Juntao Luo, PhD

CLINICAL TRIALS

PREVIOUS APPOINTMENTS

RESEARCH ABSTRACT

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, protein therapeutics, 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 delivery

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. paclitaxel, doxorubicin, cisplatin, SN38, Bortezomib and gambogic acid, 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 delivery

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 toxin^7,8, 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 

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.

Publications since 2011 

1. Wang L, Ji X, Guo D, Shi C, Luo J. Facial Solid-Phase Synthesis of Well-Defined Zwitterionic Amphiphiles for Enhanced Anticancer Drug Delivery. Mol Pharm. 2021 Jun 7;18(6):2349-2359. doi: 10.1021/acs.molpharmaceut.1c00163. Epub 2021 May 13. PubMed PMID: 33983742.
2. Guo D, Ji X, Luo J. Rational nanocarrier design towards the clinical translation of cancer nanotherapy. Biomed Mater. 2021 Feb 4;. doi: 10.1088/1748-605X/abe35a. [Epub ahead of print] PubMed PMID: 33540386.
3. Shi C, Wang X, Wang L, Meng Q, Guo D, Chen L, Dai M, Wang G, Cooney R, Luo J.* A nanotrap improves survival in severe sepsis by attenuating hyperinflammation. Nat Commun. 2020;11(1):3384. PMID: 32636379. https://www.nature.com/articles/s41467-020-17153-0
4. Guo, D., Shi, C., Wang, L., Ji, X., Zhang, S. & Luo, J.* Rationally Designed Micellar Nanocarriers for the Delivery of Hydrophilic Methotrexate in Psoriasis Treatment. ACS Applied Bio Materials 3, 4832-4846 (2020).
5. Scheibel, D.M., Guo, D., Luo, J. & Gitsov, I. A Single Enzyme Mediates the "Quasi-Living" Formation of Multiblock Copolymers with a Broad Biomedical Potential. Biomacromolecules 21, 2132-2146 (2020).
6. Wang, L., Shi, C., Wang, X., Guo, D., Duncan, T.M. & Luo, J. Zwitterionic Janus Dendrimer with distinct functional disparity for enhanced protein delivery. Biomaterials, 2019, 215, 119233, doi: 10.1016/j.biomaterials.2019.119233. (IF: 10.273)
7. Yuanbo Zhong, Brian Zeberl, Xu Wang*, Juntao Luo* Combinatorial approaches in post-polymerization modification for rational development of therapeutic delivery systems, Acta Biomaterialia, 2018, doi: 10.1016/j.actbio.2018.04.010 (IF: 6.319)
8. Xu Wang*, Changying Shi, Lili Wang, Juntao Luo* Polycation-Telodendrimer Nanocomplexes for Intracellular Protein Delivery, Colloids and Surfaces B: Biointerfaces, 2018, 162: 405-414. PMID: 29247913 (IF: 4.152)
9. Ronald J. Schroeder II, Jason Audlin, Juntao Luo, Brian D. Nicholas, Pharmacokinetics of Sodium Thiosulfate in Guinea Pig Perilymph Following Middle Ear Application, Journal of Otology, 2018, 13, 54-58.
10. Yong-Guang Jia, Jiahong Jin, Sa Liu, Li Ren, Juntao Luo, X. X. Zhu, Self-Healing Hydrogels of Low Molecular Weight Poly(vinyl alcohol) Assembled by Host-Guest Recognition, Biomacromolecules, 2018, 19 (2), 626-632. PMID: 29341595 (IF: 5.246)
11. Dandan Guo, Changying Shi, Xu Wang, Lili Wang, Shengle Zhang, Juntao Luo* Riboflavin-Containing Telodendrimer Nanocarriers for Efficient Doxorubicin Delivery: High Loading Capacity, Increased Stability, and Improved Anticancer Efficacy, Biomaterials, 2017, 141, 161-175. (IF: 8.387)
