Spatiotemporally photoradiation-controlled intratumoral depot for combination of brachytherapy and photodynamic therapy for solid tumor.
Spatiotemporally photoradiation-controlled intratumoral depot for combination of brachytherapy and photodynamic therapy for solid tumor.
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DOI：
10.1016/j.biomaterials.2015.11.064
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发表时间：
2016-02
期刊：
影响因子：
14
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Mukerji R;Schaal J;Li X;Bhattacharyya J;Asai D;Zalutsky MR;Chilkoti A;Liu W
为了在时空上控制肿瘤保留和抗癌药物的覆盖范围，我们开发了一种由常规增强递送（CED）驱动的光辐射控制的瘤内储库（PRCITD）。该肿瘤内储库由含有周期性半胱氨酸残基的重组弹性蛋白样多肽 (ELP) 组成，并在 ELP 的 N 末端与光敏剂二氢卟酚-e6 (Ce6) 结合。我们假设，这种含有半胱氨酸的 ELP (cELP) 在暴露于氧化剂，特别是光动力刺激过程中产生的单线态氧时，可以很容易地通过二硫键交联。瘤内注射后，CED 驱动可溶性多肽在整个肿瘤间质中自由分布。使用荧光分子断层扫描成像监测储库的形成和保留。当成像显示多肽已分布在整个肿瘤中时，在肿瘤部位外部施加660nm的光。这种光辐射波长会激发 Ce6 并在氧气存在的情况下产生活性氧 (ROS)。 ROS 诱导半胱氨酸硫醇的原位二硫键交联，将 ELP 生物聚合物稳定为稳定的治疗库。我们的结果表明，这种 ELP 设计在体外和体内都能有效地形成水凝胶。荧光成像和碘 125 放射性示踪剂研究表明，这些储库在裸鼠皮下肿瘤异种移植物中表现出高稳定性，并且与未交联的对照相比显着改善了瘤内保留。发现 PRCITD 提供的光动力疗法以 Ce6 剂量依赖性方式引起显着的肿瘤抑制。此外，PRCITD 联合进行的 PDT 和瘤内放射性核素治疗的组合比单独的单一疗法具有更好的抗肿瘤效果。这些结果表明 PRCITD 可以提供一个稳定的平台来提供协同抗癌药物库。
In an attempt to spatiotemporally control both tumor retention and the coverage of anticancer agents, we developed a photoradiation-controlled intratumoral depot (PRCITD) driven by convention enhanced delivery (CED). This intratumoral depot consists of recombinant elastin-like polypeptide (ELP) containing periodic cysteine residues and is conjugated with a photosensitizer, chlorin-e6 (Ce6) at the N-terminus of the ELP. We hypothesized that this cysteine-containing ELP (cELP) can be readily crosslinked through disulfide bonds upon exposure to oxidative agents, specifically the singlet oxygen produced during photodynamic stimulation. Upon intratumoral injection, CED drives the distribution of the soluble polypeptide freely throughout the tumor interstitium. Formation and retention of the depot was monitored using fluorescence molecular tomography imaging. When imaging shows that the polypeptide has distributed throughout the entire tumor, 660-nm light is applied externally at the tumor site. This photo-radiation wavelength excites Ce6 and generates reactive oxygen species (ROS) in the presence of oxygen. The ROS induce in situ disulfide crosslinking of the cysteine thiols, stabilizing the ELP biopolymer into a stable therapeutic depot. Our results demonstrate that this ELP design effectively forms a hydrogel both in vitro and in vivo. These depots exhibit high stability in subcutaneous tumor xenografts in nude mice and significantly improved intratumoral retention compared to controls without crosslinking, as seen by fluorescent imaging and iodine-125 radiotracer studies. The photodynamic therapy provided by the PRCITD was found to cause significant tumor inhibition in a Ce6 dose dependent manner. Additionally, the combination of PDT and intratumoral radionuclide therapy co-delivered by PRCITD provided a greater antitumor effect than either monotherapy alone. These results suggest that the PRCITD could provide a stable platform for delivering synergistic, anti-cancer drug depots.