Rheumatoid arthritis (RA) is an angiogenic
and chronic inflammatory
disease. One of the most extensively used first-line drugs against
RA is methotrexate (MTX), but it shows poor solubility, short in vivo
circulation, and off-target binding, leading to strong toxicity. To
overcome these shortcomings, the present study loaded MTX into nanoparticles
of human serum albumin modified with mannose (MTX-M-NPs) to target
the drug to neutrophils. MTX-M-NPs were prepared, and their uptake
by neutrophils was studied using laser confocal microscopy and flow
cytometry. A chick chorioallantoic membrane assay was used to assess
their ability to inhibit angiogenesis. The pharmacokinetics and tissue
distribution of MTX-M-NPs were investigated using fluorescence microscopy
and high-performance liquid chromatography. Their pharmacodynamics
was evaluated in a rat model with arthritis induced by collagen. Neutrophils
took up MTX-M-NPs significantly better than the same nanoparticles
(NPs) without mannose. MTX-M-NPs markedly suppressed angiogenesis
in chick embryos, and the MTX circulation was significantly longer
when it was delivered as MTX-M-NPs than as a free drug. MTX-M-NPs
accumulated mainly in arthritic joints. The retention of NPs was promoted
by mannose-derived coating in arthritic joints. Serum levels of inflammatory
cytokines, joint swelling, and bone erosion were significantly decreased
by MTX-M-NPs. In conclusion, these NPs can prolong the in vivo circulation
of MTX and target it to the sites of inflammation in RA, reducing
drug toxicity. MTX-M-NPs allow the drug to exert its intrinsic anti-inflammatory,
antiangiogenic, and analgesic properties, making it a useful drug
delivery system in RA.
Background
There is an obvious correlation between ulcerative colitis and colorectal cancer, and the risk of colorectal cancer in patients with ulcerative colitis is increasing. Therefore, the combination therapy of anti-inflammatory and anti-tumor drugs may show promising to inhibit colon cancer. 5-aminosalicylic acid (5-ASA) with anti-inflammatory function is effective for maintaining remission in patients with ulcerative colitis and may also reduce colorectal cancer risk. Histone deacetylase (HDAC) plays an essential role in the progression of colon cancer. Butyric acid (BA) is a kind of HDAC inhibitor and thus shows tumor suppression to colon cancer. However, the volatile and corrosive nature of BA presents challenges in practical application. In addition, its clinical application is limited due to its non-targeting ability and low bioavailability. We aimed to synthesize a novel dual-prodrug of 5-ASA and BA, referred as BBA, to synergistically inhibit colon cancer. Further, based on the fact that folate receptor (FR) is over-expressed in most solid tumors and it has been identified to be a cancer stem cell surface marker in colon cancer, we took folate as the targeting ligand and used carboxymethyl-β-cyclodextrin (CM-β-CD) to carry BBA and thus prepared a novel inclusion complex of BBA/FA-PEG-CM-β-CD.
Results
It was found that BBA/FA-PEG-CM-β-CD showed significant inhibition in cell proliferation against colon cancer cells SW620. It showed a pro-longed in vivo circulation and mainly accumulated in tumor tissue. More importantly, BBA/FA-PEG-CM-β-CD gave great tumor suppression effect against nude mice bearing SW620 xenografts.
Conclusions
Therefore, BBA/FA-PEG-CM-β-CD may have clinical potential in colon cancer therapy.
Graphical Abstract
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.