Cell Permeable NBD Peptide-Modified Liposomes by Hyaluronic Acid Coating for the Synergistic Targeted Therapy of Metastatic Inflammatory Breast Cancer.

Chronic inflammation is closely related to the development, deterioration, and metastasis of tumors. Recently, many studies have shown that down-regulating the expression of inflammation by blocking nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways could significantly inhibit tumor growth and metastasis. The combined application of curcumin (CUR) and celecoxib (CXB) has been proven to exert a synergistic antitumor effect via inhibiting the activation of NF-κB and STAT3. TAT-NBD (TN) peptide, a fusion peptide of NF-κB essential modulator (NEMO)-binding domain peptide (NBD) and cell-penetrating peptide (TAT), can selectively block NF-κB activating pathway resulting in tumor growth inhibition. In the present study, a novel TN-modified liposome coloading both CXB and CUR (TN-CCLP) at a synergistic ratio was first constructed with the property of synchronous release, then hyaluronic acid (HA) as CD44 targeting moiety was coated on the surface of the cationic liposome via electrostatic interaction to prepare the anionic HA/TN-CCLP. In vitro results of cytotoxicity, macrophage migration inhibition, and anti-inflammation efficacy revealed that TN-CCLP and HA/TN-CCLP were significantly superior to TN-LP and CCLP, while TN-CCLP exhibited better effects than HA/TN-CCLP due to higher cellular uptake ability. Different from in vitro data, after systematically treating 4T1 breast tumor-bearing mice, HA/TN-CCLP exerted the most striking effects on anti-inflammation, inhibition of macrophage recruitment, and antitumor because of the longest circulation time and maximum tumor accumulation. In particular, HA/TN-CCLP could availably block the lung metastasis of breast cancer. Taken together, the novel CD44 targeted TN-CCLP exhibited the potential for inhibiting tumor development and metastasis through improving inflammatory infiltration of tumor tissue.

Macrophage-biomimetic anti-inflammatory liposomes for homing and treating of aortic dissection.

Aortic dissection (AD) is a life-threatening disease featured by the dissection of intimal layer and the formation of a blood-filled false lumen within the aortic wall. Recent studies revealed that the formation and progression of AD lesions is closely related to vascular inflammation and macrophage infiltration. However, the potential efficacy of anti-inflammatory therapy on the prevention and treatment of AD has not been extensively investigated. Herein, we proposed a biomimetic anti-inflammatory liposome (PM/TN-CCLP) co-loaded with curcumin and celecoxib (CC), modified with cell-penetrating TAT-NBD fusion peptide (TN), and further camouflaged by isolated macrophage plasma membrane (PM), as a potential nanotherapy for AD. In vitro results showed that PM/TN-CCLP exhibited low cytotoxicity and elevated cellular uptake by inflammatory macrophages, and prominently inhibited the transendothelial migration, inflammatory responses and ROS generation of macrophages. Moreover, the PM/TN-CCLP treatment significantly prevented the H2O2-induced smooth muscle cell apoptosis. In vivo experiments were performed on the acute and chronic AD mouse models, respectively. The results verified the elevated accumulation of PM-camouflaged liposome at the aorta lesions. Further, the anti-inflammatory liposomes, especially PM/TN-CCLP, could reduce the rupture rate of dissection, prevent the loss of elastic fibers, and reduce MMP-9 expression as well as macrophage infiltration in the aortic lesions. Notably, as compared with free drugs and TN-CCLP, the PM/TN-CCLP treatment displayed the longest survival period along with the minimal aortic injury on both acute and chronic AD mice. Taken together, the present study suggested that the macrophage-biomimetic anti-inflammatory nanotherapy would be a promising strategy for the prevention and therapy of aortic dissection.

Tumor penetrability and anti-angiogenesis using iRGD-mediated delivery of doxorubicin-polymer conjugates.

Tumor-penetrating peptide, iRGD (internalizing RGD, CRGDK/RGPD/EC) with the similar affinity to αv integrins as conventional RGD cyclopeptide could enhance the tumor penetrability of drugs by binding to neuropilin-1 (NRP-1) that over-expressed on both angiogenic blood vessels and tumor cells. Comparing with our previous study, in which a RGD cyclopeptide (RGDyC) was bound to PEGylated polyamidoamine (PAMAM) dendrimer with doxorubicin (DOX) by acid-sensitive cis-aconityl linkage (PEG-PAMAM-cis-aconityl-DOX, PPCD), the present study selected iRGD instead of previous RGD to produce iRGD-PPCD conjugate. The effect of iRGD-mediated PPCD on tumor penetration was compared with the conventional RGD ones via administration of RGDs-modified PPCD (iRGD/RGDs-PPCD) and co-administration of RGDs and PPCD (iRGD/RGD + PPCD). C6 cells were selected as the cell model owing to the highest expression of αv integrins and NRP-1 among four tumor cell lines. In vitro cytotoxicity and cellular uptake showed no significant difference between RGD-PPCD and iRGD-PPCD, but glioma spheroid penetration study showed that RGD-PPCD, iRGD-PPCD and iRGD + PPCD penetrated into C6 spheroids with a depth of 115 µm, 144 µm and 150 µm, respectively, indicating that the iRGD-mediated PPCD delivery system had a stronger penetrating ability than the RGD ones. In vivo results also demonstrated the superiority of iRGD system over RGD ones. After systemic administration, iRGD-mediated PPCD increased tumor vascular permeability, decreased tumor vascular density and average vascular diameter. Correspondingly, the iRGD system exhibited stronger penetration ability, higher accumulation in brain tumor. The median survival time of iRGD + PPCD, iRGD-PPCD and RGD-PPCD treatment groups were 61, 57.5 and 43.5 days. The present findings strongly suggested that the iRGD-mediated drug delivery system could significantly improve the efficacy of tumor therapy through enhancing tumor accumulation and penetration as compared to the conventional RGD ones.