Biomineralized Polydopamine Nanoparticle-Based Sodium Alginate Hydrogels for Delivery of Anti-serine/Threonine Protein Kinase B-Rapidly Accelerated Fibrosarcoma siRNA for Metastatic Melanoma Therapy.
Jianxiu LuJixin SongPeiying ZhangYing HuangXiaomin LuHua DaiJuqun XiPublished in: ACS nano (2023)
Malignant melanoma, as a highly aggressive skin cancer, is strongly associated with mutations in serine/threonine protein kinase B-RAF (BRAF, where RAF stands for rapidly accelerated fibrosarcoma). Targeted therapy with anti-BRAF small interfering RNA (siBRAF) represents a crucial aspect of metastatic melanoma treatment. In this study, an injectable hydrogel platform based on sodium alginate (SA), with multifunctions of photothermal and Ca 2+ -overload cell apoptosis, was explored as a siBRAF carrier for metastatic melanoma therapy. We employed polydopamine nanoparticles (PDAs) as a photothermal core and constructed a calcium phosphate (CaP) shell via biomineralization (PDA@CaP) to load siBRAF (PDA@siBRAF/CaP). The pH-sensitive CaP shell facilitated the release of Ca 2+ under the weakly acidic tumor microenvironment, triggering the gelation of PDA@siBRAF/CaP-SA to localized release siBRAF at tumor sites with the interruption of the RAS-RAF-MEK-ERK (MAPK) pathway. Besides, the continuous release of Ca 2+ could also lead to Ca 2+ -overload cell apoptosis. Moreover, the photothermal effect of PDA regulated the release kinetics, resulting in coordinated therapeutic abilities of individual components in the PDA@siBRAF/CaP-SA hydrogels. Consequently, the effective inhibition of tumor growth and metastasis was achieved in vitro and in vivo using a highly metastatic melanoma cell line B16F10 as the model, by combining photothermal ablation, Ca 2+ overload, and BRAF silencing. Our work provides a proof-of-concept for an injectable hydrogel system that simultaneously targets multiple mechanisms involved in melanoma progression and has the potential to be translated into clinical use for the metastatic melanoma therapy.
Keyphrases
- protein kinase
- drug delivery
- hyaluronic acid
- tissue engineering
- cancer therapy
- drug release
- photodynamic therapy
- skin cancer
- wound healing
- cell proliferation
- signaling pathway
- pi k akt
- wild type
- transcription factor
- extracellular matrix
- high throughput
- mesenchymal stem cells
- bone marrow
- risk assessment
- magnetic nanoparticles