阿霉素(Dox)的化疗疗效,一种用于治疗多种实体瘤的有效抗癌药物,严重损害了它的心脏毒性。为了克服这一缺点,并利用纳米制剂的最大治疗潜力,合理设计和合成了磁性纳米颗粒,将Dox和吲哚菁绿(ICG)共封装在脂质体载体中,并用环状RGD肽标记。这些磁性脂质体(T-LMD)在几种癌细胞系(即肺,乳房,皮肤,与Dox的临床脂质体纳米制剂(Lippod™)相比,脑和肝癌)联合或不联合γ辐射或磁热疗。发现化学放射致敏的机制涉及JNK介导的促凋亡信号轴的激活和DNA双链断裂的延迟修复。ICG标记的T-LMD的实时成像表明,与脱靶器官相比,T-LMD的肿瘤积累高出约6-18倍(肾脏,肝脏,脾,脾肠,与Lippod™相比,肺和心脏)并导致其更高的组合(化学-放射-热疗)肿瘤治疗功效。此外,血清CK-MB水平提示T-LMD对心脏组织无明显毒性,组织学分析,抗氧化酶活性(过氧化氢酶和GST)和心脏纤维化标志物,提示其在癌症靶向多模式治疗中的潜力。
The chemo-therapeutic efficacy of Doxorubicin (Dox), a potent anti-cancer drug used in the treatment of several solid tumors, is severely compromised by its cardio-toxicity. To overcome this shortcoming and exploit the utmost theranostic potential of nano-formulations, magnetic nanoparticles co-encapsulated with Dox and indocyanine green (ICG) in a liposomal carrier and tagged with cyclic RGD peptide were rationally designed and synthesized. These magneto-liposomes (T-LMD) showed αvβ3-integrin receptor targeting and higher cyto-toxicity in several cancer cell lines (i.e. lung, breast, skin, brain and liver cancer) in combination with or without gamma radiation or magnetic hyperthermia therapy as compared to clinical liposomal nano-formulation of Dox (Lippod™). Mechanism of chemo-radio-sensitization was found to involve activation of JNK mediated pro-apoptotic signaling axis and delayed repair of DNA double strand breaks. Real time imaging of ICG labeled T-LMD suggested ~6-18 fold higher tumor accumulation of T-LMD as compared to off-target organs (kidney, liver, spleen, intestine, lungs and heart) and resulted in its higher combinatorial (chemo-radio-hyperthermia) tumor therapy efficacy as compared to Lippod™. Moreover, T-LMD showed insignificant toxicity to the heart tissue as suggested by serum levels of CK-MB, histo-pathological analysis, anti-oxidant enzyme activities (Catalase and GST) and markers of cardiac fibrosis, suggesting its potential for targeted multi-modal therapy of cancer.