Companion Diagnostic 64Cu-Liposome Positron Emission Tomography Enables Characterization of Drug Delivery to Tumors and Predicts Response to Cancer Nanomedicines.

Deposition of liposomal drugs into solid tumors is a potentially rate-limiting step for drug delivery and has substantial variability that may influence probability of response. Tumor deposition is a shared mechanism for liposomal therapeutics such that a single companion diagnostic agent may have utility in predicting response to multiple nanomedicines. Methods: We describe the development, characterization and preclinical proof-of-concept of the positron emission tomography (PET) agent, MM-DX-929, a drug-free untargeted 100 nm PEGylated liposome stably entrapping a chelated complex of 4-DEAP-ATSC and 64Cu (copper-64). MM-DX-929 is designed to mimic the biodistribution of similarly sized therapeutic agents and enable quantification of deposition in solid tumors. Results: MM-DX-929 demonstrated sufficient in vitro and in vivo stability with PET images accurately reflecting the disposition of liposome nanoparticles over the time scale of imaging. MM-DX-929 is also representative of the tumor deposition and intratumoral distribution of three different liposomal drugs, including targeted liposomes and those with different degrees of PEGylation. Furthermore, stratification using a single pre-treatment MM-DX-929 PET assessment of tumor deposition demonstrated that tumors with high MM-DX-929 deposition predicted significantly greater anti-tumor activity after multi-cycle treatments with different liposomal drugs. In contrast, MM-DX-929 tumor deposition was not prognostic in untreated tumor-bearing xenografts, nor predictive in animals treated with small molecule chemotherapeutics. Conclusions: These data illustrate the potential of MM-DX-929 PET as a companion diagnostic strategy to prospectively select patients likely to respond to liposomal drugs or nanomedicines of similar molecular size.

CT characteristics and differential diagnosis of tumor deposition adjacent to colorectal cancer / 中华消化外科杂志

