Dai Gaole, Chu Jacky C H, Chan Cecilia Ka Wing, Choi Chung Hang Jonathan, Ng Dennis K P
Department of Chemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
Nanoscale. 2021 Oct 1;13(37):15899-15915. doi: 10.1039/d1nr04278e.
A thioketal-linked dimer of 3,4-dihydroxy-L-phenylalanine was prepared which underwent self-polymerisation in the presence of doxorubicin (Dox) in an ethanol/water (1 : 4, v/v) mixture with ammonia. The resulting Dox-encapsulated polydopamine (PDA) nanoparticles were further conjugated with molecules of a zinc(II) phthalocyanine (Pc)-based photosensitiser and a peptide containing the heptapeptide QRHKPRE sequence (labelled as QRH) that can target the epidermal growth factor receptor (EGFR) overexpressed in cancer cells. Upon internalisation into these cells through receptor-mediated endocytosis, these nanoparticles labelled as PDA-Dox-Pc-QRH were disassembled gradually cleavage of the thioketal linkages by the intrinsic intracellular reactive oxygen species (ROS). The stacked Pc molecules were then disaggregated, resulting in activation of their photosensitising property upon irradiation. The ROS generated by the activated Pc promoted further degradation of the nanoparticles and release of Dox, thereby enhancing cell death by synergistic chemo and photodynamic therapy. Systemic injection of PDA-Dox-Pc-QRH into EGFR-overexpressed tumour-bearing nude mice led to targeted delivery to the tumour, and subsequent light irradiation caused complete tumour ablation without inducing notable toxicity.
制备了一种3,4-二羟基-L-苯丙氨酸的硫酮连接二聚体，其在阿霉素（Dox）存在下，于乙醇/水（1∶4，v/v）混合液与氨中进行自聚合反应。所得包封有Dox的聚多巴胺（PDA）纳米颗粒进一步与基于锌（II）酞菁（Pc）的光敏剂分子以及含有七肽QRHKPRE序列（标记为QRH）的肽缀合，该肽可靶向癌细胞中过表达的表皮生长因子受体（EGFR）。通过受体介导的内吞作用内化进入这些细胞后，这些标记为PDA-Dox-Pc-QRH的纳米颗粒通过细胞内固有活性氧（ROS）对硫酮键的裂解而逐渐分解。然后堆积的Pc分子解聚，导致其在光照下光敏特性被激活。活化的Pc产生的ROS促进纳米颗粒的进一步降解和Dox的释放，从而通过协同化疗和光动力疗法增强细胞死亡。将PDA-Dox-Pc-QRH全身注射到过表达EGFR的荷瘤裸鼠体内导致其靶向递送至肿瘤，随后的光照导致肿瘤完全消融且未引起明显毒性。
