Non-invasive monitoring of intra-tumor drug concentration and therapeutic response using optical spectroscopy

• Published in: Journal of controlled release 2010-03, Vol.142 (3), p.457-464
• Main Authors: PALMER, Gregory M, BORUTA, Richard J, VIGLIANTI, Benjamin L, LAN LAN, SPASOJEVIC, Ivan, DEWHIRST, Mark W
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacokinetics; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Chemotherapy; Chromatography, High Pressure Liquid; Combined Modality Therapy; Dose-Response Relationship, Drug; Doxorubicin - administration & dosage; Doxorubicin - pharmacokinetics; Doxorubicin - therapeutic use; Drug Evaluation, Preclinical; Drug Monitoring - methods; Fiber Optic Technology; General pharmacology; Hyperthermia, Induced; Liposomes; Medical sciences; Mice; Mice, Nude; Models, Biological; Monte Carlo Method; Neoplasms, Experimental - diagnosis; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - therapy; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Spectrometry, Fluorescence
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2009.10.034

Optical spectroscopy was used to monitor changes in tumor physiology with therapy, and its influence on drug delivery and treatment efficacy for hyperthermia treatment combined with free doxorubicin or a low-temperature sensitive liposomal formulation. Monte Carlo-based modeling techniques were used to characterize the intrinsic absorption, scattering, and fluorescence properties of tissue. Fluorescence assessment of drug concentration was validated against HPLC and found to be significantly linearly correlated (r=0.88). Cluster analysis on the physiologic data obtained by optical spectroscopy revealed two physiologic phenotypes prior to treatment. One of these was relatively hypoxic, with relatively low total hemoglobin content. This hypoxic group was found to have a significantly shorter time to reach 3 times pre-treatment volume, indicating a more treatment resistant phenotype (p=0.003). Influence of tumor physiology was assessed in more detail for the liposomal doxorubicin+hyperthermia group, which demonstrated a highly significant correlation between pre-treatment hemoglobin saturation and tumor growth delay, and also between post-hyperthermia total hemoglobin content and tumor drug delivery. Finally, it was found that the doxorubicin concentration, measured in vivo using fluorescence techniques significantly predicted for chemoresponse (hazard ratio: 0.34, p=0.0007). The ability to characterize drug delivery and tumor physiology in vivo makes this a potentially useful tool for evaluating the efficacy of targeted delivery systems in preclinical studies, and may be translatable for monitoring and predicting individual treatment responses in the clinic.