Biocompatible Materials; Biomedical Engineering; Brain Injuries; Brain Neoplasms; Genetic Therapy; Drug Delivery Systems; Stroke; Nanomedicine; Cell- and Tissue-Based Therapy
Our research group focuses on developing translational nanomedicine, gene therapy, and stem cell therapy for treatment of neurological disorders through a unique combination of material science, biology, and engineering.
Extensive Research Description
Nanomaterials for non-viral gene delivery
In addition to insufficient delivery efficiency, traditional non-viral vectors, due to bearing a high density of positive charge, often have significant toxicity. Our initial efforts in developing non-viral gene delivery carriers focused on engineering negatively charged nanoparticles (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 those NPs may limit their potential for clinical translation. To simplify the formulation, we synthesized a family of novel terpolymers 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 those polymers, a balance of positive charge, molecular weight, and hydrophobicity, enable gene delivery with high efficiency and minimal toxicity (Zhou J. et al. Nature Materials, 2012; Han L. et al. ACS Nano, 2016). Recently, we further refined the chemistry to synthesized grafted terpolymers, which can form core-shell nanostructure and deliver genes more efficiently than the first generation terpolymer NPs. 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). Now, we are working on synthesizing novel materials that form single component NPs for CRISPR/Cas9 delivery.
Nanomaterials for oral drug delivery
Due to its convenience and high patient compliance, oral drug delivery remains ideal for most patients. To develop approaches for oral drug delivery, we took an unusual approach to seek nanomaterials in the nature. Through this approach, 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) penetration. Inspired by this discovery, we have synthesized a group of novel polymeric materials that are optimal for oral drug delivery. We found that those novel materials enable oral delivery of a range of therapeutics, including protein drugs such as insulin and antibodies, for disease treatment.
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), 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; 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 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) (Han L. et al. ACS Nano, 2016; Han L. et al. Nanomedicine. 2016; and Chen Z. et al. Adv Funct Mater. 2017).
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).
Biology of brain cancer stem cells (BCSCs)
I was among the first pioneering group of scientists studying cancer stem cells in solid tumors. 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 (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 those systems described above.
Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma
Zhou J, Patel TR, Sirianni RW, Strohbehn G, Zheng MQ, 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. Proc Natl Acad Sci U S A. 2013
Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery
Zhou J, Liu J, Jiang Z, Patel T, Weller C, Piepmeier JM, Saltzman WM, Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery, Nature Materials, 2011, 11(1):82-90
Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance
Zhou J, Wulfkuhle J, Zhang H, Gu P, Yang Y, Margolick JB, Liotta LA, Petricoin III E, and Zhang Y. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci U S A, 2007, 41(104):16158-63
- Activatable protein nanoparticles for targeted delivery of therapeutic peptides • 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
- Targeted delivery of CRISPR/Cas9-mediated cancer gene therapy via liposome-templated hydrogel nanoparticles • 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
- Increased nanoparticle delivery to brain tumors by autocatalytic priming for improved treatment and imaging • 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.
