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Local targeted therapy of liver metastasis from colon cancer by galactosylated liposome encapsulated with doxorubicin.

ABSTRACT: Since regional drug administration enables to maintain a high drug concentration within tumors, we compared the plasma concentration and biodistribution of doxorubicin (Dox) from drug-loaded conventional liposomes by local or systemic administration. The results demonstrated that drug concentration was substantially improved in liver as well as a decrease in blood and other organs by spleen injection mimicking portal vein perfusion (regional administration). To further investigate the targeted therapeutic effect of galactosylated liposome encapsulated doxorubicin (Dox) by regional administration, liver targeting liposomes were prepared by incorporating galactosylated-DPPE to conventional liposomes. Liposome uptake and targeting were verified in vitro and in vivo by fluorescence microscopy and xenogen IVIS imaging system, respectively. The results showed that galactose targeted liposomes presented a stronger specific cell uptake by human hepatocellular carcinoma HepG2 cells compared to the non-targeted liposomes. In vivo fluorescence imaging showed that the intra-hepatic deposition of conventional and galactosylated liposomes via spleen injection was more than that via tail vein administration, and galactosylated liposomes had higher fluorescent intensity over conventional liposomes in the liver post spleen administration. The anti-tumor effect of various drug administration routes for both liposomal formulations was evaluated using a murine liver metastasis model of colon cancer. The results indicated that tumor progression in the liver and mesenteric lymph nodes was significantly suppressed by Dox-loaded galactosylated liposomes via spleen injection, while no significance was observed in non-targeted formulations. Our data indicated that local perfusion of galactosylated liposomal doxorubicin had a great promise for the treatment of liver metastasis from colon cancer.

SUBMITTER: Zhao C

PROVIDER: S-EPMC3770687 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Local targeted therapy of liver metastasis from colon cancer by galactosylated liposome encapsulated with doxorubicin.

Zhao Chen C Feng Qiang Q Dou Zengpei Z Yuan Wei W Sui Chenguang C Zhang Xinghua X Xia Guimin G Sun Hongfang H Ma Jie J

PloS one 20130911 9

Since regional drug administration enables to maintain a high drug concentration within tumors, we compared the plasma concentration and biodistribution of doxorubicin (Dox) from drug-loaded conventional liposomes by local or systemic administration. The results demonstrated that drug concentration was substantially improved in liver as well as a decrease in blood and other organs by spleen injection mimicking portal vein perfusion (regional administration). To further investigate the targeted t ...[more]

PMID: 24040096

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Project description:Background: We have previously shown that alendronate, an amino-bisphosphonate, when reformulated in liposomes, can significantly enhance the efficacy of cytotoxic chemotherapies and help remodel the immunosuppressive tumor microenvironment towards an immune-permissive milieu resulting in increased anticancer efficacy. In addition, we have previously shown that the strong metal-chelating properties of alendronate can be exploited for nuclear imaging of liposomal biodistribution. To further improve anticancer efficacy, a pegylated liposome formulation co-encapsulating alendronate and doxorubicin (PLAD) has been developed. In this study, we examined the effects of PLAD on the tumor immunologic milieu in a mouse fibrosarcoma model in which the tumor microenvironment is heavily infiltrated with tumor-associated macrophages (TAM) that are associated with poor prognosis and treatment resistance. Methods: Doxorubicin biodistribution, characterization of the tumor immunologic milieu, cellular doxorubicin uptake, and tumor growth studies were performed in Balb/c mice bearing subcutaneously implanted WEHI-164 fibrosarcoma cells treated intravenously with PLAD, pegylated liposomal doxorubicin (PLD), free doxorubicin, or vehicle. Results: PLAD delivery resulted in a high level of tumor doxorubicin that was 20 to 30-fold greater than in free doxorubicin treated mice, and non-significantly higher than in PLD treated mice. PLAD also resulted in increased uptake in spleen and slightly lower plasma levels as compared to PLD. Importantly, our results showed that PLAD, and to a lesser extent PLD, shifted cellular drug uptake to TAM and to monocytic myeloid-derived suppressor cells (MDSC), while there was no drug uptake in neutrophilic MDSC or lymphoid cells. Free doxorubicin cellular drug uptake was below detectable levels. PLAD, and to a lesser extent PLD, also induced significant changes in number and functionality of tumor-infiltrating TAM, MDSC, Treg, NKT, and NK cells that are consistent with enhanced antitumor immune responses in the tumor microenvironment. In contrast, free doxorubicin induced moderate changes in the tumor microenvironment that could promote (decreased Treg) or be detrimental to antitumor immune responses (decreased M1 TAM and NK cells). These immune modulatory effects are reflected in the therapeutic study which showed that PLAD and PLD inhibited tumor growth and significantly prolonged survival, while free doxorubicin showed little or no anticancer activity. Conclusion: We show that liposomal delivery of doxorubicin not only alters pharmacokinetics, but also dramatically changes the immune modulatory activity of the drug cargo. In addition, our data support that the PLAD nanotheranostic platform further enhances some immune changes that may act in synergy with its cytotoxic chemotherapy effects.

Project description:This study sheds light on the biodistribution of orally administered, liposome-encapsulated bacteriophages, and their transcytosis through intestinal cell layers. Fluorochrome-labeled bacteriophages were used together with a non-invasive imaging methodology in the in vivo visualization of bacteriophages in the stomach and intestinal tract of mice. In those studies, phage encapsulation resulted in a significant increase of the labeled phages in the mouse stomach, even 6 h after their oral administration, and without a decrease in their concentration. By contrast, the visualization of encapsulated and non-encapsulated phages in the intestine were similar. Our in vivo observations were corroborated by culture methods and ex vivo experiments, which also showed that the percentage of encapsulated phages in the stomach remained constant (50%) compared to the amount of initially administered product. However, the use of conventional microbiological methods, which employ bile salts to break down liposomes, prevented the detection of encapsulated phages in the intestine. The ex vivo data showed a higher concentration of non-encapsulated than encapsulated phages in liver, kidney, and even muscle up to 6 h post-administration. Encapsulated bacteriophages were able to reach the liver, spleen, and muscle, with values of 38% ± 6.3%, 68% ± 8.6%, and 47% ± 7.4%, respectively, which persisted over the course of the experiment. Confocal laser scanning microscopy of an in vitro co-culture of human Caco-2/HT29/Raji-B cells revealed that Vybrant-Dil-stained liposomes containing labeled bacteriophages were preferably embedded in cell membranes. No transcytosis of encapsulated phages was detected in this in vitro model, whereas SYBR-gold-labeled non-encapsulated bacteriophages were able to cross the membrane. Our work demonstrates the prolonged persistence of liposome-encapsulated phages in the stomach and their adherence to the intestinal membrane. These observations could explain the greater long-term efficacy of phage therapy using liposome-encapsulated phages.

Dataset Information

Local targeted therapy of liver metastasis from colon cancer by galactosylated liposome encapsulated with doxorubicin.

Publications

Local targeted therapy of liver metastasis from colon cancer by galactosylated liposome encapsulated with doxorubicin.

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