Kucharczyk Kamil, Florczak Anna, Kaminska Alicja, Guzniczak Natalia, Sikorska Agata, Deptuch Tomasz, Dams-Kozlowska Hanna
Department of Cancer Immunology, Poznan University of Medical Sciences, 61-866 Poznan, Poland; Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland.
Department of Cancer Immunology, Poznan University of Medical Sciences, 61-866 Poznan, Poland.
Int J Biol Macromol. 2024 Jun;269(Pt 1):132016. doi: 10.1016/j.ijbiomac.2024.132016. Epub 2024 Apr 30.
Silk is a biocompatible and biodegradable material that enables the formation of various morphological forms, including nanospheres. The functionalization of bioengineered silk makes it possible to produce particles with specific properties. In addition to tumor cells, the tumor microenvironment (TME) includes stromal, immune, endothelial cells, signaling molecules, and the extracellular matrix (ECM). Matrix metalloproteinases (MMPs) are overexpressed in TME. We investigated bioengineered spider silks functionalized with MMP-responsive peptides to obtain targeted drug release from spheres within TME. Soluble silks MS12.2MS1, MS12.9MS1, and MS22.9MS2 and the corresponding silk spheres carrying MMP-2 or MMP-2/9 responsive peptides were produced, loaded with doxorubicin (Dox), and analyzed for their susceptibility to MMP-2/9 digestion. Although all variants of functionalized silks and spheres were specifically degraded by MMP-2/9, the MS22.9MS2 nanospheres showed the highest levels of degradation and release of Dox after enzyme treatment. Moreover, functionalized spheres were degraded in the presence of cancer cells releasing MMP-2/9. In the 2D and 3D spheroid cancer models, the MMP-2/9-responsive substrate was degraded and released from spheres when loaded into MS22.9MS2 particles but not into the control MS2 spheres. The present study demonstrated that a silk-based MMP-responsive delivery system could be used for controlled drug release within the tumor microenvironment.
丝绸是一种生物相容性和可生物降解的材料，能够形成包括纳米球在内的各种形态形式。生物工程丝绸的功能化使得生产具有特定性质的颗粒成为可能。除了肿瘤细胞外，肿瘤微环境（TME）还包括基质细胞、免疫细胞、内皮细胞、信号分子和细胞外基质（ECM）。基质金属蛋白酶（MMPs）在肿瘤微环境中过度表达。我们研究了用MMP反应肽功能化的生物工程蜘蛛丝，以实现肿瘤微环境内球体的靶向药物释放。制备了可溶性丝MS12.2MS1、MS12.9MS1和MS22.9MS2以及携带MMP-2或MMP-2/9反应肽的相应丝球，装载阿霉素（Dox），并分析它们对MMP-2/9消化的敏感性。尽管功能化丝和球体的所有变体都被MMP-2/9特异性降解，但MS22.9MS2纳米球在酶处理后显示出最高水平的降解和Dox释放。此外，功能化球体在释放MMP-2/9的癌细胞存在下会降解。在二维和三维球体癌症模型中，当装入MS22.9MS2颗粒而非对照MS2球体时，MMP-2/9反应性底物会从球体中降解并释放出来。本研究表明，基于丝绸的MMP反应性递送系统可用于肿瘤微环境内的药物控释。