Full List of PubMed Publications
- Kranz M, Bergmann R, Kniess T, Belter B, Neuber C, Cai Z, Deng G, Fischer S, Zhou J, Huang Y, Brust P, Deuther-Conrad W, Pietzsch J: Bridging from Brain to Tumor Imaging: (S)-(-)- and (R)-(+)-[18F]Fluspidine for Investigation of Sigma-1 Receptors in Tumor-Bearing Mice. Molecules. 2018 Mar 20; 2018 Mar 20. PMID: 29558382
- Wang T, Hurwitz O, Shimada SG, Tian D, Dai F, Zhou J, Ma C, LaMotte RH: Anti-nociceptive effects of bupivacaine-encapsulated PLGA nanoparticles applied to the compressed dorsal root ganglion in mice. Neurosci Lett. 2018 Mar 6; 2018 Feb 3. PMID: 29355697
- 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. Adv Mater. 2018 Feb; 2018 Jan 8. PMID: 29315863
- Chen Y, Su M, Li Y, Gao J, Zhang C, Cao Z, Zhou J, Liu J, Jiang Z: Enzymatic PEG-Poly(amine-co-disulfide ester) Nanoparticles as pH- and Redox-Responsive Drug Nanocarriers for Efficient Antitumor Treatment. ACS Appl Mater Interfaces. 2017 Sep 13; 2017 Sep 1. PMID: 28819967
- John SF, Aniemeke E, Ha NP, Chong CR, Gu P, Zhou J, Zhang Y, Graviss EA, Liu JO, Olaleye OA: Characterization of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone as a novel inhibitor of methionine aminopeptidases from Mycobacterium tuberculosis. Tuberculosis (Edinb). 2016 Dec; 2016 Sep 28. PMID: 27856197
- Han L, Cai Q, Tian D, Kong DK, Gou X, Chen Z, Strittmatter SM, Wang Z, Sheth KN, Zhou J: Targeted drug delivery to ischemic stroke via chlorotoxin-anchored, lexiscan-loaded nanoparticles. Nanomedicine. 2016 Oct; 2016 Mar 30. PMID: 27039220
- Chen Z, Patel JM, Noble PW, Garcia C, Hong Z, Hansen JE, Zhou J: A lupus anti-DNA autoantibody mediates autocatalytic, targeted delivery of nanoparticles to tumors. Oncotarget. 2016 Sep 13. PMID: 27494868
- Han L, Kong DK, Zheng MQ, Murikinati S, Ma C, 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 Apr 26; 2016 Mar 16. PMID: 26967254
- Chen Y, Gou X, Kong DK, Wang X, Wang J, Chen Z, Huang C, Zhou J: EMMPRIN regulates tumor growth and metastasis by recruiting bone marrow-derived cells through paracrine signaling of SDF-1 and VEGF. Oncotarget. 2015 Oct 20. PMID: 26416452
- Cai Q, Chen Z, Kong DK, Wang J, Xu Z, Liu B, Chen Q, Zhou J: Novel microcatheter-based intracarotid delivery approach for MCAO/R mice. Neurosci Lett. 2015 Jun 15; 2015 Apr 18. PMID: 25899778
- Strohbehn G, Coman D, Han L, Ragheb RR, Fahmy TM, Huttner AJ, Hyder F, Piepmeier JM, Saltzman WM, Zhou J: Imaging the delivery of brain-penetrating PLGA nanoparticles in the brain using magnetic resonance. J Neurooncol. 2015 Feb; 2014 Nov 18. PMID: 25403507
- Sirianni RW, Zheng MQ, Patel TR, Shafbauer T, Zhou J, Saltzman WM, Carson RE, Huang Y: Radiolabeling of poly(lactic-co-glycolic acid) (PLGA) nanoparticles with biotinylated F-18 prosthetic groups and imaging of their delivery to the brain with positron emission tomography. Bioconjug Chem. 2014 Dec 17; 2014 Dec 1. PMID: 25322194
- Ediriwickrema A, Zhou J, Deng Y, Saltzman WM: Multi-layered nanoparticles for combination gene and drug delivery to tumors. Biomaterials. 2014 Nov; 2014 Aug 8. PMID: 25112935
- Zhou J, Patel TR, Sirianni RW, Strohbehn G, Zheng MQ, 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. Proc Natl Acad Sci U S A. 2013 Jul 16; 2013 Jul 1. PMID: 23818631
- Patel T, Zhou J, Piepmeier JM, Saltzman WM: Polymeric nanoparticles for drug delivery to the central nervous system. Adv Drug Deliv Rev. 2012 May 15; 2011 Dec 20. PMID: 22210134
- Zhou J, Patel TR, Fu M, Bertram JP, Saltzman WM: Octa-functional PLGA nanoparticles for targeted and efficient siRNA delivery to tumors. Biomaterials. 2012 Jan; 2011 Oct 19. PMID: 22014944
- Zhou J, Atsina KB, Himes BT, Strohbehn GW, Saltzman WM: Novel delivery strategies for glioblastoma. Cancer J. 2012 Jan-Feb. PMID: 22290262
- 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. Nat Mater. 2011 Dec 4; 2011 Dec 4. PMID: 22138789
- Zhou J, Zhang Y: Preclinical development of cancer stem cell drugs. Expert Opin Drug Discov. 2009 Jul; 2009 Jun 9. PMID: 23489167