生物分布和内吞作用。靶向还可改善NCs的口服给药，以治疗胃肠道（GI）疾病或实现全身吸收。然而，靶向部分的胃肠道不稳定性损害了这一策略。我们探讨了将抗体包被的NCs封装在微胶囊中是否能防止其在胃中降解，从而在肠道环境中实现NCs的释放和靶向。我们使用了包被有抗细胞间黏附分子-1抗体（抗ICAM）或非特异性IgG的纳米颗粒。将NCs（约160纳米）封装在具有藻酸盐核心、有无壳聚糖外壳的约180微米微胶囊中。我们发现微胶囊内NCs的封装率>95%，储存时微胶囊中NCs的释放率<10%。在胃pH值下NCs释放极少（<10%），在肠道pH值下突发释放（75-85%），壳聚糖可使其略有减弱。与未封装的NCs相比，释放后封装的NCs对降解的保护作用增强（3-4倍），细胞靶向性提高（8-20倍）。小鼠灌胃显示，与未封装的NCs相比，微封装为胃肠道中的抗ICAM NCs提供了38-65%的更大保护，胃滞留率降低40%，肠道生物分布增强4-9倍。因此，抗体靶向NCs的微封装可能使主动靶向策略在口服药物递送中有效。
