Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Lee H

PROVIDER: S-EPMC5928891 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Lee Helen H Gaddy Daniel D Ventura Manuela M Bernards Nicholas N de Souza Raquel R Kirpotin Dmitri D Wickham Thomas T Fitzgerald Jonathan J Zheng Jinzi J Hendriks Bart S BS

Theranostics 20180321 9

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. <b>Methods:</b> We describe the development, characterization and preclinical proof-of-concept of the positron emission tomography (PET) agent, ...[more]

PMID: 29721081

Similar Datasets

Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Project description:BackgroundThe hybrid imaging positron emission tomography/magnetic resonance (PET/MR) is an important tool in the management of pediatric oncology patients, particularly in malignant musculoskeletal pathologies, because it combines the functional and metabolic information of tumor provided by PET with the high soft-tissue contrast and the functional information offered by magnetic resonance imaging (MRI).MethodsWe performed an observational retrospective study that included pediatric patients diagnosed with primary bone or soft-tissue sarcomas in the Pediatric Hematology and Oncology Unit at the HM Montepríncipe University Hospital, Boadilla del Monte, Madrid (Spain) who underwent whole-body 18F-fluorodeoxyglucose (18F-FDG) PET/MRI as a staging study and for follow-up evaluation for treatment response from September 2017 to January 2023. This study explores the protocols, the practical application of the PET/MRI technique and our clinical experience at our center in the diagnosis and follow-up of primary bone tumors and soft-tissue sarcomas in children.ResultsSeventy-one 18F-PET/MR studies were performed on 39 patients. Most of them (55%) were initial extension studies and (45%) were follow-up studies. Most of the patients studied were male (74.4%) with a median age of 15 years. Of the 39 cases, 51% were primary bone tumors while 18% were Langerhans cell histiocytosis and 21% soft tissue tumors. Of the 71 studies, five showed metastases at the initial diagnosis, three presented lymph node involvement, one with local infiltration, and one with pulmonary metastasis.ConclusionsPET/MR has represented a significant advancement in the evaluation of pediatric malignant neoplasms, with specific applications in musculoskeletal tumors showing clear benefits over PET/CT. The primary advantage is the reduction in ionizing radiation doses and the assessment of soft tissues, making it an excellent option for malignant musculoskeletal pathologies in pediatric patients who often require long-term follow-up. It is particularly useful for early tumor detection and functional therapy monitoring in oncology. The development of new protocols is making studies increasingly faster and better tolerated, even without the need for anesthesia. PET/MRI has shown to increase diagnostic accuracy in primary bone and soft tissue tumors, as it allows for the comprehensive evaluation of their morpho-metabolic characteristics, locoregional, and distant involvement in a single study. It is also useful in surgical planning and post-treatment follow-up.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets