CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing

Abstract

Nanoparticle-based therapeutics are being used to treat patients with solid tumors. Whereas nanoparticles have been shown to preferentially accumulate in solid tumors of animal models, there is little evidence to prove that intact nanoparticles localize to solid tumors of humans when systemically administered. Here, tumor and adjacent, nonneoplastic tissue biopsies are obtained through endoscopic capture from patients with gastric, gastroesophageal, or esophageal cancer who are administered the nanoparticle CRLX101. Both the pre- and postdosing tissue samples adjacent to tumors show no definitive evidence of either the nanoparticle or its drug payload (camptothecin, CPT) contained within the nanoparticle. Similar results are obtained from the predosing tumor samples. However, in nine of nine patients that were evaluated, CPT is detected in the tumor tissue collected 24-48 h after CRLX101 administration. For five of these patients, evidence of the intact deposition of CRLX101 nanoparticles in the tumor tissue is obtained. Indications of CPT pharmacodynamics from tumor biomarkers such as carbonic anhydrase IX and topoisomerase I by immunohistochemistry show clear evidence of biological activity from the delivered CPT in the posttreatment tumors.

Keywords: clinical trial; gastric cancer; nanomedicine; nanoparticles; tumor targeting.

Conflict of interest statement

Conflict of interest statement: M.E.D. is a consultant to Cerulean Pharma Inc. and owns stock in the company.

Figures

Fig. 1.

Schematic of CRLX101 and study design. (A) CRLX101 nanoparticle design and particle formation including image of particles under cryoelectron microscopy. (B) Design of clinical trial.

Fig. 2.

Detection of camptothecin (CPT) fluorescence following CRLX101 treatment in mice and humans. (A) Presence of CPT in mice bearing two different human tumor xenografts. CPT is apparent 24 h after a single CRLX101 dose and appears as bright, punctate dots (green dots) with a patchy distribution throughout the tissue. (B) CPT signal in nonneoplastic and tumor tissue of a single patient under different dosing states. Positive CPT signal (green dots) is seen only in the posttreatment tumor tissue. (C) CPT signal in posttreatment nonneoplastic and tumor tissue for three other patients.

Fig. 3.

CPT–PEG colocalization. Tissue samples were stained with an anti-PEG antibody to identify the polymer component of CRLX101. Evidence of colocalized CPT signal (bright green dots) and PEG stain (red dots) were observed in five of nine patients. White arrows indicate points of stain colocalization.

Fig. 4.

Pharmacodynamics investigation of tumor biomarkers. Tumor tissues of six patients were stained for two different tumor biomarkers (CA IX and Topo-I) before and after treatment with CRLX101. The results shown here are indicative of the trend observed in the six individual tissue series.