Optimization of a nanomedicine-based silicon phthalocyanine 4 photodynamic therapy (Pc 4-PDT) strategy for targeted treatment of EGFR-overexpressing cancers.
Optimization of a nanomedicine-based silicon phthalocyanine 4 photodynamic therapy (Pc 4-PDT) strategy for targeted treatment of EGFR-overexpressing cancers.
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优化基于纳米医学的硅邻苯烷氨酸4光动力疗法（PC 4-PDT）策略，用于靶向EGFR过表达的癌症。
DOI：
10.1021/mp300256e
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发表时间：
2012-08-06
影响因子：
4.9
通讯作者：
Sen Gupta A
中科院分区：
文献类型：
--
作者：
Master AM;Livingston M;Oleinick NL;Sen Gupta A
目前癌症治疗的临床主要手段，即手术切除、化疗和放疗，会造成严重创伤、全身毒性以及组织功能/外观的损害，特别是当因肿瘤复发而需要重复治疗时。因此，像光动力疗法（PDT）这样的替代治疗策略引起了临床上的极大关注，它能够有效且选择性地根除肿瘤，并且如果需要可以安全地重复进行。我们之前已经证明，第二代光敏剂Pc 4可以被配制成聚合物胶束，并且这些胶束可以利用GE11肽配体特异性地靶向表皮生长因子受体（EGFR）过度表达的癌细胞，以增强Pc 4的细胞特异性递送和内化。在当前的研究中，我们报告了胶束纳米制剂的EGFR靶向性和Pc 4负载量的体外优化，以及相应光照射条件的优化，以使Pc 4在体外对EGFR过度表达细胞的递送、内化以及随后由PDT诱导的细胞毒性最大化。在我们的研究中，吸收和荧光光谱被用于监测GE11修饰的负载Pc 4的胶束的细胞特异性摄取以及胶束包裹的Pc 4产生的细胞毒性单线态氧，以确定最佳配体密度和Pc 4负载量。研究发现，含有10摩尔% GE11修饰的聚合物成分的胶束制剂在最短的孵育时间内导致EGFR过度表达的A431细胞的摄取量最高。此外，在这些胶束制剂中，每毫克聚合物负载约50μg Pc 4会导致单线态氧产生量最高。当含有这些优化参数的制剂在体外对A431细胞进行光动力疗法效果测试时，含有400 nM Pc 4的制剂剂量以及在200 mJ/cm²的能量密度下照射400秒的光照射时长导致了接近100%的细胞死亡。
The current clinical mainstays for cancer treatment, namely, surgical resection, chemotherapy and radiotherapy, can cause significant trauma, systemic toxicity, and functional/cosmetic debilitation of tissue, especially if repetitive treatment becomes necessary due to tumor recurrence. Hence there is significant clinical interest in alternate treatment strategies like photodynamic therapy (PDT) which can effectively and selectively eradicate tumors and can be safely repeated if needed. We have previously demonstrated that the second-generation photosensitizer Pc 4 can be formulated within polymeric micelles, and these micelles can be specifically targeted to EGFR-overexpressing cancer cells using GE11 peptide ligands, to enhance cell-specific Pc 4 delivery and internalization. In the current study, we report on the in vitro optimization of the EGFR-targeting, Pc 4 loading of the micellar nanoformulation, along with optimization of the corresponding photoirradiation conditions to maximize Pc 4 delivery, internalization and subsequent PDT-induced cytotoxicity in EGFR-overexpressing cells in vitro. In our studies, absorption and fluorescence spectroscopy were used to monitor the cell-specific uptake of the GE11-decorated Pc 4-loaded micelles and the cytotoxic singlet oxygen production from the micelle-encapsulated Pc 4, to determine the optimum ligand density and Pc 4 loading. It was found that the micelle formulations bearing 10 mole% of GE11-modified polymer component resulted in the highest cellular uptake in EGFR-overexpressing A431 cells within the shortest incubation periods. Also, the loading of ~50 μg Pc 4 per mg of polymer in these micellar formulations resulted in the highest levels of singlet oxygen production. When formulations bearing these optimized parameters were tested in vitro on A431 cells for PDT effect, a formulation dose containing 400 nM Pc 4 and photoirradiation duration of 400 seconds at a fluence of 200 mJ/cm2 yielded close to 100% cell death.
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影响因子：
3.3
作者：
Gollmer, Anita;Arnbjerg, Jacob;Ogilby, Peter R.
通讯作者：
Ogilby, Peter R.
影响因子：
3.4
作者：
Pitsillides, CM;Joe, EK;Lin, CP
通讯作者：
Lin, CP
影响因子：
2.7
作者：
Kopelman, R;Koo, YEL;Ross, BD
通讯作者：
Ross, BD
影响因子：
5.8
作者：
Piette, J;Volanti, C;Agostinis, P
通讯作者：
Agostinis, P
影响因子：
5.4
作者：
Milane, Lara;Duan, Zhen-feng;Amiji, Mansoor
通讯作者：
Amiji, Mansoor