Jacob Berlin’s research group is focused on the application of nanomaterials for the diagnosis and treatment of cancer. As part of City of Hope’s “bench-to-bedside” continuum, the Berlin lab is committed to developing novel therapies that will change patients’ outcomes. City of Hope is a world leader in clinical trials and with on-campus facilities capable of producing materials suitable for clinical trial use, the Berlin lab is focused on getting nanoparticle treatments into the clinic in a rapid manner.
Synthesis and Applications of Low Polydispersity Nanoparticle Aggregates
To improve the treatment and diagnosis of cancer, we leverage advantageous physical properties of nanoparticle aggregates. Nanoparticle aggregates can improve tumor imaging, drug delivery, photothermal ablation, and have other materials applications. To be used in these contexts, aggregates must be produced uniformly, which can be extremely challenging to control. This control can be achieved with sophisticated linkers (e.g. DNA or synthetic polymers), but these linkers are often expensive, difficult to modify, or possess their own bioactivity that may complicate the behavior of the aggregates. We are the first group to develop a straightforward covalent assembly of biocompatible nanoparticle aggregates using readily available small molecule-based cross linkers. We have achieved remarkably low polydispersity. Furthermore, our aggregates can be readily surface functionalized for diverse applications. We are now investigating use of these aggregates for cancer diagnosis and therapy.
Figure 1. A low magnification TEM (on the left) illustrates the low polydispersity of the aggregates. A higher magnification TEM (on the right) demonstrates that each aggregate is built from smaller nanoparticles.
Stem Cell/Nanoparticle Constructs for Targeted Cancer Therapy (in collaboration with Dr. Karen Aboody)
To improve drug delivery to tumors, free drugs can be loaded into nanoparticles. Despite improvements gained by this loading, targeted tumors still receive a small fraction of the injected nanoparticle-drug conjugate. One culprit is the nanoparticles’ poor tumor penetration. Effective penetration is blocked by three obstacles: 1) dense tumor matrices; 2) outward fluid-pressure gradients; and 3) inefficient infiltration of vasculature to the tumor’s interior. To overcome these and other challenges present in conventional drug delivery, better tumor-targeting materials must be identified. In this context, Dr. Karen Aboody, our collaborator, has been developing tumor-tropic neural stem cells as cancer therapeutics. She has shown that neural stem cells can cross the blood-brain-barrier, selectively migrate to invasive tumors and penetrate into tumor interiors. We are leveraging this tumor targeting and penetration to augment nanoparticle-mediated drug delivery, by functionalizing neural stem cells with a variety of nanoparticles. These nanoparticle-bearing neural stem cells will release a chemotherapy drug at tumor interiors; or they will be stimulated to cause local thermal ablation.
Figure 2. Neural stem cells can transport to tumors surface-conjugated nanoparticles loaded with drugs (top) or internalized nanoparticles that cause local heating when exposed to a near infrared laser (NIR, bottom).
Developing Nanoparticles for Glioblastoma Immunotherapy (in collaboration with Dr. Behnam Badie)
Even when treated with aggressive current therapies, most patients with glioblastoma survive less than two years. Immunotherapy is being studied as a potential treatment; and examples of such therapies include injecting modified immune cells and cytotoxic antibodies. Unfortunately, the tumors are locally immunosuppressive and heterogeneous, which may limit the efficacy of these therapies. We are developing a targeted strategy to enhance immune responses to malignant gliomas and generate a more universal response to multiple tumor antigens, . Oligodeoxynucleotides that contain an unmethylated CpG motif (CpG) activate the innate immune system through TLR-9 signaling. While free CpG has been tested in Phase II clinical trials in Europe, efficacy has been disappointing. As shown by our collaborator, Dr. Badie, the delivery of CpG on carbon nanotubes (CNT) dramatically enhances the activity of the CpG. A single intratumoral injection of low-dose CNT-CpG (not free CpG, blank CNT, or CNT/CpG mixture) eradicated GL261 gliomas in more than half of tumor-bearing mice. We are now working together to optimize the CNT-CpG formulation in preparation for future clinical translation.
