H7K(R2)2-modified pH-sensitive self-assembled nanoparticles delivering small interfering RNA targeting hepatoma-derived growth factor for malignant glioma treatment

The lack of effective glioma therapeutics mandates the development of novel treatment strategies. Hepatoma-derived growth factor (HDGF) has been considered as a potential glioma therapeutic target, and its expression level in gliomas is positively related to the malignant grade. Although there are no effective and specific inhibitors against this target, small interfering RNA targeting HDGF (siHDGF)-mediated RNA interference (RNAi) can inhibit the target protein function by knockdown of HDGF expression. However, the application of siHDGF in glioma research and therapy is hampered by the challenge to safe and effective in vivo systemic delivery of siHDGF to gliomas. To address this question, we develop the peptide H7K(R2)2-modified pH-sensitive self-assembled hybrid nanoparticles encapsulating siHDGF (H7K(R2)2-PSNPs (siHDGF)). The acidic glioma microenvironment is beneficial to the membrane penetration of H7K(R2)2-PSNPs and the encapsulated siHDGF. Following systemic administration, H7K(R2)2-PSNPs (siHDGF) can effectively deliver siHDGF into the brain and malignant glioma cells, and therefore can significantly downregulate HDGF expression, inhibit malignant phenotypes of glioma cells, result in reduced tumor volumes and prolonged survival times in nude mice bearing U251 human glioblastoma. Thus, systemic administration of H7K(R2)2-PSNPs (siHDGF) offers an effective way for the targeted delivery of siHDGF and may serve as a practical malignant glioma therapy. [Display omitted] •H7K(R2)2-PSNPs were developed to deliver siHDGF for malignant glioma treatment.•Acidic microenvironment attenuates the interaction of PLGA core and polyhistidine.•The pH responsiveness confers the tumor targeting to H7K(R2)2-PSNPs.•Intravenously administrated H7K(R2)2-PSNPs deliver siHDGF into malignant gliomas.•H7K(R2)2-PSNPs (siHDGF) have potent anti-glioma effects in vitro and vivo.