Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, KY, 40536, USA.
Department of Bioengineering, School of Engineering, University of Louisville, 2301 South Third, Louisville, KY, 40292, USA.
Pharm Res. 2017 Nov;34(11):2385-2402. doi: 10.1007/s11095-017-2245-9. Epub 2017 Aug 24.
To develop polymer nanoassemblies (PNAs) modified with halofluorochromic dyes to allow for the detection of liver metastatic colorectal cancer (CRC) to improve therapeutic outcomes.
We combine experimental and computational approaches to evaluate macroscopic and microscopic PNA distributions in patient-derived xenograft primary and orthotropic liver metastatic CRC tumors. Halofluorochromic and non-halofluorochromic PNAs (hfPNAs and n-hfPNAs) were prepared from poly(ethylene glycol), fluorescent dyes (Nile blue, Alexa546, and IR820), and hydrophobic groups (palmitate), all of which were covalently tethered to a cationic polymer scaffold [poly(ethylene imine) or poly(lysine)] forming particles with an average diameter < 30 nm.
Dye-conjugated PNAs showed no aggregation under opsonizing conditions for 24 h and displayed low tissue diffusion and cellular uptake. Both hfPNAs and n-hfPNAs accumulated in primary and liver metastatic CRC tumors within 12 h post intravenous injection. In comparison to n-hfPNAs, hfPNAs fluoresced strongly only in the acidic tumor microenvironment (pH < 7.0) and distinguished small metastatic CRC tumors from healthy liver stroma. Computational simulations revealed that PNAs would steadily accumulate mainly in acidic (hypoxic) interstitium of metastatic tumors, independently of the vascularization degree of the tissue surrounding the lesions.
The combined experimental and computational data confirms that hfPNAs detecting acidic tumor tissue can be used to identify small liver metastatic CRC tumors with improved accuracy.
开发经卤氟变色染料修饰的聚合物纳米组装体（PNAs），以检测肝转移性结直肠癌（CRC），改善治疗效果。
我们结合实验和计算方法来评估源自患者的异种移植原发性和正交肝转移性 CRC 肿瘤的宏观和微观 PNA 分布。卤氟变色和非卤氟变色 PNAs（hfPNAs 和 n-hfPNAs）是由聚乙二醇、荧光染料（尼罗蓝、Alexa546 和 IR820）和疏水性基团（棕榈酸）制备的，所有这些都共价连接到阳离子聚合物支架[聚乙烯亚胺或聚赖氨酸]上，形成平均直径 < 30nm 的颗粒。
在 24 小时的调理条件下，染料缀合的 PNAs 没有聚集，并且显示出低的组织扩散和细胞摄取。hfPNAs 和 n-hfPNAs 在静脉注射后 12 小时内都在原发性和肝转移性 CRC 肿瘤中积累。与 n-hfPNAs 相比，hfPNAs 仅在酸性肿瘤微环境（pH < 7.0）中强烈荧光，并将小的转移性 CRC 肿瘤与健康的肝基质区分开来。计算模拟表明，PNAs 将主要稳定地积累在转移性肿瘤的酸性（缺氧）间质中，而与周围病变组织的血管化程度无关。
实验和计算数据的综合证实，检测酸性肿瘤组织的 hfPNAs 可用于以更高的准确性识别小的肝转移性 CRC 肿瘤。
