Department of Chemistry, Faculty of Science, Alexandria University, Alexandria 21321, Egypt; Technology Management Department (TMD), Egypt-Japan University of Science and Technology (E-JUST), Egypt.
Department of Pharmaceutics, Faculty of Pharmacy, Damanhur University, Damanhur, Egypt; Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Colloids Surf B Biointerfaces. 2021 Jun;202:111694. doi: 10.1016/j.colsurfb.2021.111694. Epub 2021 Mar 13.
Despite the active research towards introducing novel anticancer agents, the long-term sequelae and side effects of chemotherapy remain the major obstacle to achieving clinical success. Recent cancer research is now utilizing the medicinal chemistry toolbox to tailor novel 'smart' carrier systems that can reduce the major limitations of chemotherapy ranging from non-specificity and ubiquitous biodistribution to systemic toxicity. In this aspect, various stimuli-responsive polymers have gained considerable interest due to their intrinsic tumor targeting properties. Among these polymers, poly(N-isopropylacrylamide (PNIPAM) has been chemically modified to tune its thermoresponsivity or even copolymerized to endow new stimulus responsiveness for enhancing tumor targeting. Herein, we set our design rationale to impart additional active targeting entity to pH/temperature-responsive PNIPAM-based polymer for more efficient controlled payloads accumulation at the tumor through cellular internalization via synthesizing novel "super intelligent" lactoferrin conjugated PNIPAM-acrylic acid (LF-PNIPAM-co-AA) copolymer. The synthesized copolymer was physicochemically characterized and evaluated as a smart nanocarrier for targeting breast cancer. In this regard, Honokiol (HK) was utilized as a model anticancer drug and encapsulated in the nanoparticles to overcome its lipophilic nature and allow its parenteral administration, for achieving sustainable drug release with targeting action. Results showed that the developed HK-loaded LF-PNIPAM-co-AA nanohydrogels displayed high drug loading capacity reaching to 18.65 wt.% with excellent physical and serum stability. Moreover, the prepared HK-loaded nanohydrogels exhibited efficient in vitro and in vivo antitumor activities. In vivo, HK-loaded nanohydrogels demonstrated suppression of VEGF-1 and Ki-67 expression levels, besides inducing apoptosis through upregulating the expression level of active caspase-3 in breast cancer-bearing mice. Overall, the developed nanohydrogels (NGs) with pH and temperature responsivity provide a promising nanocarrier for anticancer treatment.
尽管人们积极研究引入新型抗癌药物，但化疗的长期后遗症和副作用仍是实现临床成功的主要障碍。最近的癌症研究现在利用药物化学工具箱来定制新型“智能”载体系统，以减少化疗的主要局限性，从非特异性和广泛的生物分布到全身毒性。在这方面，各种刺激响应聚合物因其内在的肿瘤靶向特性而引起了相当大的兴趣。在这些聚合物中，聚（N-异丙基丙烯酰胺（PNIPAM）已被化学修饰以调整其温度响应性，甚至共聚以赋予新的刺激响应性以增强肿瘤靶向性。在这里，我们的设计原理是赋予 pH/温度响应性 PNIPAM 基聚合物额外的主动靶向实体，以通过细胞内吞作用更有效地将控释载药积累在肿瘤部位，方法是合成新型“超智能”乳铁蛋白偶联的 PNIPAM-丙烯酸（LF-PNIPAM-co-AA）共聚物。合成的共聚物进行了物理化学表征，并作为靶向乳腺癌的智能纳米载体进行了评估。在这方面，利用厚朴酚（HK）作为模型抗癌药物并将其包封在纳米粒子中，以克服其亲脂性并允许其进行肠胃外给药，从而实现具有靶向作用的可持续药物释放。结果表明，开发的载 HK 的 LF-PNIPAM-co-AA 纳米水凝胶具有高达 18.65wt.%的高载药量，具有出色的物理和血清稳定性。此外，所制备的载 HK 的纳米水凝胶表现出高效的体外和体内抗肿瘤活性。在体内，载 HK 的纳米水凝胶在荷瘤小鼠中通过上调活性 caspase-3 的表达水平，除了抑制 VEGF-1 和 Ki-67 的表达水平外，还表现出抑制肿瘤生长的作用。总之，具有 pH 和温度响应性的开发的纳米水凝胶（NG）为癌症治疗提供了一种有前途的纳米载体。
