Journal
JOURNAL OF CONTROLLED RELEASE
Volume 325, Issue -, Pages 10-24Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2020.03.049
Keywords
Melanoma; Multifunctional carrier; pH-sensitive; TRAIL; Combined therapy
Funding
- National Natural Science Foundation of China [81690261, 81872824]
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Malignant melanoma, a highly dangerous type of skin cancer, is usually resistant to pro-apoptosis agents such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) due to low death receptor expression levels. After verifying combination of chemotherapy drug paclitaxel (PTX) and TRAIL could significantly enhance their anti-melanoma effects, we developed a liposomal melanoma target-delivery system with tumor microenvironment responsiveness (TRAIL-[Lip-PTX](C18-TR)) to co-deliver TRAIL and PTX. TRAIL is attached to negatively-charged liposome surface while PTX is encapsulated inside, with final surface modification of a stearyl chain (C18) fused pH-sensitive cell-penetrating peptide (TR). Here, C18-TR could specifically binds to melanoma-rich integrin receptors alpha(v)beta(3) for melanoma targeting, help release TRAIL in low pH microenvironment by reversing the liposomal charge, and facilitate consequent liposome internalization. TRAIL-[Lip-PTX](C18-TR) displayed significantly better in vitro half-maximal inhibitory concentration (IC50) than other formulations, and an in vivo tumor inhibition rate of 93.8%. Mechanistic study revealed that this synergistic effect is associated with the upregulation of death receptors DR4/5 by PTX. This co-delivery system significantly improved TRAIL-based therapy against melanoma, and provided a simple platform to co-deliver other drugs/agents for melanoma treatment.
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