In vivo study of doxorubicin-loaded cell-penetrating peptide-modified pH-sensitive liposomes: biocompatibility, bio-distribution, and pharmacodynamics in BALB/c nude mice bearing human breast tumors.
In vivo study of doxorubicin-loaded cell-penetrating peptide-modified pH-sensitive liposomes: biocompatibility, bio-distribution, and pharmacodynamics in BALB/c nude mice bearing human breast tumors.
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DOI：
10.2147/dddt.s149814
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Wang ZQ
中科院分区：
文献类型：
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作者：
Ding Y;Cui W;Sun D;Wang GL;Hei Y;Meng S;Chen JH;Xie Y;Wang ZQ
药物传递载体的体内评价对临床翻译至关重要。在携带人乳腺癌肿瘤的BALB/c裸鼠中，我们研究了负载阿霉素（DOX）的新型细胞穿透肽（CPP）修饰ph敏感脂质体（CPPL (DOX)） （CPP密度为4%）的生物相容性、药代动力学和药效学。在CPPL中，将聚乙二醇（PEG）与硬脂酸酯通过酸可降解的腙键偶联形成的聚乙二醇衍生物（peg2000 - hz -硬脂酸酯）插入脂质体表面，CPP通过与硬脂酸酯偶联直接附着在脂质体表面，同时实现长血液循环时间，提高CPP靶向肿瘤的选择性和有效性。与聚乙二醇脂质体相比，CPPL使DOX在肿瘤中的积累增加了1.9倍（p<0.01），并且由于DNA破坏导致更多的细胞凋亡以及相对较低的肿瘤生长比（T/C%）。组织学检查未见正常组织出现任何坏死或炎症迹象，但在用CPPL（DOX）治疗动物后，在肿瘤中发现了大的细胞溶解区。我们的研究结果提供了关于CPPL（DOX）在体内分布的重要和详细的信息，揭示了它们的肿瘤穿透能力和治疗乳腺癌的潜力。
In vivo evaluation of drug delivery vectors is essential for clinical translation. In BALB/c nude mice bearing human breast cancer tumors, we investigated the biocompatibility, pharmacokinetics, and pharmacodynamics of doxorubicin (DOX)-loaded novel cell-penetrating peptide (CPP)-modified pH-sensitive liposomes (CPPL) (referred to as CPPL(DOX)) with an optimal CPP density of 4%. In CPPL, a polyethylene glycol (PEG) derivative formed by conjugating PEG with stearate via acid-degradable hydrazone bond (PEG2000-Hz-stearate) was inserted into the surface of liposomes, and CPP was directly attached to liposome surfaces via coupling with stearate to simultaneously achieve long circulation time in blood and improve the selectivity and efficacy of CPP for tumor targeting. Compared to PEGylated liposomes, CPPL enhanced DOX accumulation in tumors up to 1.9-fold (p<0.01) and resulted in more cell apoptosis as a result of DNA disruption as well as a relatively lower tumor growth ratio (T/C%). Histological examination did not show any signs of necrosis or inflammation in normal tissues, but large cell dissolving areas were found in tumors following the treatment of animals with CPPL(DOX). Our findings provide important and detailed information regarding the distribution of CPPL(DOX) in vivo and reveal their abilities of tumor penetration and potential for the treatment of breast cancer.