PhotoChemLab, Department of Drug and Health Sciences, University of Catania, I-95125 Cayania, Italy.
CycloLab, Cyclodextrin R&D Ltd., Illatos út 7, H-1097 Budapest, Hungary.
Molecules. 2022 Mar 16;27(6):1918. doi: 10.3390/molecules27061918.
In this contribution, we report a strategy to enhance the therapeutic action of the chemotherapeutic Sorafenib (SRB) through its combination with a multifunctional β-cyclodextrin-based polymer able to deliver nitric oxide (NO) and emit green fluorescence upon visible light excitation (PolyCDNO). The basically water-insoluble SRB is effectively encapsulated in the polymeric host (1 mg mL) up to a concentration of 18 μg mL. The resulting host-guest supramolecular complex is able to release SRB in sink conditions and to preserve very well the photophysical and photochemical properties of the free PolyCDNO, as demonstrated by the similar values of the NO release and fluorescence emission quantum efficiencies found. The complex PolyCDNO/SRB internalizes in HEP-G2 hepatocarcinoma, MCF-7 breast cancer and ACHN kidney adenocarcinoma cells, localizing in all cases mainly at the cytoplasmic level. Biological experiments have been performed at SRB concentrations below the IC and with light doses producing NO at nontoxic concentrations. The results demonstrate exceptional mortality levels for PolyCDNO/SRB upon visible light irradiation in all the different cell lines tested, indicating a clear synergistic action between the chemotherapeutic drug and the NO. These findings can open up exciting avenues to potentiate the anticancer action of SRB and, in principle, to reduce its side effects through its use at low dosages when in combination with the photo-regulated release of NO.
在本研究中，我们报告了一种策略，通过将化疗药物索拉非尼（SRB）与一种能够递送一氧化氮（NO）并在可见光激发下发出绿色荧光的多功能β-环糊精基聚合物（PolyCDNO）结合，来增强其治疗作用。基本不溶于水的 SRB 可有效地被包封在聚合物主体（1mg/mL）中，浓度高达 18μg/mL。所得主客体超分子复合物在溶酶体条件下能够释放 SRB，并很好地保持游离 PolyCDNO 的光物理和光化学性质，从释放的 NO 和荧光发射量子效率的相似值可以看出这一点。复合物 PolyCDNO/SRB 能够内化进入 HEP-G2 肝癌、MCF-7 乳腺癌和 ACHN 肾腺癌细胞，在所有情况下主要定位于细胞质水平。在 SRB 浓度低于 IC 且光照剂量产生非毒性浓度的 NO 的条件下进行了生物学实验。结果表明，在所有测试的不同细胞系中，可见光照射下的 PolyCDNO/SRB 具有异常高的死亡率，表明化疗药物和 NO 之间存在明显的协同作用。这些发现为增强 SRB 的抗癌作用开辟了令人兴奋的途径，并可通过在与光调节的 NO 释放联合使用时以低剂量使用来降低其副作用，这在原则上是可行的。
