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Targeting CAMKII to reprogram tumor-associated macrophages and inhibit tumor cells for cancer immunotherapy with an injectable hybrid peptide hydrogel
- Source :
- Theranostics
- Publication Year :
- 2020
- Publisher :
- Ivyspring International Publisher, 2020.
-
Abstract
- Simultaneously targeted treatment of tumor cells and their surrounding growth-supporting immune cells is a promising strategy to reshape immunosuppressive tumor microenvironment (TME) and potentiate host innate and adaptive antitumor immune responses. Methods: We designed a series of melittin-(RADA)n hybrid peptide sequences with varying self-assembling motifs of RADA and screened out a melittin-(RADA)6 peptide that has an optimal gel-formation ability and in vitro antitumor activity. Results: The formed melittin-(RADA)6 (MR52) hydrogel scaffold could be loaded with a specific Ca2+/calmodulin-dependent protein kinase II (CAMKII) inhibitor, KN93, originally found to have both direct tumoricidal activity and macrophages-reprogramming ability, for potent immunotherapy against melanoma and hepatoma ascites in mice models. Our MR52 hydrogel has an interweaving nanofiber-like structure, possesses direct antitumor and controlled drug release properties, and promotes the enhanced intracellular uptake of loaded cargo. Compared to free KN93, the MR52-KN93 hydrogel (MRK) improved the killing effects and levels of immunogenic cell death (ICD) on tumor cells significantly. Due to the dual role of KN93, the injection of the MRK hydrogel retarded the growth of subcutaneous melanoma tumors dramatically and resulted in a high number of mature dendritic cells of draining lymph nodes, significantly enhancing the portion of cytotoxic T cells and reduced number of M2-like tumor-associated macrophages (TAMs) in tumors. Using a mouse model of malignant ascites (MAs), where traditional therapy was ineffective, we demonstrated that the MRK hydrogel treatment offered a significantly prolonged survival compared to controls. Following treatment with the MRK hydrogel, macrophages had elevated programmed cell death protein ligand-1 (PD-L1) expression, promising follow-up combined anti-PD-1 therapy that confers a cure rate of approximately 30% against MAs in mice models. Conclusion: Thus, the MRK hydrogel may serve as a prospective platform for antitumor applications.
- Subjects :
- 0301 basic medicine
Male
Benzylamines
medicine.medical_treatment
Melanoma, Experimental
Medicine (miscellaneous)
B7-H1 Antigen
Mice
Random Allocation
0302 clinical medicine
Liver Neoplasms, Experimental
Cancer immunotherapy
Tumor-Associated Macrophages
Cytotoxic T cell
Cellular Reprogramming Techniques
Molecular Targeted Therapy
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
Mice, Inbred BALB C
Sulfonamides
Chemistry
Melanoma
Ascites
Hydrogels
Neoplasm Proteins
030220 oncology & carcinogenesis
Immunogenic cell death
Female
Immunotherapy
Oligopeptides
Injections, Intraperitoneal
Research Paper
CAMKII
Drug Compounding
Recombinant Fusion Proteins
Antineoplastic Agents
03 medical and health sciences
Immune system
medicine
Animals
Amino Acid Sequence
Protein Kinase Inhibitors
Tumor microenvironment
cancer immunotherapy
Macrophage Activation
medicine.disease
Melitten
In vitro
Mice, Inbred C57BL
Hydrogel
030104 developmental biology
Cancer research
anti-PD-1
Tumor Escape
Drug Screening Assays, Antitumor
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Subjects
Details
- Language :
- English
- ISSN :
- 18387640
- Volume :
- 10
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Theranostics
- Accession number :
- edsair.doi.dedup.....e969146c537a7b6224c5fd90da21ba60