Purpose: Therapeutic nanoparticles are designed to deliver their drug payloads through enhanced permeability and retention (EPR) in solid tumors. The extent of EPR and its variability in human tumors is highly debated and has been proposed as an explanation for variable responses to therapeutic nanoparticles in clinical studies. Experimental Design: We assessed the EPR effect in patients using a 64Cu-labeled nanoparticle, 64Cu-MM-302 (64Cu-labeled HER2-targeted PEGylated liposomal doxorubicin), and imaging by Positron Emission Tomography/Computed Tomography (PET/CT). Nineteen patients with HER2-positive metastatic breast cancer underwent 2-3 PET/CT scans post-administration of 64Cu-MM-302 as part of a clinical trial of MM-302 plus trastuzumab with and without cyclophosphamide (NCT01304797). Results: Significant background uptake of 64Cu-MM-302 was observed in liver and spleen. Tumor accumulation of 64Cu-MM-302 at 24-48 h varied 35-fold (0.52 to 18.5 %ID/kg) including deposition in bone and brain lesions, and was independent of systemic plasma exposure. Computational analysis quantified rates of deposition and washout, indicating peak liposome deposition at 24-48 h. Patients were classified based on 64Cu-MM-302 lesion deposition using a cut-point that is comparable to a response threshold in preclinical studies. In a retrospective exploratory analysis of patient outcomes relating to drug levels in tumor lesions, high 64Cu-MM-302 deposition was associated with more favorable treatment outcomes (hazard ratio = 0.42). Conclusions: These findings provide important evidence and quantification of the EPR effect in human metastatic tumors, and support imaging nanoparticle deposition in tumors as a potential means to identify patients well-suited for treatment with therapeutic nanoparticles.
- Received December 19, 2016.
- Revision received March 8, 2017.
- Accepted March 8, 2017.
- Copyright ©2017, American Association for Cancer Research.