12. Lili Wang, Changying Shi, Forrest A. Wright, Dandan Guo, Xu Wang, Richard J.H. Wojcikiewicz, Juntao Luo* Multifunctional telodendrimer nanocarriers for the targeted co-delivery of bortezomib and doxorubicin to reboot their synergy in ovarian cancer treatment, Cancer Research, 2017, 77(12), 3293-3305. PMID: 28396359 (IF: 9.329)
13. Xu Wang, Changying Shi, Li Zhang, Mei Yun Lin, Dandan Guo, Lili Wang, Yan Yang, Thomas M. Duncan, Juntao Luo* Structure-Based Nanocarrier Design for Protein Delivery. ACS Macro Letter, 2017, 6, 267–271 (IF: 6.185)
14. Christine M. Burrer, Helen Auburn, Xu Wang, Juntao Luo, Fardokht A. Abulwerdi, Zaneta Nikolovska-Coleska, Gary C. Chan Mcl-1 Small-Molecule Inhibitors Encapsulated into Nanoparticles Exhibit Increased Killing Efficacy towards HCMV-Infected Monocytes. Antiviral Research, 2017, 138, 40-46. PMID: 27914937 (IF: 4.909)
15. Xu Wang, Alexa Bodman, Changying Shi, Dandan Guo, Lili Wang, Walter A Hall, Juntao Luo* Tunable Lipidoid-Telodendrimer Hybrid Nanoparticles for Intracellular Protein Delivery in Brain Tumor Treatment. SMALL. 2016, 12(31), 4185-4192. PMID: 27375237 (IF: 8.643)
16. Xu Wang, Changying Shi, Li Zhang, Alexa Bodman, Dandan Guo, Lili Wang, Walter A Hall, Stephan Wilkens, Juntao Luo* Affinity-Controlled Protein Encapsulation into Sub-30 nm Telodendrimer Nanocarriers by Multivalent and Synergistic Interactions. Biomaterials. 2016, 101: 258–271. PMID: 27294543 (IF: 8.387)
17. Wenjuan Jiang, Xiaoyi Wang, Dandan Guo, Juntao Luo, Shikha Nangia Drug-Specific Design of Telodendrimer Architecture for Effective Doxorubicin Encapsulation. The Journal of Physical Chemistry B, 2016, 120(36), 9766-77, PMID: 27513183 (IF: 3.187)
18. Wenjuan Jiang; Juntao Luo; Shikha Nangia. Multiscale Approach to Investigate Self-Assembly of Telodendrimer Based Nanocarriers for Anticancer Drug Delivery. Langmuir. 2015, 31(14):4270-80. PMID:25532019 (IF: 3.993)
19. Changying Shi; Dandan Guo; Kai Xiao; Xu Wang; Lili Wang; Juntao Luo* A drug-specific nanocarriers design for efficient anticancer therapy. Nature Communications. 2015, 9; 6: 7449. PMID: 26158623. (IF: 11.329; citations: 53)
20. Gaofei Xu, Changying Shi, Dandan Guo, Lili Wang, Yun Ling, Xiaobing Han, Juntao Luo* Functional-segregated coumarin-containing telodendrimer nanocarriers for efficient delivery of SN-38 for colon cancer treatment. Acta Biomaterialia. 2015, 21:85-98. PMID: 25910639 (IF: 6.025)
21. Wenzhe Huang, Xu Wang, Changying Shi, Dandan Guo, Gaofei Xu, Lili Wang, Alexa Bodman, Juntao Luo* Fine-tuning vitamin e-containing telodendrimers for efficient delivery of gambogic Acid in colon cancer treatment. Molecular Pharmaceutics. 2015, 12(4):1216-29. PMID: 25692376 (IF: 4.384)
22. Liqiong Cai; Gaofei Xu; Changying Shi; Dandan Guo; Xu Wang; Juntao Luo* Telodendrimer Nanocarrier for Co-delivery of Paclitaxel and Cisplatin: A Synergistic Combination Nanotherapy for Ovarian Cancer Treatment. Biomaterials. 2015, 37C:456-468. PMID: 25453973 (IF: 8.387; citations: 62)
