Combination of mitochondria impairment and inflammation blockade to combat metastasis

Abstract

Targeted induction of mitochondria impairment has emerged as a promising strategy for anti-metastasis therapy. However, problems such as limited mitochondria targeting efficiency, undesired drug leakage and insufficient drug release inside mitochondria remain crucial challenges for mitochondria-targeting therapy. Here, we constructed an N-(2-hydroxypropyl) methacrylamide (HPMA) polymer based cationic system that could target to mitochondria and facilitate on demand drug release in response to excessive mitochondrial reactive oxygen species. Whereas, this drug delivery system is still challenged by limitations of (1) in vivo application, and (2) inflammatory tumor microenvironment (TME). On one aspect, to prolong blood circulation and increase tumor targeting, we designed a nanocomposite (PDT-NCs) that assembled from the cationic HPMA polymer and anionic hyaluronic acid via electrostatic interaction. On another aspect, a celecoxib loaded liposome (Lip-Cel) was further fabricated to alleviate inflammation in TME by downregulating various metastasis-associated factors. Ultimately, PDT-NCs and Lip-Cel led to a drastic improvement in the suppression of primary tumor growth and distant lung metastasis. Our work provided a generalizable approach of mitochondria dysfunction and inflammation blockade to combat metastatic tumors.

Keywords: Anti-metastasis therapy; Combination therapy; Inflammatory tumor microenvironment; Mitochondria impairment; Reactive oxygen species.