Category: Preclinical Development
Purpose: Nanoparticle-based chemo- and radiotherapy are major topics of research in nanoparticle drug delivery, but a significant number of products have failed to reach the market. The heterogeneity of tumors in cancer patients often causes failures in translating preclinical results to the clinic. Imaging tumors may provide insights in treatment selection and bridge the translational gaps. The current contrast agents used for X-ray computed tomography (CT) have short circulation half-lives and can fail to promote adequate contrast enhancement between tumors and healthy tissues. Furthermore, commercial contrasts do not provide insights on nanoparticle accumulation due to their small molecular volume. To address this issue, we developed a contrast agent-containing nanocapsule system with a long circulation time that facilitates passive accumulation in tumors taking advantage of the enhanced permeability and retention (EPR) effect of tumors, thus increasing the sensitivity of tumor imaging.
Methods: An amphiphilic triblock copolymer (PEG-PCL(Ch)) was designed in-house to stabilize nanocapsules containing perfluorooctyl bromide (PFOB), a compound which displays high X-ray attenuation. Nanocapsules were optimized and manufactured via double-emulsion method, following physicochemical characterization. Xenograft tumor model was established by subcutaneously injecting luciferase-transfected OVCAR-8 cells to the mice’s right flanks. Biodistribution (tumor size 75-100 mm3) was assessed via X-ray CT (IVIS® SpectrumCT, Perkin Elmer) post intravenous administration. Iohexol was used as control (commercial contrast). Tumors were collected 48 hours post-injection and analyzed via high-resolution X-ray computed microscopy (Xradia 520 Versa, ZEISS).
Results: PFOB-containing nanocapsules were successfully manufactured to a maximum PFOB loading of 40% (v/v). Nanocapsules displayed core-shell structures, with z-average particle size of 230.5 ± 4.2 nm. Adequate colloidal stability was found over 2-months storage (4°C). Via X-ray CT, nanocapsules were detected in tumors as early as 3 h post-injection. Maximum tumor accumulation occurred at 12 h. The half-life in circulation was 9.7 ± 1.2 h (one-compartment i.v. bolus model). Iohexol did not display relevant tumor contrast enhancement compared with PFOB nanocapsules (Figure 1). Accumulation followed a non-homogeneous pattern due to the tumor’s heterogeneity (Figure 2).
Conclusion: PFOB-containing nanocapsules were feasible at a much higher PFOB loading compared with similar formulations due to the intrinsic properties of the in-house copolymer. Nanocapsules were able to enhance the CT contrast to a greater extent compared with Iohexol. This platform showed potential for future clinical applications in image-guided cancer therapy and tumor vasculature assessment due to its enhanced contrastability and passive tumor accumulation in a preclinical model. Understanding how, when and why nanoparticles accumulate in tumor tissues would allow treatments to be individually tailored, increasing chances of therapeutic success in the clinic.
André Beringhs– Storrs, Connecticut
André Beringhs– Storrs, Connecticut
Dennis Ndaya– Storrs, Connecticut
Athina Kominia– Storrs, Connecticut
Michael Jay– Chapel Hill, North Carolina
Hong Yuan– Chapel Hill, North Carolina
Rajeswari Kasi– Storrs, Connecticut
Xiuling Lu– Associate Professor, University of Connecticut, Storrs, Connecticut
Andre Beringhs– Research Assistant, University of Connecticut, Storrs, Connecticut