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Purpose: Targeted nanotherapies are being developed to improve tumor drug delivery and enhance therapeutic response. Techniques that can predict response will facilitate clinical translation and may help define optimal treatment strategies. We evaluated the efficacy of diffusion-weighted magnetic resonance imaging to monitor early response to CRLX101 (a cyclodextrin-based polymer particle containing the DNA topoisomerase I inhibitor camptothecin) nanotherapy (formerly IT-101), and explored its potential as a therapeutic response predictor using a mechanistic model of tumor cell proliferation.Experimental Design: Diffusion MRI was serially conducted following CRLX101 administration in a mouse lymphoma model. Apparent diffusion coefficients (ADCs) extracted from the data were used as treatment response biomarkers. Animals treated with irinotecan (CPT-11) and saline were imaged for comparison. ADC data were also input into a mathematical model of tumor growth. Histological analysis using cleaved-caspase 3, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling, Ki-67, and hematoxylin and eosin (H&E) were conducted on tumor samples for correlation with imaging results.Results: CRLX101-treated tumors at day 2, 4, and 7 posttreatment exhibited changes in mean ADC = 16 ± 9%, 24 ± 10%, 49 ± 17%, and size (TV) = −5 ± 3%, −30 ± 4%, and −45 ± 13%, respectively. Both parameters were statistically greater than controls [p(ADC) ≤ 0.02, and p(TV) ≤ 0.01 at day 4 and 7], and noticeably greater than CPT-11–treated tumors (ADC = 5 ± 5%, 14 ± 7%, and 18 ± 6%; TV = −15 ± 5%, −22 ± 13%, and −26 ± 8%). Model-derived parameters for cell proliferation obtained using ADC data distinguished CRLX101-treated tumors from controls (P = 0.02).Conclusions: Temporal changes in ADC specified early CRLX101 treatment response and could be used to model image-derived cell proliferation rates following treatment. Comparisons of targeted and nontargeted treatments highlight the utility of noninvasive imaging and modeling to evaluate, monitor, and predict responses to targeted nanotherapeutics. Clin Cancer Res; 19(9); 2518–27. ©2013 AACR.

PDF file - 64K, Boxplots of cellular proliferation rates for different treatment groups calculated by applying ADC data to a logistic model of tumor growth. Boxplots for (A) control, (B) CRLX101 and (C) CPT-11 animals between day 0/2, day 0/4, day 2/4, and day 4/7 are shown.

PDF file - 74K, P-values of histological comparisons of CRLX101 and CPT-11 cohorts with controls on different days. Statistically significant values are highlighted (p < 0.01, *, p < 0.05, �).

PDF file - 112K, Quantitative histological assessment of CRLX101 and CPT-11 response. Tumors treated with CRLX101 (5 mg/kg), CPT-11 (100 mg/kg) or saline were harvested for histology on days 0, 2, 4, and 7. Tumor samples were subsequently sectioned and stained with (A) Cleaved caspase-3 (co-stained with hematoxylin), (B) TUNEL (co-stained with hematoxylin), (C) Ki-67 (co-stained with hematoxylin) and (D) H&E. Three fields of view from each tumor slide were analyzed to obtain measurements of positive cleaved caspase-3 and TUNEL staining, percentage of Ki-67 expression and cellular density (as demonstrated by hematoxylin staining). Statistically significant values, as compared to the control cohort for each time point, are highlighted (p < 0.01, *, p < 0.05, �). Error bars denote standard error.

To understand the current state of radiology residents' exposure to nuclear medicine and molecular imaging (NM/MI), determine key factors that may attract more trainees into the field, and identify differentiating aspects between those specializing in NM/MI and those who are not.An anonymous web-based survey was sent to contacts at all diagnostic radiology residency programs in the United States for dissemination to their residents, collecting information about trainees' NM/MI exposure during residency and factors that may attract them to NM/MI.A total of 198 trainees responded to the survey, 34 of whom plan on pursuing a career in NM/MI. Most trainees reported early exposure to NM/MI during residency; most (97.4%) reported ample exposure to general NM/MI and oncologic studies. Less than 3% of trainees reported adequate exposure to therapies, neurological applications, molecular imaging/research advances, and physics. Respondents reported a need for better quality education (38.9%) and exposure to mentors (28.8%) as ways to attract trainees to NM/MI. Routinely encountered clinical pathology was the most interesting for those specializing in NM/MI (29.4%), whereas lifestyle was the most attractive aspect of NM/MI for those not pursuing a career in the field (27.4%). NM/MI-associated research was the least attractive for those specializing in NM/MI (35.3%), while job market concerns was the least attractive aspect for those not specializing in NM/MI (37.2%). Trainees planning to specialize in NM/MI reported higher satisfaction with their orientation to NM/MI during their first clinical rotation compared to those who do not plan to specialize in the field (3.03/5.00 and 2.67/5.00, respectively, p = 0.04).This survey highlights several factors that training programs and national societies can target to improve interest in NM/MI among radiology residents. We found that optimized education initiatives, including improved orientation to the field, increased mentoring, and career opportunities are essential levers for recruiting radiology trainees into the NM/MI workforce.