Engineered microparticles loaded with pyrogallol (PG) and indocyanine green (ICG), named PG/ICG@MPs, have shown promise in repolarizing tumor-associated macrophages (TAMs) and inhibiting colorectal cancer progression. The study, published in Translational Medicine, details how these microparticles target tumor tissues, modulate arginine metabolism, and enhance the efficacy of photodynamic therapy.
Arginase Overexpression in Colorectal Cancer
Arginase, particularly ARG1, is highly expressed in various tumors, including colorectal cancer. This overexpression supports tumor growth by depleting arginine, an essential amino acid for immune cell function. Researchers found significantly higher levels of ARG1 in colorectal cancer tissues compared to normal tissues, indicating that targeting arginase could be a viable therapeutic strategy.
PG/ICG@MPs: Synthesis and Characterization
PG/ICG@MPs were synthesized with a drug loading capacity of 3.342 ng of PG and 0.43 μg of ICG per μg of protein. Transmission electron microscopy (TEM) revealed a saucer-like morphology with diameters of approximately 350 nm. The microparticles exhibited good biostability and were efficiently internalized by colorectal cancer cells via endocytosis.
Targeted Delivery and Metabolic Reprogramming
Fluorescence microscopy and in vivo imaging demonstrated that PG/ICG@MPs selectively accumulated in colorectal cancer cells, showcasing excellent targeting ability. Once inside the tumor cells, PG/ICG@MPs inhibited ARG1 expression and enhanced the levels of inducible nitric oxide synthase (iNOS). qPCR analysis confirmed that PG/ICG@MP treatment, especially when combined with laser irradiation, significantly decreased ARG1 mRNA levels and increased iNOS mRNA expression.
Enhanced Nitric Oxide Production and ROS Generation
PG/ICG@MPs promoted nitric oxide (NO) production, which is crucial for inhibiting mitochondrial function and enhancing reactive oxygen species (ROS) production. The Griess assay confirmed that PG/ICG@MPs exhibited the highest NO production compared to other treatment groups. Increased NO levels led to mitochondrial dysfunction, reduced ATP production, and enhanced the effectiveness of photodynamic therapy.
Repolarization of TAMs to M1-like Macrophages
TAMs, particularly M2-like macrophages, promote tumor cell proliferation and metastasis. PG/ICG@MPs effectively repolarized TAMs into M1-like macrophages, which secrete antitumor factors such as TNFα and iNOS. In vitro co-culture systems showed that PG/ICG@MP treatment upregulated M1-related markers (TNFα and iNOS) while downregulating M2-related markers (ARG1 and MRC1).
In Vivo Efficacy and Safety
In vivo studies using MC38 cell-derived subcutaneous tumor models demonstrated that PG/ICG@MPs, combined with 808 nm laser irradiation, significantly inhibited tumor growth. The PG/ICG@MP + laser group exhibited the lowest tumor weight compared to other groups. Biochemical analysis of blood samples revealed no significant toxicity, and hematoxylin-eosin (HE) staining of major organs showed no significant differences between treatment groups.
Clinical Implications
These findings suggest that PG/ICG@MPs hold significant potential as a targeted therapeutic approach for colorectal cancer. By modulating arginine metabolism, repolarizing TAMs, and enhancing photodynamic therapy, PG/ICG@MPs offer a novel strategy to inhibit tumor progression and improve patient outcomes. Further clinical trials are warranted to validate these preclinical results and assess the efficacy and safety of PG/ICG@MPs in human patients.
