Unique Advantages of Dendrimers-Structured Mesoporous Silica Nanoparticles over Traditional Hollow Ones in Delivering Bcl2-Functional Converting Peptide for Multidrug Resistant Cancer Treatment.

Innovative silica nanomaterials have made the significant advancements in curative therapy against cancers with multidrug resistance (MDR). The study on different-nanostructured mesoporous silica nanoparticles (MSNs) with discrepant pore sizes affecting biomacromolecules in resisting cancer MDR hasn't been reported yet. In this study, a systematic comparison of 6 nm-pore sized hollow-structured MSNs (HMSNs) and 10 nm-pore sized dendrimers-structured MSNs (LMSNs) for delivering Bcl-2-functional converting peptide (N9) or doxorubicin (DOX) to overcome cancer MDR is comprehensively carried out both in in vitro and in vivo resistant tumor models. The results show that both LMSNs and HMSNs exert no significant difference in delivering DOX to treat drug-resistant cancers. However, compared with N9@HMSNs, N9@LMSNs display the increased loading efficiency, the improved cell-penetrative capability, the higher cancer cell apoptosis effect, the enhanced tumor accumulation and retention efficiency, and the final elevated tumor inhibition efficiency. Unexpectedly, naked LMSNs without surface modification especially at high dosage produce relatively more serious toxicity than HMSNs whatever in cells, zebrafish embryo or mice models. Collectively, the data provide the sufficient theoretical evidence that LMSNs might be a better choice for delivering biomacromolecules to treat resistant cancers after appropriate surface functionalization such as with PEGylation to weaken its intrinsic toxicity.

Wu Y ，Ma F ，Yu L ，Lin R ，Lin S ，Guo Z ，Zhou M ，Li M ，Zhang Y ，Xie J ... -  《-》

Macroporous silica nanoparticles for delivering Bcl2-function converting peptide to treat multidrug resistant-cancer cells.

The abundance of B cell lymphoma gene 2 (Bcl-2) is closely correlated with the resistance of cancer cells to chemotherapeutic agents, and a peptide derived from orphan nuclear receptor Nur77 can convert Bcl-2 from a protector to a killer of cancer cells. However, successful application of the Bcl-2-converting peptide to treat drug-resistant cancer cells depends on an efficient delivery carrier. Mesoporous silica nanoparticles (MSNs) have been extensively studied as promising candidates for small molecule drug delivery. However, the effective encapsulation and intracellular delivery of peptides using small pore-sized MSNs still remain a great technical challenge. In this paper, an effective delivery platform for Bcl-2-converting peptide was fabricated by us to treat multidrug resistant-cancer cells via tuning the surface functionality of macroporous silica nanoparticles. The resulting large-sized pore silica nanoparticles, especially those modified with thiol group, exhibited the high Bcl-2-converting peptide-loading efficiency of over 40%. Moreover, the peptide induced MCF7/DOX cells into apoptotic status by penetrating cytomembrane into mitochondria and being bound with Bcl-2 to expose the BH3 domain with the aid of various surface functionalities-decorated MSNs. In particular, amine-modified surface of MSNs caused the greater influence on the cell apoptosis-inducing effects of peptide in comparison with other functionalities-modified ones. Taken together, our study, for the first time, demonstrates a special approach towards pore size and surface functionality-collectively modulated silica-based nanostructural material for effective delivery of bio-macromolecules (e.g., Bcl-2-converting peptide) to treat the multidrug resistant-cancer cells with elevated Bcl-2 levels.

Xu W ，Ge P ，Niu B ，Zhang X ，Liu J ，Xie J ... -  《-》

Enhanced Efficacy against Drug-Resistant Tumors Enabled by Redox-Responsive Mesoporous-Silica-Nanoparticle-Supported Lipid Bilayers as Targeted Delivery Vehicles.

Yang S ，Zhang B ，Zhao X ，Zhang M ，Zhang M ，Cui L ，Zhang L ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

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

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.

Xie J ，Xu W ，Wu Y ，Niu B ，Zhang X ... -  《-》

TPGS functionalized mesoporous silica nanoparticles for anticancer drug delivery to overcome multidrug resistance.

Multidrug resistance (MDR) has become a very serious problem in cancer therapy. To effectively reverse MDR in tumor treatments, a new pH-sensitive nano drug delivery system (NDDS) composed of mesoporous silica nanoparticles (MSNs) and d-a-tocopheryl poly-ethylene glycol 1000 succinate (TPGS) copolymers was synthesized to deliver doxorubicin (DOX) into drug-resistant breast cancer cell line (MCF-7/ADR). DOX@MSNs-TPGS were characterized to have a single peak size distribution, high DOX loading efficiency and a pH-dependent drug release profile. MSNs-TPGS were internalized via caveolae, clathrin-mediated endocytosis and energy-dependent cellular uptake. The DOX@MSNs-TPGS exhibited 10-fold enhanced cell killing potency compared to free DOX and DOX@MSNs. The enhanced MDR reversal effect was ascribed to the higher amount of cellular uptake of DOX@MSNs-TPGS in MCF-7/ADR cells than that of free DOX and DOX@MSNs, as a result of the inhibition of P-gp mediated drug efflux by TPGS. In vivo studies of NDDS in tumor-bearing mice showed that DOX@MSNs-TPGS displayed better efficacy against MDR tumors in mice and reached the tumor site more effectively than DOX and DOX@MSNs, with minimal toxicity. These results suggest DOX@MSNs-TPGS developed in this study have promising applications to overcome drug resistance in tumor treatments.

Zhao P ，Li L ，Zhou S ，Qiu L ，Qian Z ，Liu X ，Cao X ，Zhang H ... -  《-》