Department of Biophysics, Paulista School of Medicine, Federal University of Sao Paulo , Sao Paulo 04023-062, Brazil.
Department of Physical-Chemistry, Institute of Chemistry, Federal University of Rio Grande do Sul , Porto Alegre 91501-970, Brazil.
Biomacromolecules. 2018 Feb 12;19(2):499-510. doi: 10.1021/acs.biomac.7b01630. Epub 2018 Jan 17.
Biomaterials conceived for vectorization of bioactives are currently considered for biomedical, biological, and environmental applications. We have produced a pH-sensitive biomaterial composed of natural source alginate and chitosan polysaccharides for application as a drug delivery system via oral administration. The composite particle preparation was in situ monitored by means of isothermal titration calorimetry. The strong interaction established between the macromolecules during particle assembly led to 0.60 alginate/chitosan effective binding sites with an intense exothermic effect and negative enthalpy variation on the order of a thousand kcal/mol. In the presence of model drugs mebendazole and ivermectin, with relatively small and large structures, respectively, mebendazole reduced the amount of chitosan monomers available to interact with alginate by 27%, which was not observed for ivermectin. Nevertheless, a state of intense negative Gibbs energy and large entropic decrease was achieved, providing evidence that formation of particles is thermodynamically driven and favored. Small-angle X-ray scattering provided further evidence of similar surface aspects independent of the presence of drug. The physical responses of the particles to pH variation comprise partial hydration, swelling, and the predominance of positive surface charge in strong acid medium, whereas ionization followed by deprotonation leads to compaction and charge reversal rather than new swelling in mild and slightly acidic mediums, respectively. In vivo performance was evaluated in the treatment of endoparasites in Corydoras fish. Systematically with a daily base oral administration, particles significantly reduced the infections over 15 days of treatment. The experiments provide evidence that utilizing particles granted and boosted the action of the antiparasitic drugs, leading to substantial reduction or elimination of infection. Hence, the pH-responsive particles represent a biomaterial with prominent characteristics that is promising for the development of targeted oral drug delivery.
用于生物活性物质载体化的生物材料目前被认为可用于生物医学、生物学和环境应用。我们制备了一种由天然来源的海藻酸钠和壳聚糖多糖组成的 pH 敏感型生物材料，用作口服给药的药物递送系统。通过等温滴定量热法原位监测复合粒子的制备过程。大分子在粒子组装过程中建立的强相互作用导致 0.60 个有效结合部位的海藻酸钠/壳聚糖，具有强烈的放热效应和负焓变，大约为千卡路里/摩尔。在存在结构相对较小和较大的模型药物甲苯咪唑和伊维菌素的情况下，甲苯咪唑使可与海藻酸钠相互作用的壳聚糖单体减少了 27%，而伊维菌素则没有观察到这种情况。然而，形成粒子的状态仍然是强烈的负吉布斯自由能和较大的熵减小，这表明粒子的形成是由热力学驱动的，并且是有利的。小角 X 射线散射进一步提供了证据，表明在没有药物存在的情况下，表面具有相似的形态。粒子对 pH 值变化的物理响应包括部分水合、膨胀和在强酸介质中带正表面电荷，而电离和随后的去质子化导致在温和和微酸性介质中分别发生致密化和电荷反转而不是新的膨胀。体内性能在治疗 Corydoras 鱼内寄生虫的实验中进行了评估。每天口服基础剂量，粒子在 15 天的治疗中显著减少了感染。实验证明，利用粒子赋予和增强了抗寄生虫药物的作用，导致感染的大量减少或消除。因此，pH 响应性粒子代表了一种具有显著特性的生物材料，有望开发靶向口服药物递送。
