Macroporous organosilicon nanocomposites co-deliver Bcl2-converting peptide and chemotherapeutic agent for synergistic treatment against multidrug resistant cancer

• Published in: Cancer letters 2020-01, Vol.469, p.340-354
• Main Authors: Xie, Jingjing, Xu, Weixia, Wu, Yuehuang, Niu, Boning, Zhang, Xiaokun
• Format: Article
• Language: English
• Subjects: Animal models; Apoptosis; Bcl-2 protein; Bcl2-converting peptide; Biocompatibility; Cancer; Cancer resistance treatment; Cancer therapies; Conversion; Doxorubicin; Drug delivery systems; Drug development; Drug resistance; Hybrid nanocomposites; Liver cancer; Lymphoma; Macroporous silica nanoparticles; Multidrug resistance; Multidrug resistant organisms; Nanocomposites; Nanoparticles; Peptides; Side effects; Silica; Synergistic effect
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.10.018

Therapeutic biomacromolecules are confronted with in vivo challenges of low bio-stability and poor tumor tissue-penetration. Herein, we report for the first time, our development and characterization of a hybrid nanocomposite for delivering a Bcl-2-converting peptide (NuBCP9, N9 hereafter) and testing its efficacy alone or together with doxorubicin (DOX). The hybrid nanocomposite is composed of the internal large pore sized-mesoporous silica nanoparticles (MSNs) and the external highly-branched polyamidoamine (PAMAM) dendrimers, into which N9 peptide and DOX were encapsulated for the different sub-cellular delivery to treat drug-resistant cancer. The nanocomposite possessed the particle and pore sizes of ~37 nm and ~8 nm, which displayed the superior tumor penetration capacity over naked MSNs both in cultured-3D tumor sphere and in live animal models. Moreover, the dual drug nanocomposite exhibited a great synergistic anticancer effect on Bcl-2-positive cancer cells in vitro and animals with the negligible toxic side effects. The tumor inhibition rate of the nanocomposite (89%) was five times as much as the two drugs combination. This design provides a new effective, safe and versatile strategy to fabricate large pore-sized MSNs with the organic-inorganic hybrid framework to concurrently transport therapeutic peptides and chemotherapeutics to the specific sub-cellular locations for the synergistic cancer therapy and drug resistance reversal, which has significant impact on the development of improved cancer therapeutics. •Macroporous organosilicon nanocomposites were fabricated by re-engineering of large pore sized-MSNs and PAMAM dendrimers.•The nanocomposites were effective in sub-cellular delivery of Bcl-2-converting peptide and chemotherapeutic.•The nanocomposites enhanced the tumor penetration capability of therapeutic peptide.•The dual drug nanocomposites exhibited the synergistic anticancer efficiency on Bcl-2-positive cancers.•The nanocomposites showed great in vivo biosafety with the negligible toxic side effects.