Abstract
Poor biodistribution and accumulation of chemotherapeutics in tumors due to limitations on diffusive transport and high intra-tumoral pressures (Jain RK, Nat Med. 7(9):987–989, 2001) have prompted the investigation of adjunctive therapies to improve treatment outcomes. Hyperthermia has been widely applied in attempts to meet this need, but it is limited in its ability to reach tumors in deeply located body regions. High-intensity radiofrequency (RF) electric fields have the potential to overcome such barriers enhancing delivery and extravasation of chemotherapeutics. However, due to factors, including tumor heterogeneity and lack of kinetic information, there is insufficient understanding of time-resolved interaction between RF fields and tumor vasculature, drug molecules and nanoparticle (NP) vectors. Intravital microscopy (IVM) provides time-resolved high-definition images of specific tumor microenvironments, overcoming heterogeneity issues, and can be integrated with a portable RF device to enable detailed observation over time of the effects of the RF field on kinetics and biodistribution at the microvascular level. Herein, we provide a protocol describing the safe integration of IVM with a high-powered non-invasive RF field applied to 4T1 orthotopic breast tumors in live mice. Results show increased perfusion of NPs in microvasculature upon RF hyperthermia treatment and increased perfusion, release and spreading of injected reagents preferentially in irregular vessels during RF exposure.Electronic supplementary materialThe online version of this article (doi:10.1186/s12645-016-0016-7) contains supplementary material, which is available to authorized users.
Highlights
Poor tumor accumulation of chemotherapeutics and diffusive transport limitations due to high intra-tumoral pressures (Jain 2001), altered architecture of tumoral-vasculature networks, and heterogeneous cell populations (Weiswald et al 2015) represents a major clinical challenge in the treatment of cancer (Chauhan et al 2011; Kleeff et al 2007; Hicks et al 2003; Lankelma et al 1999; Minchinton and Tannock 2006; Primeau et al 2005)
Hyperthermia in combination with chemotherapy has been widely used in attempts to overcome these barriers or enhance the potency of the standard chemotherapy; the clinical application of hyperthermia for cancer treatment has been hampered by the inability to
We have recently found that high-intensity short-wave radiofrequency (RF) electric fields may reach regions inaccessible via conventional modes of generating tumor hyperthermia (Ware et al 2015) and affect tumor vasculature and dense tumor micro-regions to enhance the delivery and extravasation of chemotherapeutics
Summary
Poor tumor accumulation of chemotherapeutics and diffusive transport limitations due to high intra-tumoral pressures (Jain 2001), altered architecture of tumoral-vasculature networks, and heterogeneous cell populations (Weiswald et al 2015) represents a major clinical challenge in the treatment of cancer (Chauhan et al 2011; Kleeff et al 2007; Hicks et al 2003; Lankelma et al 1999; Minchinton and Tannock 2006; Primeau et al 2005). We have recently found that high-intensity short-wave radiofrequency (RF) electric fields may reach regions inaccessible via conventional modes of generating tumor hyperthermia (Ware et al 2015) and affect tumor vasculature and dense tumor micro-regions to enhance the delivery and extravasation of chemotherapeutics This phenomenon is aided by the low tissue-specific absorption rates and widespread whole-body penetration of RF radiation. There is still a lack of knowledge of the time-resolved innate interaction between RF fields and tumor vasculature, drug molecules or nanoparticle (NP) vectors, and efficient treatment schedules have yet to be determined These deficiencies are partly due to researchers often using ‘end point’ measures of total drug concentration and comparing results between tumors grown in different species. This practice leads to the loss of information regarding the time kinetics and process of drug delivery, and further compounding inter-tumor, or even intra-tumor heterogeneity, inevitably causes difficulties in results interpretation
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