Efficiency of Different Treatment Regimens Combining Anti-tumor and Anti-inflammatory Liposomes for Metastatic Breast Cancer.

Nanomedicines such as liposomes have been widely exploited in the treatment of tumors, and are also involved in combination therapies to enhance anti-tumor efficacy and reduce side effects. However, few studies have systematically discussed the significance and optimized regimens for nanomedicine-based combination therapy. In this study, we used anti-inflammatory and anti-tumor liposomes for co-administration, and compared three regimens: intermittent, metronomic, or sequential administration (IA, MA, and SA). The anti-inflammatory liposome HA/TN-CCLP was constructed in our previous research, which co-loaded curcumin (CUR) and celecoxib (CXB), modified with TAT-NBD peptide (TN) and finally coated with hyaluronic acid (HA), thereby inhibiting NF-κB and STAT3 pathways in the treatment of metastatic breast cancer. Furthermore, doxorubicin liposomes with and without TN modification (namely TN-DOXLP and DOXLP) were constructed and administrated with HA/TN-CCLP. The anti-tumor and anti-metastasis efficacy of different regimens was investigated. Results showed that in vitro cytotoxicity of DOXLP and TN-DOXLP was significantly enhanced when combined with HA/TN-CCLP. In vivo experiments also revealed the superiority of three combination therapies in inhibiting tumor growth, prolonging the survival of tumor-bearing mice, inducing apoptosis, and reducing lung metastases. In particular, the combination therapy could reduce MDSCs (Gr-1+/CD11b+) and CSCs (CD44+/CD24+) infiltration, which are two important factors in tumor metastasis and recurrence. Among three regimens, sequential administration (SA) showed the best therapeutic outcome and was especially effective for the inhibition of CSCs. In general, the results demonstrated that combination therapy, particularly the sequential administration of anti-inflammatory and anti-tumor liposome, was superior to monotherapy in inhibiting the development and metastasis of inflammation-related tumors.

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.