Increased Plasma Colloid Osmotic Pressure Facilitates the Uptake of Therapeutic Macromolecules in a Xenograft Tumor Model

Abstract

Elevated tumor interstitial fluid pressure (TIFP) is a characteristic of most solid tumors. Clinically, TIFP may hamper the uptake of chemotherapeutic drugs into the tumor tissue reducing their therapeutic efficacy. In this study, a means of modulating TIFP to increase the flux of macromolecules into tumor tissue is presented, which is based on the rationale that elevated plasma colloid osmotic pressure (COP) pulls water from tumor interstitium lowering the TIFP. Concentrated human serum albumin (20% HSA), used as an agent to enhance COP, reduced the TIFP time-dependently from 8 to 2 mm Hg in human tumor xenograft models bearing A431 epidermoid vulva carcinomas. To evaluate whether this reduction facilitates the uptake of macromolecules, the intratumoral distribution of fluorescently conjugated dextrans (2.5 mg/ml) and cetuximab (2.0 mg/ml) was probed using novel time domain nearinfrared fluorescence imaging. This method permitted discrimination and semiquantification of tumor-accumulated conjugate from background and unspecific probe fluorescence. The coadministration of 20% HSA together with either dextrans or cetuximab was found to lower the TIFP significantly and increase the concentration of the substances within the tumor tissue in comparison to control tumors. Furthermore, combined administration of 20% HSA plus cetuximab reduced the tumor growth significantly in comparison to standard cetuximab treatment. These data demonstrate that increased COP lowers the TIFP within hours and increases the uptake of therapeutic macromolecules into the tumor interstitium leading to reduced tumor growth. This model represents a novel approach to facilitate the delivery of therapeutics into tumor tissue, particularly monoclonal antibodies.

Enzymatic Depletion of Tumor Hyaluronan Induces Antitumor Responses in Preclinical Animal Models

“…3A). Although the mechanisms that determine increased tumor IFP are poorly understood and complex, they appear to involve compressed or abnormal blood vessels, poorly developed or absent lymphatics, and alterations in ECM components such as elevated HA, collagen, and other proteoglycans (31,37,38). As the DU145 tumors (HA low ) were capable of generating elevated tumor IFP, elevated HA is clearly not required for IFP.…”

“…Examples include vascular endothelial growth factor antagonists, tumor necrosis factor α, and PGE 1 (33,39,40). Recently, Hofmann et al (38) proposed increasing drug delivery to tumors by increasing plasma colloid osmotic pressure, thereby trafficking water from the tumor interstitium to reduce tumor IFP. Alternatively, Brekken and colleagues (14) showed that intratumoral injections of a bovine hyaluronidase depolymerized HA in osteosarcoma tumor xenografts in mice and reduced tumor IFP.…”

Multiplexed mAbs: a new strategy in preclinical time-domain imaging of acute myeloid leukemia

“…NIR imaging scans ( ex ϭ 670 nm, em ϭ 700 LP, laser repetition rate 80 MHz, raster scan points 1 mm apart) were obtained 24 hours after administration of Alexa Fluor 680-labeled mAbs (total mAb concentration of 1 g/g) as described previously. 19 For GFP fluorescence imaging, an eXplore Optix imager (ART Inc) configured for GFP-imaging experiments ( ex ϭ 470 nm, em ϭ 500 LP, laser repetition rate 40 MHz, raster scan points 1 mm apart) and fluorescence gating of GFP fluorescence lifetime (2.65 ns) was performed as described previously. 12 Optix MX2 (ART Inc) was used for bioluminescence imaging (raster scan points 1 mm apart).…”

“…However, the application of multispectral and, in particular, timedomain optical imaging techniques can at least partially circumvent these issues. Although the use of time-domain optical imaging strategies can enhance signal-to-noise contrast via gating of a fluorophore-specific fluorescence lifetime, 18,19 the expression of sufficient numbers of epitope on target cells is an inescapable constraint for targeted imaging strategies.…”

Biomechanical Forces Shape the Tumor Microenvironment

“…6,46 Tumors exhibit high IFP because of tumor-associated angiogenesis and the resultant breakdown of endothelial barrier function, which also leads to high oncotic forces in tumors, similar to blood plasma. 9,38,96 These fluid pressures can be as high as capillary blood pressure,~20 mmHg, compared to normal interstitial fluid pressures, which typically hover near 0 mmHg.…”