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Pre-Targeting and Direct Immunotargeting of Liposomal Drug Carriers to Ovarian Carcinoma

Background Epidermal growth factor receptor (EGFR) is overexpressed in many solid tumor types, such as ovarian carcinoma. Immunoliposome based drug targeting has shown promising results in drug delivery to the tumors. However, the ratio of tumor-to-normal tissue concentrations should be increased to... Full description

Journal Title: PLoS ONE 2012, Vol.7(7)
Main Author: Lehtinen, Julia
Other Authors: Raki, Mari , Bergström, Kim A , Uutela, Päivi , Lehtinen, Katariina , Hiltunen, Annukka , Pikkarainen, Jere , Liang, Huamin , Pitkänen, Sari , Määttä, Ann-Marie , Ketola, Raimo A , Yliperttula, Marjo , Wirth, Thomas , Urtti, Arto
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ID: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0041410 ; PMCID: 3406029 ; PMID: 22844475
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title: Pre-Targeting and Direct Immunotargeting of Liposomal Drug Carriers to Ovarian Carcinoma
format: Article
creator:
  • Lehtinen, Julia
  • Raki, Mari
  • Bergström, Kim A
  • Uutela, Päivi
  • Lehtinen, Katariina
  • Hiltunen, Annukka
  • Pikkarainen, Jere
  • Liang, Huamin
  • Pitkänen, Sari
  • Määttä, Ann-Marie
  • Ketola, Raimo A
  • Yliperttula, Marjo
  • Wirth, Thomas
  • Urtti, Arto
subjects:
  • Research Article
  • Biology
  • Chemistry
  • Medicine
ispartof: PLoS ONE, 2012, Vol.7(7)
description: Background Epidermal growth factor receptor (EGFR) is overexpressed in many solid tumor types, such as ovarian carcinoma. Immunoliposome based drug targeting has shown promising results in drug delivery to the tumors. However, the ratio of tumor-to-normal tissue concentrations should be increased to minimize the adverse effects of cytostatic drugs. Methodology/Principal Findings We studied the EGFR-targeted doxorubicin immunoliposomes using pre-targeting and local intraperitoneal (i.p.) administration of the liposomes. This approach was used to increase drug delivery to tumors as compared to direct intravenous (i.v.) administration of liposomes. EGFR antibodies were attached on the surface of PEG coated liposomes using biotin-neutravidin binding. Receptor mediated cellular uptake and cytotoxic efficacy of EGFR-targeted liposomes were investigated in human ovarian adenocarcinoma (SKOV-3 and SKOV3.ip1) cells. In vivo distribution of the liposomes in mice was explored using direct and pre-targeting approaches and SPECT/CT imaging. Targeted liposomes showed efficient and specific receptor-mediated binding to ovarian carcinoma cells in vitro , but the difference in cytotoxicity between targeted and non-targeted liposomes remained small. The relatively low cytotoxic efficacy is probably due to insufficient doxorubicin release from the liposomes rather than lack of target binding. Tumor uptake of targeted liposomes in vivo was comparable to that of non-targeted liposomes after both direct and pre-targeting administration. For both EGFR-targeted and non-targeted liposomes, the i.p. administration increased liposome accumulation to the tumors compared to i.v. injections. Conclusions/Significance Intraperitoneal administration of liposomes may be a beneficial approach to treat the tumors in the abdominal cavity. The i.p. pre-targeting method warrants further studies as a potential approach in cancer therapy.
