Systemic anti-tumour effects of local thermally sensitive liposome therapy.

PURPOSE: There were two primary objectives of this study: (1) to determine whether treatment of a tumour site with systemically administered thermally sensitive liposomes and local hyperthermia (HT) for triggered release would have dual anti-tumour effect on the primary heated tumour as well as an unheated secondary tumour in a distant site, and (2) to determine the ability of non-invasive optical spectroscopy to predict treatment outcome. The optical end points studied included drug levels, metabolic markers flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide phosphate (NAD(P)H), and physiological markers (total haemoglobin (Hb) and Hb oxygen saturation) before and after treatment. MATERIALS AND METHODS: Mice were inoculated with SKOV3 human ovarian carcinoma in both hind legs. One tumour was selected for local hyperthermia and subsequent systemic treatment. There were four treatment groups: control, DOXIL (non-thermally sensitive liposomes containing doxorubicin), and two different thermally sensitive liposome formulations containing doxorubicin. Optical spectroscopy was performed prior to therapy, immediately after treatment, and 6, 12, and 24 h post therapy. RESULTS: Tumour growth delay was seen with DOXIL and the thermally sensitive liposomes in the tumours that were heated, similar to previous studies. Tumour growth delay was also seen in the opposing tumour in the thermally sensitive liposome-treated groups. Optical spectroscopy demonstrated correlation between growth delay, doxorubicin (DOX) levels, and changes of NAD(P)H from baseline levels. Hb and Hb saturation were not correlated with growth delay. DISCUSSION: The study demonstrated that thermally sensitive liposomes affect the primary heated tumour as well as systemic efficacy. Non-invasive optical spectroscopy methods were shown to be useful in predicting efficacy at early time points post-treatment.

Overcoming limitations in nanoparticle drug delivery: triggered, intravascular release to improve drug penetration into tumors.

Traditionally, the goal of nanoparticle-based chemotherapy has been to decrease normal tissue toxicity by improving drug specificity to tumors. The enhanced permeability and retention effect can permit passive accumulation into tumor interstitium. However, suboptimal delivery is achieved with most nanoparticles because of heterogeneities of vascular permeability, which limits nanoparticle penetration. Furthermore, slow drug release limits bioavailability. We developed a fast drug-releasing liposome triggered by local heat that has already shown substantial antitumor efficacy and is in human trials. Here, we show that thermally sensitive liposomes (Dox-TSL) release doxorubicin inside the tumor vasculature. Real-time confocal imaging of doxorubicin delivery to murine tumors in window chambers and histologic analysis of flank tumors illustrates that intravascular drug release increases free drug in the interstitial space. This increases both the time that tumor cells are exposed to maximum drug levels and the drug penetration distance, compared with free drug or traditional pegylated liposomes. These improvements in drug bioavailability establish a new paradigm in drug delivery: rapidly triggered drug release in the tumor bloodstream.

Thresholds for thermal damage to normal tissues: an update.

The purpose of this review is to summarise a literature survey on thermal thresholds for tissue damage. This review covers published literature for the consecutive years from 2002-2009. The first review on this subject was published in 2003. It included an extensive discussion of how to use thermal dosimetric principles to normalise all time-temperature data histories to a common format. This review utilises those same principles to address sensitivity of a variety of tissues, but with particular emphasis on brain and testis. The review includes new data on tissues that were not included in the original review. Several important observations have come from this review. First, a large proportion of the papers examined for this review were discarded because time-temperature history at the site of thermal damage assessment was not recorded. It is strongly recommended that future research on this subject include such data. Second, very little data is available examining chronic consequences of thermal exposure. On a related point, the time of assessment of damage after exposure is critically important for assessing whether damage is transient or permanent. Additionally, virtually no data are available for repeated thermal exposures which may occur in certain recreational or occupational activities. For purposes of regulatory guidelines, both acute and lasting effects of thermal damage should be considered.

One-stop-shop tumor imaging: buy hypoxia, get lactate free.

The ability to noninvasively assess physiological changes in solid tumors is desired for its diagnostic and therapeutic potential. In this issue of JCI, Matsumoto and colleagues reveal their development and use of a novel imaging approach, combining pulsed electron paramagnetic resonance imaging (EPRI) with conventional MRI to image squamous cell carcinoma tumor-bearing mice (See the related article beginning on page 1965). This method provides coregistered images of oxygenation and blood volume/flow with the underlying anatomy and concentrations of metabolites such as lactate and choline. This technique, combining functional and anatomic imaging, shows immediate preclinical applicability in monitoring factors that control tumor hypoxia and metabolism and may have future clinical potential for monitoring tumor response to treatment.