title: Liposomal prednisolone inhibits tumor growth in a spontaneous mouse mammary carcinoma model.
abstract: Cancers are abundantly infiltrated by inflammatory cells that are modulated by tumor cells to secrete mediators fostering tumor cell survival and proliferation. Therefore, agents that interfere with inflammatory signaling molecules or specific immune cell populations have been investigated as anticancer drugs. Corticosteroids are highly potent anti-inflammatory drugs, whose activity is intensified when targeted by nanocarrier systems. Liposome-targeted corticosteroids have been shown to inhibit tumor growth in different syngeneic murine tumor models as well as human xenograft mouse models, which is attributed to a switch in the tumor microenvironment from a pro-inflammatory to an anti-inflammatory state. Despite the recognized value of implantation tumor models in preclinical research, the "acute" inflammation induced by inoculation of tumor cells together with the exponential tumor growth in a relatively short period of time does not resemble slow progressive human disease that develops in situ. Therefore, in this study, the antitumor effect of liposomal corticosteroids was investigated in a clinically more relevant setting of transgenic mice developing spontaneous breast carcinomas. Here we show that liposomal prednisolone phosphate inhibits the growth of spontaneous breast carcinoma. Interestingly, the liposomal prednisolone was significantly more active than free drug. At 72h after injection of the liposomal formulation, 3μg prednisolone per gram of tumor tissue was recovered whereas no drug could be recovered after injection of the free agent. This indicates that, despite etiological and morphological differences between implanted and spontaneous tumor models, EPR-mediated accumulation of drug occurs to similar extent in this spontaneous mammary carcinoma model as in the syngeneic tumor models. Finally, we analyzed miRNA profiles in the MMTV/neu model and showed that the top 10 of miRNAs in the MMTV/neu tumor consisted of miRNAs with a known involvement in breast carcinoma proliferation and metastasis. The only exception was the appearance of miR-146b, a known inflammation-regulating miRNA species, after liposomal prednisolone treatment.
authors: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Anil K
authors: AK
authors: Deshantri
authors: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Medical Sciences, University of Torino, Torino, Italy.
authors: Sander A A
authors: SA
authors: Kooijmans
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Sylvia A
authors: SA
authors: Kuijpers
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Maria
authors: M
authors: Coimbra
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Astrid
authors: A
authors: Hoeppener
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Gert
authors: G
authors: Storm
authors: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Marcel H A M
authors: MH
authors: Fens
authors: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. Electronic address: R.M.Schiffelers@uu.nl.
authors: Raymond M
authors: RM
authors: Schiffelers
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D008081:Liposomes; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism; D011239:Prednisolone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D005938:Glucocorticoids; D008081:Liposomes; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C009022:prednisolone phosphate; D011239:Prednisolone
keywords: Liposomes; Prednisolone; Spontaneous breast cancer; miRNAs