Graduate Studies Faculty
Juntao Luo, PhD
- Associate Professor of Pharmacology
Research Programs and Affiliations
- Biomedical Sciences Program
- Cancer Research Program
Education & Fellowships
- PhD: NanKai University, China, 2003, Polymer Chemistry and Physics
- BS: NanKai University, China, 1998, Chemistry
- University of California at Davis, 2008–2011
Nanomedicine, drug delivery, cancer imaging and cancer treatment; gene delivery and gene therapy, protein/peptide delivery. biomaterials in tissue engineering; combinatorial chemistry and drug discovery; High throughput screening; microarrays.
- Structure-based nanocarrier design for efficient drug delivery
Languages Spoken (Other Than English)
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Engineering Nano-medicine and Molecular Devices towards Clinical Translation
The motivation of our research is to develop nanomedicine, molecular tools and devices through fundamental innovation for disease treatments with the goal of clinical translation from bench to bedside. Our research is based on the conjugation chemistry, peptide chemistry, combinatorial chemistry, polymer chemistry and material chemistry; and our research test beds involve biochemical and molecular biology, cellar signaling and viability, as well as animal models for disease treatments. We have accumulated significant experience and expertise in molecular simulation, pharmacology, cancer biology and immunology for therapeutic development. Our contributions to the field are the development of a novel unique transformative telodendrimer nanoplatform and a computational-combinatorial approach to accelerate the structure-based nanocarrier design and development for the delivery of drug,1-5 protein therapeutics,6-9 as well as gene therapeutics. This technique has been further developed into molecular devices or functional hydrogels to attenuate pathogenic molecules or for local drug delivery in disease treatments, e.g. cancer, diabetes, inflammatory and autoimmune diseases, sepsis and other critical medical situations (trauma, burn, cardiac surgery, pancreatitis and cytokine-release syndrome, etc.).
I. Structure-based nanocarrier design for drug delivery3
Nanomedicine have demonstrated the reduced the side-effect and improved efficacy in disease treatments in comparison to the free drug molecules. Compared to the classical lipid/liposome nanocarriers, polymeric nanoparticles possess much diverse chemical and physical microenvironments for the delivery of various type of drug molecules. However, the current polymeric nanocarrier design still follows the empirical and "trial and error" approaches (Fig. 1a-I), due to the unfavorable features of polymer materials, e.g. heterogeneous molecular weight distribution, limited chemical diversity and poor control in the self-assembly. The uncertainty in structure-property relationship of polymeric nanocarriers for drug delivery poses significant risk for clinical development, therefore, hindering the enthusiasm of pharmaceutical industries on nanomedicine development. An emerging predictable nanoplatform is essential to break the bottle-neck and to accelerate nanomedicine development.
I have developed a linear-dendritic telodendrimer nanoplatform, which has a precise dendritic structure for drug loading.10-17 Peptide chemistry was applied for the construction of telodendrimer, which enables the modular design and structural modification. The flexible dendritic structures of telodendrimer interact with drug molecules sufficiently in the core of nanocarrier, which warrants structural optimization to improve drug encapsulation. The presence of a facial amphiphilic cholic acid as co-building blocks secures the dispersion and stability of nanoparticles during structure engineering. Therefore, we can apply computational approach to virtually screen a library of molecules to identify drug-binding molecules (DBMs), which then can be conjugated on the periphery of telodendrimer to form a library of nanocarriers for the systematic optimization for a given drug delivery (Fig. 1b). Compared to the traditional "Fishing Approach" (Fig 1a-I) for nanocarrier development, telodendrimer nanoplatform provides a transformative, focused and structure-based approach to optimize nanocarrier for in vivo drug delivery. The predictable structure-property relationship, well-defined structure and unlimited chemical diversity for systematic optimization of telodendrimer nanoplatform meet the criteria for therapeutic development in pharmaceutical industry. Importantly, it increases the chance for nanomedicine to cross "the Death Valley" before clinical testing, given an optimized efficacy and the predictable nanomedicine (Fig 1a-II).
