Systemic effects of angiogenesis inhibition alter pharmacokinetics and intratumoral delivery of nab-paclitaxel

Abstract

Angiogenesis is critical to the growth of tumors. Vascularization-targeting agents, with or without cytotoxic drugs, are widely used for the treatment of several solid tumors including esophagogastric adenocarcinoma. However, little is known about the systemic effects of anti-angiogenic therapies and how this affects the pharmacokinetics and intratumoral delivery of cytotoxic agents. In this study, patient-derived xenograft mouse models of esophageal adenocarcinoma were used to identify the effects of DC101, a murine vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor, on the pharmacokinetics and the intratumoral uptake of nab-paclitaxel (NPTX). We showed that DC101 had large systemic effects resulting in decreased vasculature of intraperitoneally located organs. As a consequence, after intraperitoneal administration of NPTX, plasma uptake (5.029 ± 4.35 vs. 25.85 ± 2.27 mM) and intratumoral delivery (5.48 ± 5.32 vs. 38.49 ± 2.805 pmol/mg) of NPTX were greatly impaired in DC101-treated animals compared to control animals. Additionally, routes of NPTX elimination were altered upon angiogenesis inhibition; unchanged renal clearance and intraperitoneal accumulation of NPTX were observed, but NPTX levels were significantly lower in the liver. Histological examination of the intestine revealed a reduced thickness of the intestinal wall following DC101 therapy and suggested seepage of intraperitoneally injected NTPX through the intestinal wall to explain its reduced uptake in liver, plasma, and tumor tissue. These data explain several adverse effects observed in the clinic when using anti-angiogenic therapies and also imply that the combined use of anti-angiogenesis and cytotoxic agents in both preclinical and clinical setting is still suboptimal. ARTICLE HISTORY

Rapid stromal remodeling by short‐term VEGFR2 inhibition increases chemotherapy delivery in esophagogastric adenocarcinoma

“…DC101, a murine VEGFR2 inhibitor and a gift from ImClone Systems (Eli Lilly and Company, Indianapolis, IN, USA), and nab‐paclitaxel (NPTX, Abraxane, Celgene, Summit, NJ, USA) were reconstituted as described earlier (Steins et al , ). For multi‐agent DCE‐MRI, the contrast agents were a high molecular weight (MW, 59 517 Da) generation 5 dendrimer (G5‐PPI‐(PEG 6 GdDOTA) 64 ), an intermediate MW (7317 Da) generation 2 dendrimer (G2‐PPI‐(PEG 6 GdDOTA) 8 ), and a low MW (754 Da) gadoterate meglumine (Gd‐DOTA, Dotarem®, Guerbet, Villepinte, France).…”

“…Female athymic nude Foxn1 nu mice were maintained and inoculated with 007B cells as described previously (Steins et al , ). Tumor cells were injected on the right hind limb to prevent motion artifacts during MRI scanning.…”

“…For analysis of intratumoral NPTX uptake following ST DC101, 3 of 5 mice had to be excluded due to failed intravenous NPTX injection in which both plasma and tumor concentrations were too low to analyze. Snap‐frozen tumor samples were processed and measured with liquid chromatography/tandem mass spectrometry (LC‐MS/MS) as described earlier (Steins et al , ). To correct for injection error, tumor NPTX concentrations were normalized against the plasma NPTX concentration of each mouse (i.e., relative NPTX uptake).…”

Patient-derived xenograft: a developing tool for screening biomarkers and potential therapeutic targets for human esophageal cancers

“…Apatinib also exhibited its potential efficacy in patients with metastatic ESCC when combined with docetaxel [ 143 ]. Moreover, inhibition of VEGFR2 using DC101, a murine VEGFR2 inhibitor, delayed tumor growth and prolonged survival of animals with EAC xenografts [ 144 ]. However, vascular regression induced by DC101 impaired the uptake of intraperitoneally administered nab-paclitaxel [ 144 ].…”

Challenges and Opportunities for Childhood Cancer Drug Development

“…Although of interest, one has to interpret combination studies with some caution when the modulator is combined with standard of care drugs at doses far below the maximum tolerated dose (MTD), where potentiation of toxicity would not have been identified using this experimental design. While antiangiogenic agents can "normalize" tumor vasculature, reduce interstitial pressure, and enhance uptake of cytotoxic agents (Goel et al, 2012;Jain, 2014), antiangiogenic drugs may also have negative effects on intratumoral delivery of anticancer agents (Steins et al, 2017). Recently, two antiangiogenic agents, bevacizumab, an antibody that binds Pediatric Cancer Drug Development to and neutralizes VEGF, and the macrocyclic lactone temsirolimus (a rapamycin analog) that selectively inhibits the TOR complex 1 through a non-ATP competitive mechanism to inhibit angiogenesis (Guba et al, 2002), were compared in a "backbone" in patients with rhabdomyosarcoma at relapse.…”