Zhou Lab

General Information

Biographical Info
Dr. Jiangbing Zhou is an Assistant Professor of Neurosurgery and Biomedical Engineering. His research centers on developing translational nanomedicine and stem cell therapy for treatment of neurological disorders, including brain cancer and neurodegenerative diseases, through a unique combination of neuroscience, stem cell biology, and emerging nanotechnology. The ultimate goal of Zhou lab research is to combine these advances to establish more effective methods to treat neurological disorders.

Education & Training
B.S. East China University of Science and Technology (1998)
M.S. Tsinghua University (2001)
Ph.D. Johns Hopkins University (2008)
Postdoctoral Fellow Yale University, Department of Biomedical Engineering

Honors & Recognition
B*CURED Foundation Clinical Research Investigator Award, 2011

Research summary

Nanotechnology approaches for drug delivery to the brain

Drug delivery to the brain is a major challenge because of the blood-brain barrier (BBB), which limits the penetration of most therapeutics to the brain. Currently, Gliadel® wafer is the only drug delivery system approved by the FDA for drug delivery to the brain. Clinically, Gliadel® wafer is placed into tumor cavity after tumor resection. However, with this approach, cargo therapeutic agents diffuse only in a few millimeters from the wafers and do not reach distant tumor cells located several centimeters away, which limits its therapeutic benefit. To improve drug distribution and retain the controlled release property, we developed an array of techniques for synthesis of brain-penetrating NPs (BP NPs) using poly(lactic-co-glycolic acid) (PLGA), fabrication of stepped catheters, and delivery via convection-enhanced delivery (CED). The combination of these advances allows the delivery of NPs over a clinically relevant volume and significantly enhanced the treatment of brain cancer in animal models (Zhou J. et al.PNAS, 2013). To prepare for clinical translation, we further engineered BP NPs for imaging by magnetic resonance (MR) (Strohbehn G. et al.J Neurooncol. 2015). To enable non-invasive delivery of therapeutics to the brain through intravenous administration, we developed an autocatalytic brain-targeted (ABT) delivery mechanism, which is achieved through surface conjugation of a brain-targeting ligand and and internal encapsulation of a BBB modulator. After intravenous administration, a small fraction of NPs enter the brain through ligand-receptor interaction, where NPs locally release the BBB modulator, which in turn enhances BBB permeability to allow additional NPs to enter the brain. As a result, the delivery efficiency autocatalytically increases with time. We validated this mechanism by testing ABT-engineered NPs in mice bearing brain tumors, stroke, or traumatic brain injury (TBI). In all cases, we found that the resulting ABT NPs efficiently penetrated the brain (Han L. et al.ACS Nano, 2016; Han L. et al.Nanomedicine. 2016; and Chen Z. et al.Adv Funct Mater. 2017). More recently, we started to develop approach for oral drug delivery to the brain. We took an unusual approach to seek nanomaterials in medicinal natural products (MNPs). We have identified a group of small molecules that form supramolecular nanoparticles (SNPs), some of which are capable of efficient drug encapsulation and gastrointestinal (GI)/brain penetration. 

In addition to synthesizing NPs for drug delivery to the brain, we are also developing approaches to engineering neural stem cells (NSCs) to mediate drug delivery to the brain. Moreover, we have designed and synthesized activatable protein NPs that can be employed for targeted delivery of therapeutic peptides to the brain (Yu X. et al. Advanced Materials, 2018).

 

Non-viral gene delivery

In addition to insufficient delivery efficiency, traditional non-viral vectors, due to bearing a high density of positive charge, have significant toxicity. Our initial efforts in developing non-viral gene delivery carriers focused on engineering negatively charged NPs for enhanced gene material encapsulation, cell penetration, and endosomal escape (Zhou J. et al. Biomaterials, 2012; Ediriwickrema A. et al.Biomaterials, 2014). Although we showed those heavily engineered NPs enabled gene delivery in high efficiency, the complicated nature of such NPs may limit their potential for clinical translation. To simplify the formulation, we synthesized a family of novel terpolymers through polymerization of diethyl sebacate (DES) and N-methyldiethanolamine (MDEA) with lactones using enzyme-catalyzed polymerization chemistry. This synthetic approach allows tuning four important parameters in a single molecule: positive charge, molecular weight, hydrophobicity, and solidity. We demonstrated that the gene delivery of cationic polymers is not only determined by charge, but by a balance of positive charge, molecular weight, and hydrophobicity. As a result, we are able to design polymers for gene delivery with high efficiency and minimal toxicity. Among all terpolymers, PDL20, could form DNA polyplex NPs and deliver genes with the greatest efficiency (Zhou J. et al. Nature Materials, 2012). However, liquid polyplex NPs have limited stability and thus are not suitable for delivery of genetic materials to the brain (Han L. et al.ACS Nano, 2016). Recently, we developed chemistry to synthesized grafted terpolymers. We found that some of the newly synthesized terpolymers could encapsulate genetic materials in a core-shell nanostructure, deliver genes more efficiently than PDL20 polyplexes and maintain the nanostructure after lyophilization (manuscript in preparation). With this exciting progress, we are currently optimizing the approach by screening a variety of new polymers. This surprising discovery may further advance our technology for gene delivery.

