Kolesnikova Olga A, Komedchikova Elena N, Zvereva Svetlana D, Obozina Anastasiia S, Dorozh Olha V, Afanasev Iurii, Nikitin Petr I, Mochalova Elizaveta N, Nikitin Maxim P, Shipunova Victoria O
Moscow Center for Advanced Studies, Kulakova str. 20, 123592, Moscow, Russia.
Moscow Institute of Physics and Technology, 9 Institutskiy Per., 141701, Dolgoprudny, Russia.
Heliyon. 2024 Jul 6;10(14):e34211. doi: 10.1016/j.heliyon.2024.e34211. eCollection 2024 Jul 30.
Cancer is unquestionably a global healthcare challenge, spurring the exporation of novel treatment approaches. In recent years, nanomaterials have garnered significant interest with the greatest hopes for targeted nanoformulations due to their cell-specific delivery, improved therapeutic efficacy, and reduced systemic toxicity for the organism. The problem of successful clinical translation of nanoparticles may be related to the fact that most in vitro tests are performed at pH values of normal cells and tissues, ranging from 7.2 to 7.4. The extracellular pH values of tumors are characterized by a shift to a more acidic region in the range of 5.6-7.0 and represent a crucial target for enhancing nanoparticle delivery to cancer cells. Here we show the method of non-active protein incorporation into the surface of HER2-targeted nanoparticles to achieve optimal cellular uptake within the pH range of the tumor microenvironment. The method efficacy was confirmed in vitro and in vivo showing the maximum binding of nanoparticles to cells at a pH value 6.4. Namely, fluorescent magnetic nanoparticles, modified with HER2-recognising affibody Z, with proven specificity in terms of HER2 recognition (with 62-fold higher cellular uptake compared to control nanoparticles) were designed for targeting cancer cells at slightly acidic pH values. The stabilizing protein, namely, bovine serum albumin, one of the major blood components with widespread availability and biocompatibility, was used for the decoration of the nanoparticle surface to alter the pH response of the targeting magnetic conjugates. The optimally designed nanoparticles showed a bell-shaped dependency of interaction with cancer cells in the pH range of 5.6-8.0 with maximum cellular uptake at pH value 6.4 close to that of the tumor microenvironment. In vivo experiments revealed that after i.v. administration, BSA-decorated nanoparticles exhibited 2 times higher accumulation in tumors compared to magnetic nanoparticles modified with affibody only. Thus, we demonstrated a valid method for enhancing the specificity of targeted nanoparticle delivery to cancer cells without changing the functional components of nanoparticles.
癌症无疑是一项全球性的医疗保健挑战,这促使人们探索新的治疗方法。近年来,纳米材料因其细胞特异性递送、提高治疗效果以及降低对机体的全身毒性而备受关注,人们对靶向纳米制剂寄予了厚望。纳米颗粒成功进行临床转化的问题可能与以下事实有关:大多数体外测试是在正常细胞和组织的pH值(7.2至7.4)下进行的。肿瘤的细胞外pH值特征是向更酸性区域偏移,范围在5.6 - 7.0之间,这是增强纳米颗粒向癌细胞递送的关键靶点。在此,我们展示了一种将非活性蛋白掺入HER2靶向纳米颗粒表面的方法,以在肿瘤微环境的pH范围内实现最佳的细胞摄取。该方法的有效性在体外和体内均得到证实,表明纳米颗粒在pH值为6.4时与细胞的结合力最大。具体而言,设计了用HER2识别亲和体Z修饰的荧光磁性纳米颗粒,其在HER2识别方面具有已证实的特异性(与对照纳米颗粒相比,细胞摄取高62倍),用于在略酸性pH值下靶向癌细胞。稳定蛋白,即牛血清白蛋白,作为血液中的主要成分之一,具有广泛的可用性和生物相容性,用于修饰纳米颗粒表面,以改变靶向磁性偶联物的pH响应。优化设计的纳米颗粒在5.6 - 8.0的pH范围内与癌细胞的相互作用呈现钟形依赖性,在接近肿瘤微环境的pH值6.4时细胞摄取量最大。体内实验表明,静脉注射后,与仅用亲和体修饰的磁性纳米颗粒相比,牛血清白蛋白修饰的纳米颗粒在肿瘤中的积累量高出2倍。因此,我们展示了一种在不改变纳米颗粒功能成分的情况下增强靶向纳米颗粒向癌细胞递送特异性的有效方法。
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