Effect of intratumoral administration on biodistribution of 64Cu-labeled nanoshells

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Isolation and Characterization of a Metastatic Hybrid Cell Line Generated by ER Negative and ER Positive Breast Cancer Cells in Mouse Bone Marrow

BACKGROUND: The origin and the contribution of breast tumor heterogeneity to its progression are not clear. We investigated the effect of a growing orthotopic tumor formed by an aggressive estrogen receptor (ER)-negative breast cancer cell line on the metastatic potential of a less aggressive ER-positive breast cancer cell line for the elucidation of how the presence of heterogeneous cancer cells might affect each other's metastatic behavior. METHODS: ER positive ZR-75-1/GFP/puro cells, resistant to puromycin and non-tumorigenic/non-metastatic without exogenous estrogen supplementation, were injected intracardiacally into mice bearing growing orthotopic tumors, formed by ER negative MDA-MB-231/GFP/Neo cells resistant to G418. A variant cell line B6, containing both estrogen-dependent and -independent cells, were isolated from GFP expressing cells in the bone marrow and re-inoculated in nude mice to generate an estrogen-independent cell line B6TC. RESULTS: The presence of ER negative orthotopic tumors resulted in bone metastasis of ZR-75-1 without estrogen supplementation. The newly established B6TC cell line was tumorigenic without estrogen supplementation and resistant to both puromycin and G418 suggesting its origin from the fusion of MDA-MB-231/GFP/Neo and ZR-75-1/GFP/puro in the mouse bone marrow. Compared to parental cells, B6TC cells were more metastatic to lung and bone after intracardiac inoculation. More significantly, B6TC mice also developed brain metastasis, which was not observed in the MDA-MB-231/GFP/Neo cell-inoculated mice. Low expression of ERα and CD24, and high expression of EMT-related markers such as Vimentin, CXCR4, and Integrin-β1 along with high CD44 and ALDH expression indicated stem cell-like characteristics of B6TC. Gene microarray analysis demonstrated a significantly different gene expression profile of B6TC in comparison to those of parental cell lines. CONCLUSIONS: Spontaneous generation of the novel hybrid cell line B6TC, in a metastatic site with stem cell-like properties and propensity to metastasize to brain, suggest that cell fusion can contribute to tumor heterogeneity

Liposomal formulations of poorly soluble camptothecin: drug retention and biodistribution

Context: Camptothecin (CPT) represents a potent anticancer drug. Its therapeutic use however is impaired by both drug solubility, hydrolysis and protein interactions in vivo. Use of liposomes as drug formulation approach could overcome some of these challenges. Objective: The objective of this study was to perform a mechanistic study of the incorporation and retention of the lipophilic parent CPT-compound in different liposome formulations using radiolabeled CPT and thus be able to identify promising CPT delivery systems. In this context we also wanted to establish an appropriate mouse tumor model, in vivo scintigraphic imaging and biodistribution methodology for testing the most promising formulation. Materials and methods: CPT retention in various liposome formulations following incubation in buffer and serum was determined. The HT-29 mouse tumor model, 111In-labeled liposomes as well as 3H-labeled CPT were used to investigate the biodistribution of liposomes and drug. Results and discussion: The ability of different liposome formulations to retain CPT in buffer was influenced by the lipid concentration and the drug:lipid ratio rather than lipid composition. The tested formulations were cleared from the blood in the following order:CPT-solutionCPTliposomes 111In-labeled liposomes, and liposomes mainly accumulated in liver. Conclusion: Lipid composition did not influence CPT retention to the same extent as earlier observed in incorporation studies. The set up for the biodistribution study works well and is suited for future in vivo studies on CPT liposomes. The biodistribution study showed that liposomes circulated longer than free drug, but premature release of drug from liposomes occurred. Further studies to develop formulations with higher retention potential and prolonged circulation are desired