We also developed NPs for targeted delivery of CRISPR/Cas9. To maximize gene editing efficiency and reduce off-target effects, we synthesized liposome-templated hydrogel nanoparticles (LHNPs) to co-deliver Cas9 in protein form with sgRNAs. We demonstrated that LHNPs allow delivery of CRISPR/Cas9 in high efficiency to peripheral as well as intracranial tumors (Chen Z. et al.Adv Funct Mater. 2017). Currently, we are working on a new generation of single component NPs for CRISPR/Cas9 delivery and have made exciting progress.

 

Biology of brain cancer stem cells (BCSCs)

I was among the first pioneering group of scientists studying cancer stem cells in solid tumors back to 2002. My early stage work not only provided substantial evidence about the importance of cancer stem cells in cancer treatment, but also suggested directions in achieving their preferential elimination (Zhou J. et al. PNAS, 2007, Zhou J. et al, BCRT, 2008, Zhou J. et al, BCRT, 2009). We recently processed over 50 human glioblastoma specimens and established an array of BCSC lines. Many of them have been characterized for their molecular signatures and tumorigenicity and pathology in mice. With this resource, we are taking a combinatory approaches to target BCSCs. By now, we have completed a genome-wide screen on selected BCSC lines and validated a few candidate genes that regulate BCSC differentiation (manuscript in submission). We have also completed a large scale drug screen on BCSCs and are currently evaluating lead drug candidates. We plan to validate the molecular targets identified through the genomic and chemical genomic approaches using proteomic approaches, such as reversed phase protein array that was used in our previous study (Zhou J. et al. PNAS). When any promising molecular target or drug candidate emerges, we will evaluate it in mouse xenografts by delivering them using these systems described above.

Selected Publications

  • Yu X, Gou X, Wu P, Han L, Tian D, Du F, Chen Z, Liu F, Deng G, Chen AT, Ma C, Liu J, Hashmi SM, Guo X, Wang X, Zhao H, Liu X, Zhu X, Sheth K, Chen Q, Fan L, Zhou J, Activatable protein nanoparticles for targeted delivery of therapeutic peptides, Advanced Materials, 2018, 1705383
  • Chen Z, Liu F, Chen Y, Liu J, Wang X, Chen A, Deng G, Liu J, Hong Z, Zhou J, Targeted delivery of CRISPR/Cas9-mediated cancer gene therapy via liposome-templated hydrogel nanoparticles. Advanced Functional Materials, 2017, 1703036
  • Han L, Kong D, Zheng MQ, Murikinati S, Yuan P, Li L, Tian D, Cai Q, Ye C, Holden D, Park JH, Gao X, Thomas JL, Grutzendler J, Carson RE, Huang Y, Piepmeier JM, Zhou J, Increased nanoparticle delivery to brain tumors by autocatalytic priming for improved treatment and imaging, ACS Nano, 2016;10(4):4209-18.
  • Zhou J, Patel TR, Sirianni RW, Strohbehn G, Zheng M-Q, Duong N, Schafbauer T, Huttner AJ, Huang Y, Carson RE, Zhang Y, Sullivan DJ, Jr., Piepmeier JM, Saltzman WM. Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma. Proceedings of the National Academy of Sciences. 2013;110(29):11751-6.
  • Zhou J, Liu J, Cheng CJ, Patel TR, Weller CE, Piepmeier JM, Jiang Z, Saltzman WM. Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery. Nature Materials. 2012;11(1):82-90.
  • Zhou J, Wulfkuhle J, Zhang H, Gu P, Yang Y, Deng J, Margolick JB, Liotta LA, Petricoin E, 3rd, Zhang Y. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proceedings of the National Academy of Sciences (Impact factor: 9.7). 2007;104(41):16158-63. 

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