Using Mechanical Interventions To Enhance Drug Transport To Bone Tumors

<p>Bone metastasis occurs when cancer cells spread from a primary site to a secondary location in bone. Current treatments for metastatic bone tumors typically involve systemic chemotherapy, bisphosphonates, radiotherapy, or surgery; however, due to morphological changes in the tumor microenvironment and elevated interstitial fluid pressure, tissue penetration of therapeutic agents is often more limited in cancerous tumors compared to normal tissue. Weight-bearing mechanical loading applied to bone, as well as other mechanical stimulations such as vibration, have been shown to cause loading-induced bone deformations that increase convective transport via interstitial fluid flow. We hypothesize that mechanical loading can increase the molecular transport of chemotherapeutic drugs to bone tumors. To test this hypothesis, a preclinical model of breast cancer metastasis to bone was used to investigate the effect of two mechanical interventions: walking on a treadmill and standing on a vibrating platform, methods that have been adopted in the management of other health-related issues such as osteoporosis. Radiolabelled drugs or tracers were administered to assess uptake before and after mechanical loading using in vivo micro-PET/CT imaging. In the first aim of this project, four pilot studies were performed to develop protocols for a replicable and standardized rat model of breast cancer metastasis. These pilot studies demonstrated promising results, with ¹⁸F-sodium fluoride uptake being significantly higher in tumor-bearing tibiae after treadmill exercise; full-body vibration showed an increasing yet non-significant uptake in tumor-bearing tibiae. Micro-PET/CT analyses of the subsequent studies in the second aim using the refined methods demonstrated variability in tracer uptake in the tumor region after loading. High-resolution micro-CT analysis of cancellous and cortical bone demonstrated variable responses to cancer cell injection, with some rats having large bone loss in the proximal tibia, and others showing a mixed bone response. Furthermore, linear regression analyses confirmed a statistically significant correlation between the decreased trabecular bone volume fraction in the proximal tibia and the tumor region that was derived from histological analysis. Due to the varied responses, additional preclinical work is necessary to fully establish the effect of treadmill walking and full body vibration on the uptake of drugs in solid tumors in bone. For the final aim, inclusion and exclusion criteria were established to identify patients who might benefit from this approach if translated to the clinic in the future. Findings from the studies in this thesis suggest that weight-bearing mechanical interventions have the potential to improve drug transport to bone tumors, potentially reducing overall systemic drug dosage and unwanted side effects. Both the treadmill and vibrating platform are low-risk and practical mechanical interventions that could easily be translated for use in oncology clinics.</p>

Name thesis:degree_name

Doctor of Philosophy (Ph.D.)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biomedical Engineering

Year dc:date.available

2024

Author dc:creator

• Gelbs, Michelle

Contributors dc:contributor

• Susannah P. Fritton

• bone
• cancer
• metastasis
• drug transport
• treadmill
• vibration
• Biomedical Engineering and Bioengineering

Repository record dc:identifier

https://academicworks.cuny.edu/cc_etds_theses/1288

OAI identifier oai:identifier

oai:academicworks.cuny.edu:cc_etds_theses-2275