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
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
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.