Numbers of rationally designed optimized nanocarriers have been developed specifically for the delivery of chemodrugs, e.g. paclitaxel17,18, doxorubicin2,3, cisplatin5, SN3819, Bortezomib20 and gambogic acid4, etc. These nanoformulations have superior drug loading capacity (20-100%, w/w), efficiency (~100%), and stability with small particle sizes (20~50 nm) for deep tissue penetration. In comparison to the clinical drugs, these nanoformulations reduce drug toxicity, prolong PK profile, increase tumor/inflammation targeting and significantly improve efficacy in cancer treatment and immune modulating therapy. Some of these nanoformulations have great potential for clinical translation.
II. Innovative nanocarrier design for in situ peptide/protein encapsulation and delivery6-9
Protein/peptide delivery system is highly demanded due to their poor stability, unfavorable PK profile and immunogenicity, etc. The mechanism for nanoparticle-based protein delivery is limited to the physical entanglement or charge trapping of proteins in nano-/micro- particles. Protein denaturation, nonspecific cell uptake and toxic chemical residues hinder the application of these approaches. A facial delivery system is still unmet for the systemic and/or intracellular protein delivery for disease treatments.
Tailored charges and hydrophobic building blocks can be precisely introduced on the periphery of telodendrimer (Fig. 2a), which compensate the charges and hydrophobic moieties on protein surface to coat protein efficiently in situ in aqueous solution. The flexible "octopus-like" framework maximizes the conformational entropy in interacting with protein surface via the synergistic multivalent hybrid charge and hydrophobic interactions. Given the precise protein structures, we can apply computational approach to screen library molecules to identify protein-binding molecules (PBMs), which can be conjugated on the telodendrimer scaffold equipped with different charge moieties to generate a library of nanocarriers to fine-tune protein loading and release (Fig. 2b). The specific engineering of the surface chemistry with the non-fouling biocompatible zwitterionic material efficiently prevents serum protein adsorption, protein exchange and premature protein release in vivo, which further improves in vivo stability and enables the controlled protein release by the fine-tuned protein binding affinity in telodendrimer.
To the best of our knowledge, this hybrid telodendrimer protein-coating technique is an unparalleled in situ approach for protein coating and encapsulation into small nanoparticles (10-20 nm), which sustains protein structure and activity for systemic and intracellular protein delivery. We have applied this approach in designing telodendrimer nanocarriers for the delivery of various protein therapeutics, for example, insulin6 and GLP-1 peptide delivery for diabetes and obesity treatment; cytotoxic proteins (diphtheria toxin7,8, TRAIL protein, cytochrome C, etc.) for cancer treatment. It can be applied to coat antibody, antibody-drug conjugates and recombinant proteins to improve their stability and reduce immunogenicity. Further, this technique provides a powerful tool for intracellular protein delivery, including antibodies and CRSPR-Cas9 protein complex, to target intracellular pathways and edit pathogenic genes directly for disease treatments. This technology can also be applied in targeted delivery of antigens for vaccine developments.
III. Novel NanoPus resin for sepsis treatment 21,22
Sepsis is caused by the systemic hyperinflammatory response to the spread insults from either infectious or non-infectious origin. Lipopolysaccharide (LPS) is known as a potent pathogenic endotoxin in sepsis induced by gram-negative (GN) bacterial infection. LPS in blood binds Toll-like receptor-4 (TLR-4) on epithelial cell, monocytes and macrophages, triggering massive production of inflammatory cytokines, which can be more destructive than protective in activating coagulation and complementary cascades and causing increased vascular permeability and tissue damage. The release of pathogen/damage associated molecular patterns (PAMPs/DAMPs) released from pathogens and the damaged cells further stimulate inflammatory reactions, causing organ failures and death. To attenuate multiple triggers and mediators in sepsis progression may be promising to control hyperinflammation and reduce mortality rate, given the failures of the single-targeted immunomodulating therapies in the clinical trials.
