A Multifunctional Nanotherapy for Targeted Treatment of Colon Cancer by Simultaneously Regulating Tumor Microenvironment

Abstract

Colitis-associated colon cancer (CAC) is a widely recognized cancer, while treatment with the existing chemotherapeutic drugs affords limited clinical benefits. Herein we proposed a site-specific, combination nanotherapy strategy for targeted treatment of CAC by the oral route. Methods : A reactive oxygen species (ROS)-responsive and hydrogen peroxide-eliminating material OCD was synthesized, which was further produced into a functional nanoparticle (OCD NP). The antioxidative stress and anti-inflammatory effects of OCD NP were examined by in vitro and in vivo experiments. By packaging an anticancer drug camptothecin-11 (CPT-11) into OCD NP, a ROS-responsive nanotherapy CPT-11/OCD NP was obtained, and its antitumor activity was evaluated by both in vitro and in vivo studies. Preliminary safety studies were also performed for CPT-11/OCD NP in mice. Results : OCD NP significantly attenuated oxidative stress and inhibited inflammatory response in different cells and mice with induced colitis. CPT-11/OCD NP could selectively release drug molecules under intestinal pH conditions and at high levels of ROS. In C26 murine colon carcinoma cells, this nanotherapy showed significantly higher antitumor activity compared to free CPT-11 and a non-responsive CPT-11 nanotherapy. Correspondingly, oral delivery of CPT-11/OCD NP notably inhibited tumorigenesis and tumor growth in mice with induced CAC. By combination therapy with the nanovehicle OCD NP in the inflammatory phase, more desirable therapeutic effects were achieved. Furthermore, CPT-11/OCD NP displayed excellent safety profile for oral administration at a dose that is 87.3-fold higher than that employed in therapeutic studies. Conclusions : Anticancer nanotherapies derived from intrinsic anti-inflammatory nanocarriers are promising for targeted combination treatment of inflammation-associated tumors by simultaneously shaping pro-inflammatory microenvironment toward a relatively normal niche sensitive to chemotherapy.

A Proresolving Peptide Nanotherapy for Site‐Specific Treatment of Inflammatory Bowel Disease by Regulating Proinflammatory Microenvironment and Gut Microbiota

“…In addition, Cy7.5‐AON exhibited significantly higher accumulation in the diseased colon, compared to Cy7.5‐APN (Figure S8, Supporting Information). This can be explained by the adhesive property of OxbCD, as demonstrated in our previous studies …”

“…Compared to ROS‐responsive nanocarriers based on other materials, such as poly(propylene sulfide), selenium‐containing copolymers, polydopamine, and materials bearing polythioether ketal or thioketal linkers, OxbCD‐derived NPs are highly sensitive to H 2 O 2 . More importantly, our comprehensive in vitro and in vivo studies have revealed good safety profile for nanocarriers based on OxbCD . Consequently, we hypothesize that the ROS‐responsive nanocarrier ON can revive orally delivered Ac2‐26 by protecting it from degradation and selective release in the inflamed colon of IBD.…”

Antioxidant Nanotherapies for the Treatment of Inflammatory Diseases

“…Interestingly, nanoparticles based on PBAP-conjugated cyclodextrin materials can effectively eliminate H 2 O 2 , thereby inhibiting inflammatory responses and oxidative stress in stimulated macrophages . These H 2 O 2 -eliminating cyclodextrin nanoparticles efficaciously alleviated the symptoms of peritonitis and colitis in mice, by reducing the counts of neutrophils and macrophages as well as inhibiting the secretion of pro-inflammatory cytokines, chemokines, and oxidative mediators Zhang Q. et al, 2019). Also, we found that nanoparticles prepared from a luminol-conjugated β-CD material (LCD) can inhibit inflammatory response, oxidative stress, and recruitment of neutrophils and macrophages .…”

Bioresponsive drug delivery systems for the treatment of inflammatory diseases

“…In all these mouse models, Tpl/OxbCD nanoparticles were more effective than Tpl/PLGA nanoparticles. In a separate study, we found that this type of H 2 O 2 -responsive and ROS-eliminating nanoparticles can potentiate in vivo antitumor activity of a ROS-responsive camptothecin-11 nanotherapy in mice with chronic colitis-associated colon cancer, by normalizing the proinflammatory microenvironment [ 320 ]. More recently, our studies showed that OxbCD nanoparticles are able to package a proresolving annexin A1-mimetic peptide Ac2-26, offering a ROS-responsive peptide nanotherapy (defined as AON) ( Fig.…”