23. Yu Shao; Changying Shi; Gaofei Xu; Dandan Guo; Juntao Luo* A photo and redox dual responsive reversibly crosslinked nanocarrier for efficient tumor-targeted drug delivery. ACS Applied Materials and Interfaces. 2014, 6(13), 10381-92. PMID:24921150 (IF: 7.504; citations: 52)
24. Changying Shi; Dekai Yuan; Shikha Nangia; Gaofei Xu; Dandan Guo; Kit S. Lam; Juntao Luo* Structure-property relationships study of a well-defined telodendrimer to improve the hemocompatibility of nanocarriers for anticancer drug delivery. Langmuir, 2014, 30 (23), 6878–6888. PMID: 24849780 (IF: 3.993)
25. Yu Shao; Yong-Guang Jia; Changying Shi; Juntao Luo; X. X. Zhu, Block and Random Copolymers Bearing Cholic Acid and Oligo(ethylene glycol) Pendant Groups: Aggregation, Thermosensitivity, and Drug Loading. Biomacromolecules, 2014, 15 (5), pp 1837–1844. PMID:24725005 (IF: 5.750)
26. Yung-Shin Sun; Yiyan Fei; Juntao Luo; Seth Dixon; James P. Landry; Kit S. Lam; X.D. Zhu Generating Small Molecule Microarrays from One-Bead One-Compound Synthetic Compound Libraries for Label-Free Detection and Discovery of Small Molecule Ligands against Protein Targets. Synthetic Communication, 2014, 44(7), 987-1001. (IF: 1.065)
27. Wei He; Juntao Luo; Feliza Bourguet; Li Xing; Sun K. Yi; Tingjuan Gao; Craig Blanchette; Paul T. Henderson; Edward Kuhn; Mike Malfatti; William J. Murphy; R. Holland Cheng; Kit S. Lam; Matthew A. Coleman. Controlling the diameter, monodispersity, and solubility of ApoA1 nanolipoprotein particles using telodendrimer chemistry. Protein Sci. 2013, 22 (8), 1078-1086. PMID: 23754445 (IF: 3.039)
28. Nicholas J. Kenyon; Jennifer M. Bratt; Joyce Lee; Juntao Luo; Lisa M. Franzi; Amir A. Zeki; Kit S. Lam. Self-assembling nanoparticles containing dexamethasone as a novel therapy in allergic airway inflammation. PLoS ONE 2013, 8, e77730. PMID: 24204939 (IF: 3.234)
29. Tzu-Yin Lin; Yuanpei Li; Hongyong Zhang; Juntao Luo; Neal Goodwin; Tingjuan Gao; Ralph De Vere White; Kit S. Lam; Chong-Xian Pan. Tumor-targeting multifunctional micelles for imaging and chemotherapy of advanced bladder cancer. Nanomedicine(Lond). 2013, 8, 1239-1251. PMID: 23199207 (IF: 4.889)
30. Yung-Shin Sun; Juntao Luo; Kit S. Lam; X.D. Zhu. Detection of formation of and disintegration of micelles by oblique-incidence reflectivity difrrence microscopy. Instrumentation Science & Technology 2013, 41, 545-555. (IF: 1.433)
31. Wenzhe Huang; Changying Shi; Yu Shao; Kit S. Lam; Juntao Luo* The Core-Inversible Micelles for Hydrophilic Drug Delivery. Chemical Communications, 2013, 49, 6674-6676. PMID:23775217 (IF: 6.567, citations 11)
32. Yu Shao; Wenzhe Huang; Changying Shi; Sean T Atkinson; Juntao Luo*. Reversibly crosslinked nanocarriers for on-demand drug delivery in cancer treatment. Therapeutic Delivery 2012, 3, 1409-1427. PMID: 23323559 (citation: 33)
33. Wenwu Xiao, Juntao Luo*, Paul Henderson,Tessta Jain, John Wriggs, Harry Tseng, Kit S Lam*, The distribution profile of a polymer nanomicelle and loaded chemotherapy drug on mouse ovarian cancer xenograft model, International Journal of Nanomedicine, 2012, 7: 1587–1597. (*corresponding author) PMID: 22605931(IF: 4.383, citations 28)
