Date of Award
Bone Cancer, Drug Delivery, Biomechanics
This thesis develops an approach to enhance drug delivery to bone tumors by implementing a non-invasive mechanical loading technique. An imaging protocol that characterizes the load-enhanced drug uptake is also presented. The long-term goal of this work is to develop a clinical protocol that enhances the delivery of therapeutic agents to bone tumors by utilizing load-bearing activity. This easy-to-implement approach could help increase drug uptake into the tumor interstitial fluid space as well as into tumor cells, thereby enhancing a drug's clinical effect while decreasing systemic drug dosage and unwanted side effects. This thesis details the process used to grow cancer cells, induce tumors in a rat model, measure tumor development, inject a radioactive tracer, apply mechanical loading non-invasively, and image and quantify drug uptake distribution in bone tumors. Assessment of 99mTc-labeled pamidronate uptake was completed in vivo using planar microSPECT (2D gamma camera scans) employing a rat model of bone metastases. The pilot study using this methodology demonstrated that non-invasive mechanical loading enhanced drug delivery to cancerous tibial tumors by 34% when compared to contralateral non-loaded, non-tumor bearing tibiae. Several improvements to this approach have been developed including 1) improved cancer cell viability after injection, 2) enhancement of cancer cell inoculation by arthrotomy surgery instead of direct tibial injection, 3) shifting from gamma camera to 3D microPET imaging, 4) use of tumor-bearing tibiae as controls, 5) use of the clinically relevant Herceptin as the injected drug, and 6) implementation of high-resolution microCT and histology to assess bone destruction from tumor growth. If additional studies in the rat model using these improved techniques demonstrate load-induced enhancement of drug delivery, the approach will be attempted in the clinic. Clinical studies will implement exercise and/or non-invasive mechanical activity to enhance drug delivery. If successful, this approach would result in an improvement in the quality of life of patients suffering from bone cancer.
Palacio, Paolo E., "Development of an Approach to Increase Drug Uptake to Bone Tumors Using Non-Invasive Mechanical Loading" (2011). CUNY Academic Works.