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

Abstract

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.

Targeting NF-κB by the Cell-Permeable NEMO-Binding Domain Peptide Improves Albuminuria and Renal Lesions in an Experimental Model of Type 2 Diabetic Nephropathy

“…Therefore, the favorable effect of the NBD peptide is not only due to the inhibition of proinflammatory NF-κB signaling, but also through the restoration of redox balance. Our findings in the context of diabetes-induced kidney disease are consistent with other studies emphasizing the powerful therapeutic effects of different NBD-based strategies in preclinical models of Duchenne muscular dystrophy [28], Parkinson's disease [50], arthritis [27], breast cancer [31] and ischemic acute kidney injury [51]. A recent phase I trial of NBD peptide administration in dogs with large B-cell lymphoma demonstrated safety and efficacy [32], offering hope for translation to human disease.…”

“…Studies have identified a specific region in the C-terminal of IKKα (L738-L743) and IKKβ (L737-L742) that is essential for adequate assembly of the IKKα/β-NEMO complex, accordingly named the NEMO-binding domain (NBD) [26,27]. Based on this region, several cell-permeable NBD peptides have been characterized, thus providing an opportunity to selectively abrogate proinflammatory NF-κB activity in preclinical experimental models of inflammatory diseases [27][28][29][30][31][32].…”

<p>Hyaluronic Acid Capped, Irinotecan and Gene Co-Loaded Lipid-Polymer Hybrid Nanocarrier-Based Combination Therapy Platform for Colorectal Cancer</p>

“…21 In vitro Cellular Uptake and Cytotoxicity Figure 4A illustrated that the cellular uptake of HA-I/ D-LPNs was higher than I/D-LPNs (P < 0.05), which may be the evidence that HA-I/D-LPNs have CD44-targeting effect. 41 In vitro cytotoxicity results showed that HA-I/ D-LPNs exhibited remarkable better cell inhibition . HA modified LPNs showed slower drug/ gene release than that of unmodified LPNs.…”

Role of STAT3 signaling pathway in breast cancer

“…Additionally, knockdown of PTPN2 leads to EGF-mediated STAT3 activation [22]. The association of chronic inflammation with breast cancer progression is widely recognized, but it can be inhibited by blocking STAT3 [23]. Other mediators of STAT3 signaling pathways are also extensively studied.…”