Objective To summarize the CT characteristics of tumor deposition adjacent to colorectal cancer (CRC),and provide the evidences for differential diagnosis.Methods The retrospective cross-sectional study was conducted.The clinicopathological data of 26 CRC patients who were admitted to the Wuxi Second People's Hospital of Nanjing Medical University from May 2015 to April 2017 were collected.Patients underwent preoperative multi-slice spiral CT scan and double-phase enhanced scan,and then received open surgery.Observation indicators:(1) characteristics of multi-slice spiral CT scan;(2) differential comparisons;(3) follow-up.Follow-up using telephone interview was performed to detect patients' prognosis once every 3 months up to May 2017.Measurement data with normal distribution were represented as (x)±s.Comparisons between groups and among groups were respectively analyzed using the t test and the one-way ANOVA.Pairwise comparison was done using the SNK method.Results (1) Characteristics of multi-slice spiral CT scan:of 26 patients,17 underwent double contrast enhanced scans of chest,abdomen and pelvic and 9 underwent double contrast scans of abdomen and pelvic.Primary tumors of 18 and 8 patients respectively located in the colon and rectum.Forty-one tumor deposits of 26 patients were collected,with number of tumor deposits of 1.6±0.9 per case,and number of tumor deposits ＜ 3 and ≥3 respectively were found in 20 and 6 patients.Tumor deposits were often isolated in the fat spaces around the rectum or colon and unconnected with the surrounding primary tumor or lymph node.Distance to the center of primary tumor was (2.6±l.0)cm (range,0.2-5.0 cm),the distance ＜2.6 cm and ≥2.6 cm were respectively detected in 22 and 19 patients.Thirty-three tumors showed signs of lobulation,22 showed signs of burr and 7 showed liquefaction necrosis,and there was a combination of multiple imaging characteristics in the same tumor deposit.The maximum width,minimum width,maximum diameter,plain scan value of CT,CT enhancement values in the arterial phase and venous phase in 41 tumor deposits were respectively (1.15 ± 0.60)cm,(1.11±0.44)cm,(1.13±0.49)cm,(27±13)HU,(28±14)HU and (49±19)HU.Of 41 tumor deposits,34 demonstrated homogeneous density in the plain scan,and obviously enhancement in early enhanced scan,with homogeneous enhancement;7 demonstrated heterogeneous density in the plain scan,with internal liquefaction necrosis,and enhanced scans showed no enhancement in the areas of necrosis and obviously early enhancement in the areas of non-necrosis.(2) Differential comparisons:26 patients underwent open surgery,including 8 with right hemectomy,2 with transverse colon resection,4 with left semicolon resection,2 with simple sigmoid resection,2 with abdominoperineal resection of rectal cancer and 8 with low anterior rectal resection,and all patients received postoperatively individualized treatment.Fifty-two lymph nodes with distance to center of primary tumor ＜ 5.0 cm that were confirmed by pathological examination were collected,including 19 metastatic lymph nodes.Of 41 tumor deposits,33 were irregular,and 8 were regular and round-like or oval-like shape.Of 19 metastatic lymph nodes,16 were regularly round-like shape,1 showed irregular shape and edge blur,and 2 were irregular with a mutual integration.The maximum width,minimum width and maximum diameter of 19 metastatic lymph nodes were respectively (1.09± 0.33) cm,(1.01 ± 0.23) cm and (1.05 ± 0.20) cm,with statistically significant differences in the above indicators between metastatic lymph nodes and tumor deposits (t =5.48,4.80,7.75,P＜0.05).The plain scan value of CT,CT enhancement values in the arterial phase and venous phase were respectively (12±7) HU,(18± 12) HU,(42± 15) HU in 19 metastatic lymph nodes and (33±6) HU,(31 ±15) HU,(53± 14)HU in 26 primary tumors,showing statistically significant differences in the plain scan value of CT and CT enhancement values in the arterial phase among tumor deposits,metastatic lymph nodes and primary tumors (F=24.43,4.46,P＜0.05),and no statistically significant difference in CT enhancement value in the venous phase (F=2.41,P＞0.05).There were statistically significant differences in the plain scan value of CT and CT enhancement values in the arterial phase between tumor deposits and metastatic lymph nodes (q =5.48,2.50,P＜0.05) and between metastatic lymph nodes and primary tumors (q =6.82,2.84,P＜0.05),and no statistically significant difference between tumor deposits and primary tumors (q =2.15,0.65,P＞0.05).Of 19 metastatic lymph nodes,11 demonstrated homogeneous density in plain scan,with a lower density compared with tumor deposits and primary tumors,and relatively homogeneous enhancement in the arterial phase of enhanced scan;8 demonstrated heterogeneous density with internal liquefaction necrosis,and ring-shaped enhancement in enhanced scan with no enhancement in the areas of necrosis.The density and enhancement range in the arterial phase and venous phase of tumor deposits were similar to primary tumors.(3) Follow-up:24 patients were followed up for 1-25 months,with a follow-up rate of 92.3％(24/26) and a median time of 17 months.Of 24 patients,2 were dead,and survival time were respectively 9 months and 21 months;22 had good survival.Conclusions Multislice spiral CT examination of tumor deposits demonstrates larger and irregular shape,with the signs of lobulation and burr,and the density in plain scan is similar to the primary tumor,with obviously enhancement in early enhanced scan.The metastatic lymph nodes are mostly round-like shape,diameter is smaller than that of tumor deposits,density in the plain scan and CT enhancement values in the arterial phase are lower than that of tumor deposits.

A gradient-loadable (64)Cu-chelator for quantifying tumor deposition kinetics of nanoliposomal therapeutics by positron emission tomography.

Effective drug delivery to tumors is a barrier to treatment with nanomedicines. Non-invasively tracking liposome biodistribution and tumor deposition in patients may provide insight into identifying patients that are well-suited for liposomal therapies. We describe a novel gradient-loadable chelator, 4-DEAP-ATSC, for incorporating (64)Cu into liposomal therapeutics for positron emission tomographic (PET). (64)Cu chelated to 4-DEAP-ATSC (>94%) was loaded into PEGylated liposomal doxorubicin (PLD) and HER2-targeted PLD (MM-302) with efficiencies >90%. (64)Cu-MM-302 was stable in human plasma for at least 48h. PET/CT imaging of xenografts injected with (64)Cu-MM-302 revealed biodistribution profiles that were quantitatively consistent with tissue-based analysis, and tumor (64)Cu positively correlated with liposomal drug deposition. This loading technique transforms liposomal therapeutics into theranostics and is currently being applied in a clinical trial (NCT01304797) to non-invasively quantify MM-302 tumor deposition, and evaluate its potential as a prognostic tool for predicting treatment outcome of nanomedicines.