Figure 3. Delivering CpG on carbon nanotubes dramatically enhances its efficacy. We are studying the mechanism of action and optimizing the formulation of the material.
January 29, 2015
March 28, 2014
Van Haute D, Longmate JM, Berlin JM. “Controlled Assembly of Biocompatible Metallic Nanoaggregates Using a Small Molecule Crosslinker.” Adv Mater. 2015 Sep;27(35):5158-64. doi: 10.1002/adma.201501602. Epub 2015 Jul 24. PMID: 26208123
White EE, Pai A, Weng Y, Suresh AK, Van Haute D, Pailevanian T, Alizadeh D, Hajimiri A, Badie B, Berlin JM. “Functionalized Iron Oxide Nanoparticles for Controlling the Movement of Immune Cells.” Nanoscale. 2015 May 7;7(17):7780-9. doi: 10.1039/c3nr04421a. PMID: 25848983
Mooney R, Roma L, Zhao D, Van Haute D, Garcia E, Kim SU, Annala AJ, Aboody KS, Berlin JM. “Neural stem cell-mediated intratumoral delivery of gold nanorods improves photothermal therapy.” ACS Nano. 2014 Dec 23;8(12):12450-60. doi: 10.1021/nn505147w. Epub 2014 Nov 17. PMID: 25375246
Mooney R, Weng Y, Garcia E, Bhojane S, Smith-Powell L, Kim SU, Annala AJ, Aboody KS, Berlin JM.Conjugation of pH-responsive nanoparticles to neural stem cells improves intratumoral therapy.J Control Release. 2014 Oct 10;191:82-9. doi: 10.1016/j.jconrel.2014.06.015. Epub 2014 Jun 18. PMID:24952368
Mooney, R., Weng, Y., Tirughana-Sambandan, R., Garcia, E., Hernandez, V., Aramburo, S., Annala, A., Berlin, J., Aboody, K. (2014). "Human Neural Stem Cell-Mediated Targeting of Nanoparticles to Brain Tumors" Future Oncol., 10(3):401-15. PMID: 24559447
Schnarr K, Mooney R, Weng Y, Zhao D, Garcia E, Armstrong B, Annala AJ, Kim SU, Aboody KS, Berlin JM. (2013). "Gold nanoparticle-loaded neural stem cells for photothermal ablation of cancer" Adv Healthc Mater., 2(7):976-82. PMID: 23592703
Suresh, AK., Weng, Y., Li, Z., Zerda, R., Van Haute, D., Williams, JC., Berlin, JM.(2013). "Matrix Metalloproteinase-Triggered Denuding Of Engineered Gold Nanoparticles For Selective Cell Uptake" Journal of Materials Chemistry B., 1(18):2341-2349. DOI: 10.1039/c3tb00435j
Badie B., Berlin JM. (2013). "The future of CpG immunotherapy in cancer" Immunotherapy, 5(1):1-3. PMID: 23256791
Sahni D, Jea A, Mata JA, Marcano DC, Sivaganesan A, Berlin JM, Tatsui CE, Sun Z, Luerssen TG, Meng S, Kent TA, Tour JM. (2013). "Biocompatibility of pristine graphene for neuronal interface" J Neurosurg Pediatr., 11(5):575-83. PMID: 23473006
Marcano DC, Bitner BR, Berlin JM, Jarjour J, Lee JM, Jacob A, Fabian RH, Kent TA, Tour JM. (2013). "Design of poly(ethylene glycol)-functionalized hydrophilic carbon clusters for targeted therapy of cerebrovascular dysfunction in mild traumatic brain injury" J Neurotrauma, 1;30(9):789-96. PMID: 22928502
Bitner BR, Marcano DC, Berlin JM, Fabian RH, Cherian L, Culver JC, Dickinson ME, Robertson CS, Pautler RG, Kent TA, Tour JM. (2012). "Antioxidant carbon particles improve cerebrovascular dysfunction following traumatic brain injury" ACS Nano, 25;6(9):8007-14. PMCID: PMC3458163
