Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Drug Deliv. 2022 Dec;29(1):2403-2413. doi: 10.1080/10717544.2022.2067600.
Non-small cell lung cancer comprises 85% of the global lung cancer cases. Conventional chemotherapeutics possess certain limitations like systemic toxicity and drug resistance that requires the development of new therapeutic agents for successful treatment of lung cancer. Actinonin, a human peptide deformylase inhibitor, has demonstrated anti-cancerous properties in various leukemias and solid cancer types. However, it has limited therapeutic application because of its low bioavailability and systemic toxicity if administered in free form. This limitation can be overcome by using nano-delivery systems that will increase the therapeutic efficacy of actinonin. In the present study, human serum albumin actinonin nanoparticles were prepared using a desolvation technique and folic acid was conjugated to lysine residues of albumin for effective delivery to the lung. The lung adenocarcinoma model was established 24 weeks after intraperitoneal administration of urethane and chemotherapeutic efficacy of free as well as nanoencapsulated actinonin was evaluated. This study demonstrated anti-proliferative potential of folic acid conjugated human serum albumin nanoparticles encapsulating actinonin. The intraperitoneally administered nanoformulation exhibited sustain release profile of actinonin with longer half-life and mean retention time. The reduced dose frequency resulted in therapeutic efficacy comparable to free drug in terms of 100% survival and reduced tumor burden along with downregulation of epidermal growth factor receptor, folate receptor α and peptide deformylase expression in lung adenocarcinoma mice model. Therefore, actinonin encapsulated albumin nanoparticles-based therapy holds great potential as an alternative strategy to improve its anti-cancerous activity against lung adenocarcinoma.
非小细胞肺癌占全球肺癌病例的 85%。传统的化疗药物存在一定的局限性，如全身毒性和耐药性，这就需要开发新的治疗药物来成功治疗肺癌。肽脱甲酰基酶抑制剂 Actinonin 在各种白血病和实体癌类型中表现出抗癌特性。然而，由于其在游离形式下生物利用度低和全身毒性，其治疗应用受到限制。可以通过使用纳米递药系统来克服这一限制，从而提高 Actinonin 的治疗效果。在本研究中，使用去溶剂化技术制备人血清白蛋白 Actinonin 纳米粒，并将叶酸偶联到白蛋白的赖氨酸残基上，以实现对肺部的有效递药。在腹腔注射尿嘧啶 24 周后建立肺腺癌模型，并评价游离和纳米包封的 Actinonin 的化疗疗效。本研究证明了叶酸偶联人血清白蛋白纳米粒包封 Actinonin 的抗增殖潜力。腹腔内给予的纳米制剂表现出 Actinonin 的缓释特征，具有更长的半衰期和平均滞留时间。减少给药频率可使治疗效果与游离药物相当，在肺腺癌小鼠模型中达到 100%的存活率和降低肿瘤负担，同时下调表皮生长因子受体、叶酸受体α和肽脱甲酰基酶的表达。因此，基于 Actinonin 包封白蛋白纳米粒的治疗具有很大的潜力，可以作为提高其抗癌活性对抗肺腺癌的替代策略。
