An in situ microenvironmental nano-regulator to inhibit the proliferation and metastasis of 4T1 tumor

Abstract

Tumor microenvironment, such as hypoxia and presence of immune cells, plays a critical role in cancer initiation, growth as well as progression, and seriously affects antitumor effect. Accordingly, we constructed a kind of multifunctional nanoparticles (NPs) with macrophage transformation and oxygen (O 2 ) generation characteristics, to regulate the tumor microenvironment. Methods: In this study, we synthesized mesoporous Prussian blue (MPB) NPs with low molecular weight hyaluronic acid (LMWHA) surface modification (LMWHA-MPB), and discovered that LMWHA-MPB could be used as an in situ macrophages converter and O 2 generator. Results: In vitro results showed after uptake by M2 macrophages, LMWHA-MPB displayed the potential in remodeling tumor-associated macrophages (TAMs) phenotype (pro-tumor M2→anti-tumor M1), and anti-metastatic effect on 4T1 cells. Furthermore, in vivo visualized near-infrared (NIR) imaging data proved IR783 labeled LMWHA-MPB NPs could selectively accumulate in tumor sites. Then plenty of O 2 generated to alleviate tumor hypoxia via catalytic decomposition of endogenous hydrogen peroxide (H 2 O 2 ). Based on these outstanding characteristics, LMWHA-MPB NPs were adopted as multifunctional nanocarriers to load sonosensitizer hematoporphyrin monomethyl ether (HMME) for O 2 self-provided sonodynamic therapy (SDT). In vivo anti-tumor results showed LMWHA-MPB/HMME could effectively inhibit the proliferation and metastasis of 4T1 tumors by improving tumor microenvironment. Conclusion: The multifunctional NPs can be used as in situ microenvironmental nano-regulators to inhibit the proliferation and metastasis of 4T1 tumor.

The twin cytokines interleukin-34 and CSF-1: masterful conductors of macrophage homeostasis

“…Ultrasound irradiation induces the production of H 2 O 2 from HMME and MPB acts as a catalyst of hydrogen peroxide (H 2 O 2 ) to produce O 2 . In vivo experiments using 4T1 tumor-bearing mice showed that ultrasound irradiation of LMWHA-MPB/HMME induced both the production of O 2 and the transformation of the tumor microenvironment 229 .…”

“…Low-molecular-weight hyaluronic acid (LMWHA) also promotes M1 macrophage polarization 228 . Based on LMWHA, multifunctional nanoparticles were developed to combine macrophage reprogramming and modulation of the microenvironment for cancer therapy 229 . Mesoporous Prussian blue nanoparticles (MPB) were coated with LMWHA and used as a cargo for sonosensitizer hematoporphyrin monomethyl ether (HMME).…”

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

“…With regard to energy metabolism, cancer cells with high glycolytic activity decrease the availability of glucose and induce an acidic microenvironment, which push TAMs towards an M2-like metabolism, strongly committed to oxidative phosphorylation and fatty acid oxidation, in contrast to M1-like macrophages, which present higher glucose uptake and aerobic glycolytic catabolism [ 182 ]. To alleviate hypoxia, hyaluronic acid NPs targeted towards TAMs have been designed to increase O 2 production in the TME, showing inhibition of tumor growth and metastasis in 4T1 tumors [ 183 , 184 ]. Inactivation of HIF-1α by restoring miR-30c expression in macrophages showed antitumoral efficacy in gastric cancer [ 185 ].…”

Glycosaminoglycans: Carriers and Targets for Tailored Anti-Cancer Therapy

“…This approach demonstrated that LMWHA-MPB penetrates M2 macrophages (pro-tumoral macrophages), which are subsequently diverted toward the M1 phenotype exhibiting anti-tumoral action. Therefore, LMWHA-MPB can induce TAMs pro-tumoral potential and can likewise be used in situ for microenvironmental tumoral regulation [ 250 ].…”