Tumor vascular permeabilization using localized mild hyperthermia to improve macromolecule transport

Abstract

The abnormal tumor vasculature presents a major challenge to the adequate delivery of chemotherapeutics, often limiting efficacy. We developed a nanoparticle-based technique to deliver localized mild hyperthermia (MHT) used to transiently alter tumor vascular transport properties and enhance transport of macromolecules into tumor interstitium. The strategy involved administering and localizing accumulation of stealth gold nanorods (GNRs, 103 μg of GNRs/g of tumor), and irradiating tumor with a low-photon laser flux (1 W/cm2) to generate MHT. The treatment increased vascular permeability within 24 h after treatment, allowing enhanced transport of macromolecules up to 54 nm in size. A mathematical model is used to describe changes in tumor mass transport properties where the rate of macromolecular exchange between interstitial and vascular region (R) and maximum dye enhancement (Ymax) of 23-nm dextran dye are analytically solved. During enhanced permeability, R increased by 200% while Ymax increased by 30% relative to untreated group in pancreatic CAPAN-1 tumors. MHT treatment also enhanced transport of larger dextran dye (54 nm) as assessed intravital microscopy, without causing occlusive cellular damage. Enhanced vascular transport was prolonged for up to 24 h after treatment, but reversible with transport parameters returning to basal levels after 36 h. This study indicates that localized mild hyperthermia treatment open a transient time-window with which to enable and augment macromolecule transport and potentially improve therapeutic efficacy.

The clinical benefit of hyperthermia in pancreatic cancer: a systematic review

“…In this temperature range, improved drug delivery and dispersion in the tumour enhances the effect of chemotherapy [28][29][30]. With improved blood flow, hypoxia is decreased, which further enhances radiation effects through an increased production of oxygen radicals.…”

Mild Hyperthermia Enhances Transport of Liposomal Gemcitabine and Improves In Vivo Therapeutic Response

“…Gem is rapidly metabolized by deoxycytidine deaminase (present in blood) into 2',2'-difluoro-2'-deoxyuridine hydrochloride (dFdU) [17] . Motivated by our recent demonstration showing that MHT treatment increases the permeability of tumor vascular endothelium and enhances trans-vascular transport of macromolecules [18] , we studied the use of MHT treatment to improve Gem Lip transport and increase efficacy in pancreatic CAPAN-1 tumor model. We designed PEGylated liposomal carriers with transition temperature higher than 42°C to ensure stability under MHT treatment conditions in order to gain insights into the transport alteration and separate out the therapeutic gains from MHT treatment alone.…”

Intravital Microscopy Imaging Approaches for Image-Guided Drug Delivery Systems

“…It allows continuous and fast acquisition of events (30–400 frames per second (fps)) [14] and is well suited for monitoring biological processes that can elucidate existing biological barriers, reveal cell-particle interactions, and shade light on cellular responses to therapy under conditions closely approximating those of physiological environments [10]. The ability to dynamically image cellular and subcellular structures combined with the possibility to perform longitudinal studies have enabled investigators to use IVM to elucidate varying biological functions that include assessment of blood flow dynamics [23], vascular morphology and permeability [8, 24], and response to therapy [25]. IVM imaging also provides structural and functional information with subcellular resolution, sufficient to identify intracellular organelles [26], identify and study trafficking of cells [27], and monitor transport of drug delivery systems of different sizes [14, 28].…”

“…IVM imaging has also be used evaluate the dynamic changes that occur in the tumor environment upon application of external stimuli such as mild hyperthermia and radiofrequency treatment [24]. These stimuli are increasingly becoming common methods with which to improve chemotherapeutic delivery by “normalizing” tumor vascular blood flow and improving transvascular transport [106, 107].…”

“…This study indicated that localized mild hyperthermia treatment provides a transient window used to augment macromolecule transport with potential improve therapeutic efficacy (Fig. 7) [24]. Other applications of IVM imaging to assess and confirm therapeutic delivery include; 1) assessment of drug-loaded liposomal carriers application of external stimuli (i.e.…”