Mitochondria-Targeted Delivery of Camptothecin Based on HPMA Copolymer for Metastasis Suppression

Abstract

Poor anti-metastasis effects and side-effects remain a challenge for the clinical application of camptothecin (CPT). Mitochondria can be a promising target for the treatment of metastatic tumors due to their vital roles in providing energy supply, upregulating pro-metastatic factors, and controlling cell-death signaling. Thus, selectively delivering CPT to mitochondria appears to be a feasible way of improving the anti-metastasis effect and reducing adverse effects. Here, we established a 2-(dimethylamino) ethyl methacrylate (DEA)-modified N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer–CPT conjugate (P-DEA-CPT) to mediate the mitochondrial accumulation of CPT. The mitochondria-targeted P-DEA-CPT could overcome multiple barriers by quickly internalizing into 4T1 cells, then escaping from lysosome, and sufficiently accumulating in mitochondria. Subsequently, P-DEA-CPT greatly damaged mitochondrial function, leading to the reactive oxide species (ROS) elevation, energy depletion, apoptosis amplification, and tumor metastasis suppression. Consequently, P-DEA-CPT successfully inhibited both primary tumor growth and distant metastasis in vivo. Furthermore, our studies revealed that the mechanism underlying the anti-metastasis capacity of P-DEA-CPT was partially via downregulation of various pro-metastatic proteins, such as hypoxia induction factor-1α (HIF-1α), matrix metalloproteinases-2 (MMP-2), and vascular endothelial growth factor (VEGF). This study provided the proof of concept that escorting CPT to mitochondria via a mitochondrial targeting strategy could be a promising approach for anti-metastasis treatment.

Poly(amidoamine) Dendrimer/Camptothecin Complex: From Synthesis to In Vitro Cancer Cell Line Studies

“…Similar findings have been reported in the literature; for example, lung cancer cells (A549) exposed to N-acetyl-D-glucosamine-labeled dendrimer (NAG-Dend)-loaded CPT (NAG-Dend-CPT) expressed slower migration of the cells into the wound area than control cells [ 44 ]. Yi and colleagues observed similar results for breast cancer cells treated with a 2-(dimethylamino)ethylmethacrylate (DEA)-modified N -(2-hydroxypropyl) methacrylamide (HPMA) copolymer-CPT conjugate (P-DEA-CPT); treated cells migrated at a significantly slower rate when compared to the control group [ 45 ]. The motility of prostate cancer cells (PC-3) treated with a CPT/bombesin analog was also reduced in comparison to the control group [ 46 ].…”

Combination of Chlorambucil and Mercaptopurine Show Effective Anti-Cancer Effects in Mice Model

“… 20 The hydroxyl group attached to the polymer can be designed to link a variety of different drugs or target ligands to create delivery systems that perform different functions. 21 , 22 However, multi-drug combined delivery systems based on polyHPMA are rarely reported.…”

Strategies to Enhance Drug Permeability across Biological Barriers—A Summary of This Important Special Issue

“…The first article of this Special Issue looks at the recent advances in cancer-targeting drug research, which have been made by overcoming the multiple biological barriers that are associated with mitochondrial targeting. Yi et al established a 2-(dimethylamino) ethyl methacrylate (DEA)-modified N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-CPT conjugate (P-DEA-CPT) to mediate the mitochondrial accumulation of CPT [1]. This mitochondria-targeting P-DEA-CPT can quickly internalize into 4T1 cells, escaping from lysosomes and accumulating inside mitochondria.…”