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 ().
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.
Summary
Paroxysmal nocturnal haemoglobinuria (PNH) is an uncommon, acquired disorder of blood cells caused by mutation of the phosphatidylinositol glycan class A (PIG‐A) gene. The disease often manifests with haemoglobinuria, peripheral blood cytopenias, and venous thrombosis. The natural history of PNH has been documented in retrospective series; but there has only been one study that correlated the more sensitive and specific flow cytometric assays that have become available in the last decade with severe symptoms associated with PNH. In a retrospective analysis of 49 consecutive patients with PNH evaluated at Johns Hopkins, large PNH clones were associated with an increased risk for thrombosis as well as haemoglobinuria, abdominal pain, oesophageal spasm, and impotence. Of the 14 (29%) patients that developed thrombosis, nine died; six of these from complications related to thromboses. According to logistic regression modelling, for a 10% change in PNH clone size, the odds ratio for risk of thrombosis was estimated to be 1·64. No patient with <61% PNH granulocytes developed a thrombosis, whereas 12 of 22 patients (54·5%) with ≥61% PNH granulocytes manifested with thrombosis. These data not only confirm that the size of the PNH clone correlates with the risk for thrombosis, but they also suggest a correlation of PNH clone size to more symptomatic PNH.
To determine whether increased dietary iron could be a risk factor for active tuberculosis, dietary iron history and human immunodeficiency virus (HIV) status were studied in 98 patients with pulmonary tuberculosis and in 98 control subjects from rural Zimbabwe. Exposure to high levels of dietary iron in the form of traditional beer is associated with increased iron stores in rural Africans. HIV seropositivity was associated with a 17.3-fold increase in the estimated odds of developing active tuberculosis (95% confidence interval [95% CI], 7.4-40.6; P<.001), and increased dietary iron was associated with a 3.5-fold increase (95% CI, 1.4-8.9; P=.009). Among patients treated for tuberculosis, HIV seropositivity was associated with a 3.8-fold increase in the estimated hazard ratio of death (95% CI, 1.0-13.8; P=.046), and increased dietary iron was associated with a 1.3-fold increase (95% CI, 0.4-6.4; P=.2). These findings are consistent with the hypothesis that elevated dietary iron may increase the risk of active pulmonary tuberculosis.
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