Similar to protein encapsulation, we can efficiently capture LPS (negatively charged-lipid structure) in telodendrimer nanoparticle via synergistic and multivalent charge and hydrophobic interactions (Fig 3A). The engineered telodendrimer nanocarrier binds LPS strongly even in the presence of serum proteins or polymyxin B (PMB), a gold standard potent LPS-binder. We have further immobilized dendritic NanoPus on the size exclusive hydrogel resins for selective and efficient removal of both LPS and cytokines via hemoperfusion to control sepsis (Fig 3B). In addition, these nanotrap resins also can efficiently scavenge DAMPs molecules, e.g. cell-free DNA and heme from plasma. Septic mice were induced by cecal ligation and puncture (CLP) procedure and cytokines in the septic blood can be efficiently removed by >95% after incubation with nanotrap resins. Further, CLP mice can be efficiently treated with nanotrap resin in combination with antibiotics by controlling both infections and inflammations (Fig 3C & 3D).
Compared to other hemoperfusion techniques failed in the controlled clinical trials for sepsis treatment, e.g. PMB-based Toraymyxin® for LPS removal and the hydrophobic porous Cytosorb® for nonspecific cytokine adsorption, our nanotrap resin provides a "all-in-one" approach to eliminate both endotoxin and cytokines and other DAMPs/PAMPs molecules from septic blood. In addition, the charge of nanotrap resin can be engineered to selectively scavenge proinflammatory or anti-inflammatory cytokines or both at the same time depending on the immune status of the patients. It is very promising to transform hemoperfusion into an effective therapy to reduce the mortality of severe sepsis in the clinic. This approach is also promising to treat critically ill patients experiencing cardiac surgery, trauma, burn or CAR T-cell therapy with the risk of cytokine storm. Recently, this project was funded by a NIH/NIGMS R01 grant. It is very promising to translate into the clinic to save lives of millions of severe septic patients.
References (selected out of 77 publications)
1. Wang, L., Shi, C., Wright, F.A., Guo, D., Wang, X., Wang, D., Wojcikiewicz, R.J.H. & Luo, J. Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in Ovarian Cancer Treatment. Cancer Res 77, 3293-3305 (2017).
2. Guo, D., Shi, C., Wang, X., Wang, L., Zhang, S. & Luo, J. Riboflavin-containing telodendrimer nanocarriers for efficient doxorubicin delivery: High loading capacity, increased stability, and improved anticancer efficacy. Biomaterials 141, 161-175 (2017).
3. Shi, C., Guo, D., Xiao, K., Wang, X., Wang, L. & Luo, J. A drug-specific nanocarrier design for efficient anticancer therapy. Nat Commun 6, 7449 (2015).
4. Huang, W., Wang, X., Shi, C., Guo, D., Xu, G., Wang, L., Bodman, A. & Luo, J. Fine-tuning vitamin E-containing telodendrimers for efficient delivery of gambogic acid in colon cancer treatment. Mol Pharm 12, 1216-1229 (2015).
5. Cai, L., Xu, G., Shi, C., Guo, D., Wang, X. & Luo, J. Telodendrimer nanocarrier for co-delivery of paclitaxel and cisplatin: A synergistic combination nanotherapy for ovarian cancer treatment. Biomaterials 37, 456-468 (2015).
6. Wang, X., Shi, C., Zhang, L., Lin, M.Y., Guo, D., Wang, L., Yang, Y., Duncan, T.M. & Luo, J. Structure-Based Nanocarrier Design for Protein Delivery. ACS Macro Letters, 267-271 (2017).
7. Wang, X., Shi, C., Zhang, L., Bodman, A., Guo, D., Wang, L., Hall, W.A., Wilkens, S. & Luo, J. Affinity-controlled protein encapsulation into sub-30 nm telodendrimer nanocarriers by multivalent and synergistic interactions. Biomaterials 101, 258-271 (2016).
