A novel dual-prodrug carried by cyclodextrin inclusion complex for the targeting treatment of colon cancer.

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-ß-cyclodextrin (CM-ß-CD) to carry BBA and thus prepared a novel inclusion complex of BBA/FA-PEG-CM-ß-CD. RESULTS: It was found that BBA/FA-PEG-CM-ß-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-ß-CD gave great tumor suppression effect against nude mice bearing SW620 xenografts. CONCLUSIONS: Therefore, BBA/FA-PEG-CM-ß-CD may have clinical potential in colon cancer therapy.

Nanoparticles that target the mitochondria of tumor cells to restore oxygen supply for photodynamic therapy: Design and preclinical validation against breast cancer.

Photodynamic therapy, in which photosensitizers locally generate cytotoxic reactive oxygen species, can treat tumor tissue with minimal effects on surrounding normal tissue, but it can be ineffective because of the anoxic tumor microenvironment. Here we developed a strategy to inactivate the mitochondria of tumor cells in order to ensure adequate local oxygen concentrations for photodynamic therapy. We conjugated the photosensitizer 5-aminolevulinic acid to the lipophilic cation triphenylphosphine, which targets mitochondria. Then we packaged the conjugate into nanoparticles that were based on biocompatible bovine serum albumin and coated with folic acid in order to target the abundant folate receptors on the tumor surface. In studies in cell culture and BALB/c mice bearing MCF-7 xenografts, we found that the nanoparticles helped solubilize the cation-photosensitizer conjugate, prolong its circulation, and enhance its photodynamic antitumor effects. We confirmed the ability of the nanoparticles to target tumor cells and their mitochondria using confocal laser microscopy and in vivo assays of pharmacokinetics, pharmacodynamics, and tissue distribution. Our results not only identify a novel nanoparticle system for treating cancer, but they demonstrate the feasibility of enhancing photodynamic therapy by reducing oxygen consumption within tumors.

Treatment of Rheumatoid Arthritis by Serum Albumin Nanoparticles Coated with Mannose to Target Neutrophils.

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.

TAT-modified tetramethylpyrazine-loaded nanoparticles for targeted treatment of spinal cord injury.

Tetramethylpyrazine (TMP) has been effectively used for treating spinal cord injury (SCI) due to its anti-inflammatory, antioxidant, and neuroprotective activity. However, its clinical application is limited due to poor water solubility and insufficient spinal cord targeting through the traditional dosage forms. Given that intravascular neutrophils are quickly recruited to the injury site as part of the inflammatory response in SCI, we conjugated the cell-penetrating HIV trans-activator of transcription (TAT) peptide to human serum albumin nanoparticles (NPs) to make a TMP delivery system (TAT-TMP-NPs) that could be internalized by neutrophils and delivered to SCI lesions. Results found that in SCI rats TAT-TMP-NPs promoted the recovery of locomotor function and the lesion area, while reducing the levels of inflammatory cytokines and oxidative stress-related factors. Safety evaluation and in vivo small-animal imaging showed that the cell-penetrating peptide TAT could enhance the uptake of TAT-TMP-NPs by neutrophils without being toxic to the body. TAT-TMP-NPs may overcome the poor water solubility and low bioavailability of TMP, showing promise for the clinical treatment of SCI.