Lifeng Qi

Proton-Sponge Coated Quantum Dots for siRNA Delivery and Intracellular Imaging

We report the rational design of multifunctional nanoparticles for short-interfering RNA (siRNA) delivery and imaging based on the use of semiconductor quantum dots (QDs) and proton-absorbing polymeric coatings (proton sponges). With a balanced composition of tertiary amine and carboxylic acid groups, these nanoparticles are specifically designed to address longstanding barriers in siRNA delivery such as cellular penetration, endosomal release, carrier unpacking, and intracellular transport. The results demonstrate dramatic improvement in gene silencing efficiency by 10-20-fold and simultaneous reduction in cellular toxicity by 5-6-fold, when compared directly with existing transfection agents for MDA-MB-231 cells. The QD-siRNA nanoparticles are also dual-modality optical and electron-microscopy probes, allowing real-time tracking and ultrastructural localization of QDs during delivery and transfection. These new insights and capabilities represent a major step toward nanoparticle engineering for imaging and therapeutic applications.

Quantum Dot−Amphipol Nanocomplex for Intracellular Delivery and Real-Time Imaging of siRNA

A new generation of nanoparticle carrier that allows efficient delivery and real-time imaging of siRNA in live cells has been developed by combining two distinct types of nanomaterials, semiconductor quantum dots and amphipols. An important finding is that, although amphipols are broadly used for solubilizing and delivering hydrophobic proteins into the lipid bilayers of cell membrane, when combined with nanoparticles, they offer previously undiscovered functionalities, including cytoplasm delivery, siRNA protection, and endosome escape. Compared with the classic siRNA carriers such as Lipofectamine and polyethyleneimine, this new class of nanocarrier works in both serum-free and complete cell culture media, which is advantageous over Lipofectamine. It also outperforms polyethyleneimine in gene silencing under both conditions with significantly reduced toxicity. Furthermore, the intrinsic fluorescence of quantum dots provides a mechanism for real-time imaging of siRNA delivery in live cells. This new multifunctional, compact, and traceable nanocarrier is expected to yield important information on rational design of siRNA carriers and to have widespread applications of siRNA delivery and screening in vitro and in vivo.

Emerging application of quantum dots for drug delivery and therapy

Quantum dots have proven themselves as powerful fluorescent probes, especially for long-term, multiplexed, and quantitative imaging and detection. Newly engineered quantum dots with integrated targeting, imaging and therapeutic functionalities have become excellent material to study drug delivery in cells and small animals. This fluorescent ‘prototype’ will provide important information in the rational design of biocompatible drug carriers and will serve as a superior alternative to magnetic and radioactive imaging contrast agents in preclinical drug screening, validation and delivery research. This Editorial article is not intended to offer a comprehensive review on drug delivery, but to highlight the breakthroughs in the emerging applications of quantum dots in this field and to provide our perspective on future research.

JAM-2 siRNA intracellular delivery and real-time imaging by proton-sponge coated quantum dots

In this study, proton-sponge coated quantum dots were prepared by using amphipol PMAL, grafted with polyethylenimine (PEI) as an encapsulation polymer. The QD-PMAL-PEI nanoparticles showed low cytotoxicity and superior gene silencing efficiency in serum-containing medium against junctional adhesion molecule-2 (JAM-2), which is over-expressed in glioma cells. Confocal microscopic analysis showed efficient siRNA intracellular release. In particular, QD-mediated JAM-2 knockdown was reported for the first time to facilitate inhibition of glioma cell migration. Furthermore, the Notch pathway served as the target for the JAM-2 gene function, confirmed by downregulation of its downstream genes HES1 and HES5. The unique proton-sponge coated QDs can serve as multifunctional siRNA carriers for efficient gene silencing and real-time intracellular imaging, and provide a base for design of novel efficient siRNA delivery carriers with high biocompatibility.

Highly efficient Gab2 siRNA delivery to ovarian cancer cells mediated by chitosan–polyethyleneimine nanoparticles

Malignant bowel obstruction (MBO) is a serious complication which causes high death rate and low quality of life (QOL) for patients diagnosed at an advanced stage of ovarian cancer. RNA interference (RNAi) could be a promising method for the treatment of ovarian cancer and could decrease the morbidity of MBO. Gab2 gene is overexpressed in ovarian cancer compared with normal ovarian tissue, and regulates the migratory behaviors and E-cadherin expression via activation of the PI3K pathway in ovarian cancer cells. Here, chitosan-polyethyleneimine (PEI, Mw 1800) copolymer nanoparticles were synthesized as nanocarriers to deliver Gab2 siRNA into SKOV3 cells. The silencing effects against the Gab2 gene and the antitumor effects by the chitosan-PEI-Gab2 siRNA nanoparticles (chitosan-PEI-Gab2 NPs) were studied. Results showed that highly efficient silencing effects against Gab2 expression and its downstream effector, AKT protein, at more than 90% deregulation were obtained by chitosan-PEI NP mediated Gab2 siRNA delivery, so as to exhibit obvious antitumor effects against SKOV3 cells with low cytotoxicity, and induce cell apoptosis in early and late stages. The study will provide novel strategies to overcome MBO in ovarian cancer by the efficient knockdown of Gab2 expression.

Meeting report: the 2009 Westlake International Conference on Personalized Medicine.

Personalized medicine heralds the future of medicine. The 2009 Westlake International Conference on Personalized Medicine held from May 29-31, 2009, in Hangzhou, China (www.westlakeconference.org) brought together approximately 200 participants and over 40 presenters from a dozen countries. The conference was discussed in detail, with focus on the following major areas of personalized medicine: preventative and predictive medicine, cancer systems biology and therapy, physiology and artificial liver systems, nanotechnology and informatics, proteomics and systems pathology, genomics and pharmacogenomics, and epigenetics and new techniques. During the conference, the Asian Association of Systems Biology and Medicine (AASBM) was officially formed, and the ad hoc steering members for each of the major Asian countries were appointed to recruit key players from each country. The IBC (Interdisciplinary Bio Central) journal was suggested as the official journal for the AASBM, as it is a truly open journal (www.ibc7.org). The Web site for AASBM will be aasbm.org.

Inhibition of glioma proliferation and migration by magnetic nanoparticle mediated JAM-2 silencing

Brain invasion is a biological hallmark of glioma that leads to its aggressiveness and prognosis. Junctional adhesion molecule-2 (JAM-2) was found to be overexpressed in human glioma. In this study, the effects of JAM-2 silencing mediated by cell-penetrating magnetic nanoparticles were investigated on glioma cell proliferation and migration in vitro and in vivo. The results showed that the deregulation of JAM-2 in glioma cell lines could cause a dramatic decrease in cell proliferation and migration in vitro. The expression level of cytoskeleton remodeling and migration associated protein genes appeared to be a downstream factor of JAM-2. Furthermore, silencing of JAM-2 expression in implanted glioma cells was found to impair in vivo tumor growth significantly. These data provide new evidence for the role of JAM-2 in the progression of glioma and show its great potential in human glioma gene therapeutics.