Effective treatment of metastatic sentinel lymph nodes by dual-targeting melittin nanoparticles

Abstract

Sentinel lymph node (SLN) metastasis is an important promoter of distant metastasis in breast cancer. Therefore, the timely diagnosis and precise treatment are crucial for patient staging and prognosis. However, the simultaneous diagnosis of metastasis and the implementation of imaging-guided SLN therapy is challenging. Here, we report a melittin-loaded and hyaluronic acid (HA)-conjugated high-density lipoprotein (HDL) mimic phospholipid scaffold nanoparticle (MLT-HA-HPPS), which dually-target to both breast cancer and its SLN and efficiently inhibit SLN metastasis in the LN metastasis model. The melittin peptide was successfully loaded onto HA-HPPS via electrostatic interactions, and MLT-HA-HPPS possesses effective cytotoxicity for breast cancer 4T1 cells. Moreover, the effective delivery of MLT-HA-HPPS from the primary tumor into SLN is monitored by NIR fluorescence imaging, which greatly benefits the prognosis and treatment of metastatic SLNs. After paracancerous administration, MLT-HA-HPPS can efficiently inhibit primary tumor growth with an inhibition rate of 81.3% and 76.5% relative to the PBS-treated control group and HA-HPPS group, respectively. More importantly, MLT-HA-HPPS can effectively inhibit the growth of the metastatic SLNs with an approximately 78.0%, 79.1%, and 64.2% decrease in SLNs weight than those in PBS, HA-HPPS, and melittin-treated mice, respectively. Taken together, the MLT-HA-HPPS may provide an encouraging theranostic of SLN drug delivery strategy to inhibit primary tumor progression and prevent SLN metastasis of breast cancer. Graphical Abstract

The current landscape of the antimicrobial peptide melittin and its therapeutic potential

“…Furthermore, Mel-HA-Lip performed more obvious antitumor effects compared with Mel-Lip ( 170 ). Dai and colleagues developed dual-targeting nanoparticles carrying melittin with HA-conjugated high-density lipoprotein (HDL) as the phospholipid scaffold (MLT-HA-HPPS) to target breast cancer and its sentinel lymph node (SLN) ( 88 ). MLT-HA-HPPS exhibited effective cytotoxicity on mouse mammary adenocarcinoma 4T1 cells.…”

“…The tumoricidal properties of melittin on breast cancer cells have been investigated ( 86 , 87 ). Melittin could impede primary tumor growth and inhibit the growth of the metastatic sentinel lymph node in breast cancer models in vitro and in vivo ( 88 ). Melittin directly acts on MCF7 breast cancer cells ( 81 , 89 ) and suppresses the migration of breast cancer cell, MDA-MB-231 cell line ( 90 ).…”

Recent advances in melittin-based nanoparticles for antitumor treatment: from mechanisms to targeted delivery strategies

“…For example, hyaluronic acid (HA) not only increases the accumulation of NPs in the CD44-expressed tumor region but also results in the release of therapeutic agents in the TME by hyaluronidase-mediated degradation of HA [ 121 ]. Therefore, the insertion of HA moieties as an effective targeting element within NP formulations is a promising strategy for tumor treatment [ 122 , 123 ]. Jia et al found that chlorin e6 (Ce6) could form a stable nanocomplex with MLT and effectively shield the hemolytic activity of MLT [ 124 ].…”