language:
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identifier: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0041410 ; PMCID: 3406029 ; PMID: 22844475
fulltext: fulltext
issn:
  • 1932-6203
  • 19326203
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titlePre-Targeting and Direct Immunotargeting of Liposomal Drug Carriers to Ovarian Carcinoma
creatorLehtinen, Julia ; Raki, Mari ; Bergström, Kim A ; Uutela, Päivi ; Lehtinen, Katariina ; Hiltunen, Annukka ; Pikkarainen, Jere ; Liang, Huamin ; Pitkänen, Sari ; Määttä, Ann-Marie ; Ketola, Raimo A ; Yliperttula, Marjo ; Wirth, Thomas ; Urtti, Arto
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descriptionBackground Epidermal growth factor receptor (EGFR) is overexpressed in many solid tumor types, such as ovarian carcinoma. Immunoliposome based drug targeting has shown promising results in drug delivery to the tumors. However, the ratio of tumor-to-normal tissue concentrations should be increased to minimize the adverse effects of cytostatic drugs. Methodology/Principal Findings We studied the EGFR-targeted doxorubicin immunoliposomes using pre-targeting and local intraperitoneal (i.p.) administration of the liposomes. This approach was used to increase drug delivery to tumors as compared to direct intravenous (i.v.) administration of liposomes. EGFR antibodies were attached on the surface of PEG coated liposomes using biotin-neutravidin binding. Receptor mediated cellular uptake and cytotoxic efficacy of EGFR-targeted liposomes were investigated in human ovarian adenocarcinoma (SKOV-3 and SKOV3.ip1) cells. In vivo distribution of the liposomes in mice was explored using direct and pre-targeting approaches and SPECT/CT imaging. Targeted liposomes showed efficient and specific receptor-mediated binding to ovarian carcinoma cells in vitro , but the difference in cytotoxicity between targeted and non-targeted liposomes remained small. The relatively low cytotoxic efficacy is probably due to insufficient doxorubicin release from the liposomes rather than lack of target binding. Tumor uptake of targeted liposomes in vivo was comparable to that of non-targeted liposomes after both direct and pre-targeting administration. For both EGFR-targeted and non-targeted liposomes, the i.p. administration increased liposome accumulation to the tumors compared to i.v. injections. Conclusions/Significance Intraperitoneal administration of liposomes may be a beneficial approach to treat the tumors in the abdominal cavity. The i.p. pre-targeting method warrants further studies as a potential approach in cancer therapy.
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titlePre-Targeting and Direct Immunotargeting of Liposomal Drug Carriers to Ovarian Carcinoma
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abstractBackground Epidermal growth factor receptor (EGFR) is overexpressed in many solid tumor types, such as ovarian carcinoma. Immunoliposome based drug targeting has shown promising results in drug delivery to the tumors. However, the ratio of tumor-to-normal tissue concentrations should be increased to minimize the adverse effects of cytostatic drugs. Methodology/Principal Findings We studied the EGFR-targeted doxorubicin immunoliposomes using pre-targeting and local intraperitoneal (i.p.) administration of the liposomes. This approach was used to increase drug delivery to tumors as compared to direct intravenous (i.v.) administration of liposomes. EGFR antibodies were attached on the surface of PEG coated liposomes using biotin-neutravidin binding. Receptor mediated cellular uptake and cytotoxic efficacy of EGFR-targeted liposomes were investigated in human ovarian adenocarcinoma (SKOV-3 and SKOV3.ip1) cells. In vivo distribution of the liposomes in mice was explored using direct and pre-targeting approaches and SPECT/CT imaging. Targeted liposomes showed efficient and specific receptor-mediated binding to ovarian carcinoma cells in vitro , but the difference in cytotoxicity between targeted and non-targeted liposomes remained small. The relatively low cytotoxic efficacy is probably due to insufficient doxorubicin release from the liposomes rather than lack of target binding. Tumor uptake of targeted liposomes in vivo was comparable to that of non-targeted liposomes after both direct and pre-targeting administration. For both EGFR-targeted and non-targeted liposomes, the i.p. administration increased liposome accumulation to the tumors compared to i.v. injections. Conclusions/Significance Intraperitoneal administration of liposomes may be a beneficial approach to treat the tumors in the abdominal cavity. The i.p. pre-targeting method warrants further studies as a potential approach in cancer therapy.
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date2012-07-26