Improved mitochondrial targeting effect of HPMA copolymer by SS20 peptide mediation and nonendocytosis pathway

Abstract

Mitochondrion plays an important role in executing cell programmed death pathway.Therefore, drugs designed to target mitochondria are supposed to make superior contributions to cancer therapy. However, the problem that drugs or drug delivery systems being sequestrated in endosomes/lysosomes needs to be solved for effective drug delivery. Here, mitochondrial targeting and nonendocytic cell entry peptide SS20 modified HPMA copolymer (P-FITC-SS20) was synthesized. With SS20 peptide modification, the uptake behavior of HPMA copolymers changed remarkably compared with unmodified ones. The internalization of P-FITC-SS20 was not influenced by endocytic inhibitors and temperature. Further, the internalized copolymers were not trapped in endosomes/lysosomes. Although cellular uptake of HPMA copolymer was decreased after SS20 peptide modification, SS20 peptide significantly improved mitochondrial accumulation of HPMA copolymers due to its outstanding mitochondrial targeting ability. Moreover, owing to lower susceptibility to macrophagocyte in blood, P-SS20-Cy5 showed longer blood circulation time and enhanced tumor accumulation. The current study validated that SS20 peptide modification is a promising strategy for mitochondrial targeting drug delivery systems and can be further applied to mitochondria associated diseases to improve therapeutic efficacy.

Enhance Mitochondrial Damage by Nuclear Export Inhibition to Suppress Tumor Growth and Metastasis with Increased Antitumor Properties of Macrophages

“…Mitochondrial dysfunction triggers mitochondria-associated intrinsic apoptosis. , XPO1 controls the nucleo-cytoplasmic trafficking of several key growth regulatory and tumor suppressor proteins. As a result, a selective inhibitor of nuclear export compound, KPT-330, was reported to have the ability to cause cell cycle arrest and apoptosis. ,, Our results showed that both KPT NPs and TL NPs displayed proapoptosis effects; what is more, their combination induced the strongest apoptosis (Figure F) as expected.…”

Enhanced Reactive Oxygen Species Generation by Mitochondria Targeting of Anticancer Drug To Overcome Tumor Multidrug Resistance

“…To achieve mitochondria targeting delivery, mitochondria-targeting signal peptides and lipophilic cations (e.g., triphenylphosphonium, dequalinium) have been used. − However, as some mitochondria targeting groups do not have a significant tumor cell targeting ability or cannot enhance cellular uptake of drugs, the simultaneous use of a cell targeting peptide or cell penetrating peptide as well as a mitochondria targeting ligand in drug delivery systems was developed . Another strategy is to use a ligand which is able to increase both cellular uptake and mitochondria targeting .…”