8. Wang, X., Bodman, A., Shi, C., Guo, D., Wang, L., Luo, J. & Hall, W.A. Tunable Lipidoid-Telodendrimer Hybrid Nanoparticles for Intracellular Protein Delivery in Brain Tumor Treatment. Small 12, 4185-4192 (2016).
9. Wang, X., Shi, C., Wang, L. & Luo, J. Polycation-telodendrimer nanocomplexes for intracellular protein delivery. Colloids Surf B Biointerfaces 162, 405-414 (2018).
10. Xiao, W., Luo, J., Jain, T., Riggs, J.W., Tseng, H.P., Henderson, P.T., Cherry, S.R., Rowland, D. & Lam, K.S. Biodistribution and pharmacokinetics of a telodendrimer micellar paclitaxel nanoformulation in a mouse xenograft model of ovarian cancer. Int J Nanomedicine 7, 1587-1597 (2012).
11. Xiao, K., et al. "OA02" peptide facilitates the precise targeting of paclitaxel-loaded micellar nanoparticles to ovarian cancer in vivo. Cancer Res 72, 2100-2110 (2012).
12. Li, Y., Xiao, W., Xiao, K., Berti, L., Luo, J., Tseng, H.P., Fung, G. & Lam, K.S. Well-defined, reversible boronate crosslinked nanocarriers for targeted drug delivery in response to acidic pH values and cis-diols. Angewandte Chemie. International Ed. In English51, 2864-2869 (2012).
13. Xiao, K., Luo, J., Li, Y., Lee, J.S., Fung, G. & Lam, K.S. PEG-oligocholic acid telodendrimer micelles for the targeted delivery of doxorubicin to B-cell lymphoma. J Control Release 155, 272-281 (2011).
14. Xiao, K., Li, Y., Luo, J., Lee, J.S., Xiao, W., Gonik, A.M., Agarwal, R.G. & Lam, K.S. The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. Biomaterials 32, 3435-3446 (2011).
15. Li, Y., Xiao, K., Luo, J., Xiao, W., Lee, J.S., Gonik, A.M., Kato, J., Dong, T.A. & Lam, K.S. Well-defined, reversible disulfide cross-linked micelles for on-demand paclitaxel delivery. Biomaterials 32, 6633-6645 (2011).
16. Luo, J., et al. Well-defined, size-tunable, multifunctional micelles for efficient paclitaxel delivery for cancer treatment. Bioconjugate chemistry 21, 1216-1224 (2010).
17. Xiao, K., Luo, J., Fowler, W.L., Li, Y., Lee, J.S., Xing, L., Cheng, R.H., Wang, L. & Lam, K.S. A self-assembling nanoparticle for paclitaxel delivery in ovarian cancer. Biomaterials 30, 6006-6016 (2009).
18. Luo, J., et al. Well-defined, size-tunable, multifunctional micelles for efficient paclitaxel delivery for cancer treatment. Bioconjug Chem 21, 1216-1224 (2010).
19. Xu, G., Shi, C., Guo, D., Wang, L., Ling, Y., Han, X. & Luo, J. Functional-segregated coumarin-containing telodendrimer nanocarriers for efficient delivery of SN-38 for colon cancer treatment. Acta Biomater 21, 85-98 (2015).
20. Wang, L., Shi, C., Wright, F.A., Guo, D., Wang, X., Wang, D., Wojcikiewicz, R.J. & Luo, J. Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in Ovarian Cancer Treatment. Cancer Research 77, 3293-3305 (2017).
21. Juntao Luo, Changying Shi & Lili Wang. Compositions and Devices for Removal of Endotoxins and Cytokines from Fluids, Provasional Application, September 6, 2017, U.S. Pat. Appln. No. 62/554,845.
22. Wang, L., Shi, C., Dai, M., Guo, D., Abdel-Razck, O., Wang, G. & Luo, J. A novel nanotrap hemoadsorption for sepsis treatment. Nature communications, under review (2018).