The research at the Dartmouth Center of Cancer Nanotechnology Excellence consists of 4 projects and is supported by 3 scientific cores.
Initial enthusiasm for antibody-targeted cancer treatment is often dampened by discouraging findings that show the targeting construct is not bound with adequate specificity and/or in therapeutically sufficient amounts. The poor performance of antibody targeting — in terms of nanoparticle-delivered therapeutics — often results from lack of understanding and optimization of the fundamental system characteristics, such as the targeting moiety, which is critical to the mechanism of cellular uptake and therefore is expected to affect significantly the specificity, tumor accumulation, and tissue distribution of the anti-cancer agent that results.
Understanding and optimizing antibody targeting is even more important in the setting of alternating magnetic field-activated magnetic nanoparticles, because the fundamental relationships between the localization, concentration, and distribution of particles and both the amounts and the mechanisms through which a therapeutic response is engendered remain largely unknown.
The central hypothesis underlying Project 1 is that magnetic nanoparticles can be targeted with substantially increased specificity to cancer cells/tissues by understanding and optimizing:
- The avidity of the interaction between targeted magnetic nanoparticles and cell surface receptors
- The type of interaction mediated by the targeting moiety upon engaging its cognate surface receptor
- The overall nanoparticle size
Understanding whether magnetic nanoparticles are actually binding to the target site in vivo is critical preclinically to developing effective methods to maximize their delivery and contrast relative to normal tissues, and is critical clinically to monitoring patients for the actual binding-performance-relative outcomes during early-stage human trials. Many methods exist to assess target-site binding ex vivo or in vitro, but no imaging technologies are available that can be used to reliably obtain this information in vivo.
Several micro-environmental factors are known to resist nanoparticles from getting to their targets, and barriers such as interstitial diffusion time and phagocytic scavenging often limit the targeting potential. The difficulties in permeating cancer tissues with high interstitial pressure and high cellularity have been exacerbated by the fact that much of the binding data are accumulated ex vivo and thus have little relationship to the in vivo situation because most of the nanoparticles do not reach their targets.
The fundamental goal of Project 2 is to provide the capability of imaging the magnetic nanoparticle binding distribution in vivo, which, when combined with the antibody-targeting optimization studies in Project 1, will be used to engineer constructs that overcome physical limitations and translate to better delivery in Project 3 and 4 studies.
Project 2 will develop and validate (through services offered in the TPB and BDAC Cores) the instrumentation associated with a new technology platform, providing a fundamentally unique way to quantify targeted magnetic nanoparticle ligand binding and distribution in vivo. This quantification will provide the data that can lead to mechanistic insight required to interpret why coated nanoparticles collect where they do in the body and how targeted delivery can be optimized and improved substantially.
Shown here at 9900x magnification, tumor cells readily take up magnetic nanoparticles (black objects). When a tumor containing nanoparticles is exposed to an alternating magnetic field, the nanoparticles will heat and kill the tumor cells.
As breast-conserving surgery combined with radiation replaces mastectomy, the need for new strategies to treat tumors recurring within a radiation field has become an area of considerable importance in the management of locally recurring breast cancers.
Project 3 will focus on this clinical need by defining a novel local treatment strategy, i.e., determining the optimal way to use alternating magnetic field-excited magnetic nanoparticle-mediated therapy to treat cancer, either as already confirmed in the breast or as potentially unidentified multi-focal micro-metastases that remain occult after initial re-treatment.
The project has both basic science and translational goals that will enhance the understanding of magnetic nanoparticle-mediated therapy, and also will explore crucial parameters that must be determined in order to design clinical trials.
Studies will be completed in one murine and two human breast tumor models to evaluate and optimize:
- Treatment variables, such as magnetic nanoparticle size, dose, incubation time, coating, targeting moiety and use of chemotherapy and ionizing radiation
- Biophysical factors, such as interstitial pressure
- Alternating magnetic field exposure characteristics, such as field strength
Large-animal models will also be used to ensure that these evaluations account for factors relevant to clinical treatment scale and volume in the breast. The experiments will consider efficacy, toxicology, and targeting and will develop technical parameters that can be directly applied to clinical trials.
Project 3 is focused on breast tumors, but it will also contribute critical new information relevant to the clinical translation of alternating magnetic field-excited magnetic nanoparticle-mediated cancer therapy for other types of solid tumors. In addition to destroying the primary tumor, magnetic nanoparticle excitation could also stimulate an anti-tumor immune response when combined with tumor vaccines and is expected to synergize with radiation and/or chemotherapy.
Epithelial ovarian cancer is responsible for the deaths of >15,000 Americans per year, and five-year-survival rates still remain below 40% for the stages at which most ovarian carcinomas are diagnosed. There is a need for new treatments to target both tumor cells that recur in a chemoresistant form following primary treatment and specific cell types in the tumor microenvironment that are recruited by and support the tumor.
Novel treatments that target chemoresistant tumor cells and other tumor-supporting but currently untargeted stromal cell types are possible through the excitation of magnetic nanoparticles. Specific targeting of magnetic nanoparticles to multiple cell types in the microenvironment of human and mouse ovarian cancers enables alternating magnetic field activation not only to kill tumor cells and tumor-supporting cells but also to elicit anti-tumor immunity and, subsequently, yield significant therapeutic benefits.
The specific aims of Project 4 are to:
- Optimize magnetic nanoparticle-mediated destruction of tumor cells and tumor-associated vascular leukocytes in preclinical (murine) ovarian cancer models
- Determine the interaction of engineered magnetic nanoparticle preparations with freshly dissociated human tumors
- Optimize therapeutic efficacy in chemoresistant human ovarian cancers
These aims will be accomplished first in an immunocompetent mouse model, and then in collaboration with our industrial partner, Adimab, using antibodies cross-reacting against mouse and human targeting.