Multimodal Cancer Treatment: Real Time Monitoring, Optimization, and Synergistic Effects

Abstract

The primary objective of this analysis is to provide the theoretical framework for a novel multimodal cancer treatment system emphasizing the use of ultrasound as a synergistic drug release mechanism, real time monitoring by MRI of hyperthermic, pO2, and ultrasound induced released effects. The aim is to provide a cure for the 20% of cancer victims who will die of complications from local solid tumors. Adjuvant therapy usually refers to surgery preceding or following chemotherapy and/or ionizing radiation treatment to decrease the risk of recurrence, but the absolute benefit for survival obtained with adjuvant therapy compared to control is only approximately 6%. Tumor hypoxia represents a primary therapeutic concern, besides multi-drug resistance (MDR), because it can reduce the effectiveness of drugs and radiotherapy; well-oxygenated cells require one-third the dose of hypoxic cells to achieve a given level of cell killing. The era of systemic and indiscriminate chemotherapeutic drug delivery into both healthy and pathologic tissues is near an end. Targeted drug delivery using nanoparticles is emerging as the new vehicle, either as a single treatment option, as part of adjuvant procedures or as a component of a multimodal cancer treatment system. There are more than 100 nanosized liposomes or particles, and conjugated anticancer agents in various stages of preclinical and clinical development. Active targeting can be achieved by site-specific delivery or site-specific triggering. Ultrasound can be utilized as both a site triggering and synergistic mechanism in drug release. The process can be monitored using MRI by a physical process called cavitation. An analysis of low frequency ultrasound exposure in combination with liposomally encapsulated doxorubicin (Caelyx) on Balb/c nude mice inoculated with a WiDr (human colon cancer) tumor cell line provided tumor growth inhibition of 30–40%. Mild hyperthermia causes mean intratumor pO2 to increase by 25% and enhances tumor radiosensitization. Hyperthermia causes the extravasation of liposome nanoparticles in deep tumor regions. Ionizing radiation improves the distribution and uptake of drugs. Liposomally encapsulated drugs and ultrasound mediated hyperthermia have been proven to circumvent MDR effects. Hyperthermic effects and pO2 monitoring of bodily fluid have been performed by MRI. It is hypothesized that increased vascularization and subsequent increase in pO2 levels to hypoxic regions, and monitoring of drug release through cavitation, can facilitate optimized real time concomitant or sequential treatments of drug therapy, hyperthermia, ionizing radiation, etc., before or after surgery. An improved therapeutic index with the use of the outlined system seems probable.