Mitha A T, Rekha M R
Biosurface Technology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Poojappura, Thiruvananthapuram, Kerala-695012, India.
J Mater Chem B. 2014 Dec 7;2(45):8005-8016. doi: 10.1039/c4tb01298d. Epub 2014 Oct 22.
Co-delivery of the anticancer drug, mitoxantrone (MTO) and the gene encoding tumor suppressor protein p53 was evaluated towards anticancer combinatorial therapy. The nanoplatforms developed herein are assembled by coupling β-cyclodextrin and the cationic polymer, polyethyleneimine to a hydrophilic polymer, pullulan (PPEICD). The β-cyclodextrin serves as a nanocontainer for the drug MTO, while the cationic moiety can condense pDNA. Acid base titrations provided insight into the buffering capacity of the PPEICD conjugate. Cytotoxicity studies by MTT assay in HepG2 and C6 cell lines and hemocompatibility studies confirmed the conjugate to be nontoxic and hemocompatible. In vitro release studies of MTO in phosphate buffered saline pH 7.4 showed an initial burst effect followed by a slow drug release. The released data fitted with the Korsmeyer-Peppas model and their diffusional exponents suggest that the drug release from the polymeric system followed diffusion and non-Fickian transport. Combined drug and gene loaded nanoplexes have a more apoptotic effect than either the drug or gene individually as confirmed by MTT assay and live dead assay. This indicated the significance of the combined drug and gene delivery system and the ability of the nanoplatform to overcome the multidrug resistance (MDR) of MTO. Moreover, preference of asialoglycoprotein receptor (ASGPR) mediated internalization for nanoparticle cellular uptake in HepG2 cell lines was identified by treating with the inhibitor asialofetuin. Cell studies in both HepG2 and C6 cell lines demonstrated that the nanoplatform PPEICD can efficiently and selectively deliver both p53 and MTO to cancer cells inducing high cell death.
评估了抗癌药物米托蒽醌（MTO）与编码肿瘤抑制蛋白p53的基因的共递送用于抗癌联合治疗的效果。本文开发的纳米平台是通过将β-环糊精和阳离子聚合物聚乙烯亚胺与亲水性聚合物支链淀粉偶联组装而成（PPEICD）。β-环糊精作为药物MTO的纳米容器，而阳离子部分可以凝聚pDNA。酸碱滴定提供了对PPEICD缀合物缓冲能力的深入了解。通过MTT法在HepG2和C6细胞系中进行的细胞毒性研究以及血液相容性研究证实该缀合物无毒且具有血液相容性。在pH 7.4的磷酸盐缓冲盐水中对MTO进行的体外释放研究显示出初始突释效应，随后是缓慢的药物释放。释放数据符合Korsmeyer-Peppas模型，其扩散指数表明药物从聚合物系统中的释放遵循扩散和非菲克传输。MTT法和活死细胞检测证实，负载药物和基因的复合纳米颗粒比单独的药物或基因具有更强的凋亡作用。这表明了联合药物和基因递送系统的重要性以及该纳米平台克服MTO多药耐药性（MDR）的能力。此外，通过用去唾液酸胎球蛋白抑制剂处理，确定了去唾液酸糖蛋白受体（ASGPR）介导的内化在HepG2细胞系中对纳米颗粒细胞摄取的偏好。在HepG2和C6细胞系中的细胞研究表明，纳米平台PPEICD可以有效地、选择性地将p53和MTO递送至癌细胞，诱导高细胞死亡率。