34. Kai Xiao; Yuanpei Li; Joyce S. Lee; Abby M. Gonik; Tiffany Dong; Gabriel Fung; Eduardo Sanchez; Li Xing; Holland R. Cheng; Juntao Luo*; Kit S Lam*. “OA02” Peptide Facilitates the Precise Targeting of Paclitaxel-Loaded Micellar Nanoparticles to Ovarian Cancer In Vivo, Cancer Research, 2012, 72, 2100-2010. (*corresponding author) PMID:22396491 (IF: 9.329; citations: 71)
35. Yuanpei Li; Wenwu Xiao; Kai Xiao; Lorenzo Berti; Juntao Luo*; Harry P. Tseng; Gabriel Fung; Kit S Lam*. Well-Defined, Reversible Boronate Crosslinked Nanocarriers for Targeted Drug Delivery in Response to pH and cis-Diols, Angewandte Chemie International Edition, 2012, 51(12), 2864-2869. (*corresponding author) PMID:22253091 (IF: 11.709; citations: 270)
    …………This work was highlighted as the Most Important Paper (MIP) in the Inside Back Cover of the Week in Angewandte Chemie International Edition 2012, 51(12), 3027. This research was highlighted as a news story in Therapeutic Delivery 2012, 3(3), 303-306.
36. Yuanpei Li, Madhu S. Budamagunta, Juntao Luo, Wenwu Xiao, John C. Voss, and Kit S. Lam, Probing of the Assembly Structure and Dynamics within Nanoparticles during Interaction with Blood Proteins. ACS Nano, 2012, 6 (11), 9485–9495. PMID: 23106540 (IF: 13.334; citations: 40)
37. Tzu-yin Lin; Hongyong Zhang; Juntao Luo; Yuanpei Li; Tingjuan Gao; PN Lara Jr, Ralph de Vere White; Kit S Lam; Chong-Xian Pan. Multifunctional targeting micelle nanocarriers with both imaging and therapeutic potential for bladder cancer. International Journal of Nanomedicine, 2012, 7, 2793-2804. PMID: 22745542 (IF: 4.383)
38. Jason Kato; Yuanpei Li; Kai Xiao; Joyce S. Lee; Juntao Luo; Joseph M. Tuscano; Robert T. O'Donnell; KitS. Lam. Disulfide cross-linked micelles for the targeted delivery of vincristine to B-cell lymphoma, Molecular Pharmaceutics. 2012, 9(6):1727-1735. PMID: 22530955 (IF: 4.384)
39. Hongyong Zhang; Juntao Luo; Yuanpei Li; Paul T. Henderson; Yanchun Wang; Sebastian Wachsmann-Hogiu; Weixin Zhao; Kit S. Lam; Chong-xian Pan. Characterization of high-affinity peptides and their feasibility for use in nanotherapeutics targeting leukemia stem cells, Nanomedicine, 2012, 8(7):1116-24. PMID:22197725 (IF: 4.889)
40. Noriko Satake; Joyce Lee; Kai Xiao; Juntao Luo; Susmita Sarangi; Astra Chang; Bridget McLaughlin; Ping Zhou; Elaina Kenney; Liliya Kraynov; et al. Nanoparticle targeted therapy against childhood acute lymphoblastic leukemia, Proceedings of SPIE - The International Society for Optical Engineering, 2011;8031:[80311U].
41. Kai Xiao; Juntao Luo *; Yuanpei Li; Joyce S. Lee; Abby M. Gonik; Gabriel Fung; Kit S. Lam*. PEG-oligocholic acid telodendrimer micelles for the targeted delivery of doxorubicin to B-cell lymphoma, Journal of Controlled Release, 2011, 155(2), 272-281. (*corresponding author) PMID:21787818 (IF: 7.705, citations 100)
42. Yuanpei Li; Kai Xiao; Juntao Luo*; Wenwu Xiao; Joyce S. Lee; Abby M. Gonik; Jason Kato; Tiffany Dong; Kit S. Lam*. Well-defined, Reversible Disulfide Cross-linked Micelles for On-demand Paclitaxel Delivery, Biomaterials, 2011, 32(27), 6633-6645. (*corresponding author) PMID:21658763 (IF: 8.387; citations: 226)