ABSTRACT
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.
Subject(s)
Antineoplastic Agents/administration & dosage , Doxorubicin/administration & dosage , Drug Delivery Systems/methods , Nanoparticles/therapeutic use , Neoplasms, Experimental/drug therapy , Animals , Cell Line, Tumor , Hot Temperature , Humans , Liposomes , Mice , Microscopy, Confocal , Xenograft Model Antitumor AssaysABSTRACT
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.