Sharpe MA, Marcano DC, Berlin JM, Widmayer MA, Baskin DS, Tour JM. (2012). "Antibody-targeted nanovectors for the treatment of brain cancers" ACS Nano, 24;6(4):3114-20. PMID: 22390360
Sano D, Berlin JM, Pham TT, Marcano DC, Valdecanas DR, Zhou G, Milas L, Myers JN, Tour JM. (2012). "Non-Covalent Assembly of Targeted Carbon Nanovectors Enables Synergistic Drug and Radiation Cancer Therapy In Vivo" ACS Nano, 6(3):2497-505. PMCID: PMC3314092
Zuhl AM, Mohr JT, Bachovchin DA, Niessen S, Hsu KL, Berlin JM, Dochnahl M, López-Alberca MP, Fu GC, Cravatt BF. (2012). "Competitive activity-based protein profiling identifies aza-?-lactams as a versatile chemotype for serine hydrolase inhibition" J Am Chem Soc. 134(11):5068-71. PMCID: PMC3326416
Berlin JM, Pham TT, Sano D, Mohamedali KA, Marcano DC, Myers JN, Tour JM. (2011). "Noncovalent functionalization of carbon nanovectors with an antibody enables targeted drug delivery" ACS Nano. 5(8):6643-50. PMCID: PMC3160510
Bachovchin DA, Mohr JT, Speers AE, Wang C, Berlin JM, Spicer TP, Fernandez-Vega V, Chase P, Hodder PS, Schürer SC, Nomura DK, Rosen H, Fu GC, Cravatt BF. (2011). "Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors" Proc Natl Acad Sci U S A. 108(17):6811-6. PMCID: PMC3084096
Berlin JM, Tour JM. (2010). "Development of novel drug delivery vehicles" Nanomedicine (Lond). 5(10):1487-9. PMID: 21143027; Marcano DC, Kosynkin DV, Berlin JM, Sinitskii A, Sun Z, Slesarev A, Alemany LB, Lu W, Tour JM. (2010). "Improved synthesis of graphene oxide" ACS Nano. 4(8):4806-14. PMID: 20731455
Berlin JM, Leonard AD, Pham TT, Sano D, Marcano DC, Yan S, Fiorentino S, Milas ZL, Kosynkin DV, Price BK, Lucente-Schultz RM, Wen X, Raso MG, Craig SL, Tran HT, Myers JN, Tour JM. (2010). "Effective drug delivery, in vitro and in vivo, by carbon-based nanovectors noncovalently loaded with unmodified Paclitaxel" ACS Nano. 4(8):4621-36. PMCID: PMC2935702
Bhattacharyya KX, Akana JA, Laitar DS, Berlin JM, Sadighi JP. (2008). "Carbon-Carbon Bond Formation on Reaction of a Copper (I) Stannyl Complex with Carbon Dioxide" Organometallics. 27(12):2682-2684. DOI:10.1021/om8001729
Berlin JM, Fu GC. (2008). "Enantioselective nucleophilic catalysis: the synthesis of aza-beta-lactams through [2+2] cycloadditions of ketenes with azo compounds" Angew Chem Int Ed Engl. 47(37):7048-50. PMCID: PMC2790040
Stewart IC, Ung T, Pletnev AA, Berlin JM, Grubbs RH, Schrodi Y. (2007). "Highly efficient ruthenium catalysts for the formation of tetrasubstituted olefins via ring-closing metathesis" Org Lett. 9(8):1589-92. PMID: 17378575
Berlin JM, Campbell K, Ritter T, Funk TW, Chlenov A, Grubbs RH. (2007). "Ruthenium-catalyzed ring-closing metathesis to form tetrasubstituted olefins" Org Lett. 9(7):1339-42. PMID: 17343392 *Featured on cover
Berlin JM, Goldberg SD, Grubbs RH. (2006). "Highly active chiral ruthenium catalysts for asymmetric cross- and ring-opening cross-metathesis" Angew Chem Int Ed Engl. 45(45):7591-5. PMID: 17054302
Funk TW, Berlin JM, Grubbs RH. (2006). "Highly active chiral ruthenium catalysts for asymmetric ring-closing olefin metathesis" J Am Chem Soc. 128(6):1840-6. PMCID: PMC2533259