Lymphatic Uptake of Liposomes after Intraperitoneal Administration Primarily Occurs via the Diaphragmatic Lymphatics and is Dependent on Liposome Surface Properties

Given Lee, Sifei Han, Iasmin Inocencio, Enyuan Cao, Jiwon Hong, Anthony R.J. Phillips, John A. Windsor, Christopher Porter, Natalie Trevaskis

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Drugs are commonly administered via the intraperitoneal (IP) route to treat localized infections and cancers in patients and to test drug efficacy and toxicity in preclinical studies. Despite this, there remain large gaps in our understanding of drug absorption routes (lymph vs blood) and pharmacokinetics following IP administration. This is particularly true when drugs are administered in complex delivery systems such as liposomes which are the main marketed formulation for several drugs that are administered intraperitoneally. This study investigated the impact of liposome surface properties (charge and PEGylation) on absorption into lymph and blood, and lymphatic disposition patterns, following IP administration. To achieve this, stable 3H-dipalmitoyl-phosphatidylcholine (DPPC) and 14C-sucrose-radiolabeled liposomes of 100-150 nm diameter with negative, neutral, or positive surface charge, or a PEGylated surface, were prepared and administered intraperitoneally to rats. Radiolabel concentrations were measured in lymph, blood, and lymph nodes (LNs). Lymph was collected from the thoracic lymph duct at either the abdomen (ABD) or the jugular-subclavian junction (JSJ). The lymphatic recovery of the radiolabels was substantially lower after administration in positively charged compared to the neutral, negative, or PEGylated liposomes. Radiolabel recovery was substantially greater (up to 18-fold) in the thoracic lymph collected at the JSJ when compared to that at the ABD, suggesting that liposomes entered the lymphatics at the diaphragm. Consistent with this, the concentration of the liposome labels was substantially higher (up to seven-fold) in mediastinal than in mesenteric LNs. Overall, this study shows how the peritoneal absorption and lymphatic disposition of drugs administered intraperitoneally can be manipulated through a careful selection of the drug delivery system and may thus be optimized to treat localized conditions such as cancers, infections, inflammatory diseases, and acute and critical illness. ©

Original languageEnglish
JournalMolecular Pharmaceutics
DOIs
Publication statusAccepted/In press - 2019

Keywords

  • drug delivery
  • intraperitoneal administration
  • liposome
  • lymphatic uptake
  • peritoneum

Cite this

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title = "Lymphatic Uptake of Liposomes after Intraperitoneal Administration Primarily Occurs via the Diaphragmatic Lymphatics and is Dependent on Liposome Surface Properties",
abstract = "Drugs are commonly administered via the intraperitoneal (IP) route to treat localized infections and cancers in patients and to test drug efficacy and toxicity in preclinical studies. Despite this, there remain large gaps in our understanding of drug absorption routes (lymph vs blood) and pharmacokinetics following IP administration. This is particularly true when drugs are administered in complex delivery systems such as liposomes which are the main marketed formulation for several drugs that are administered intraperitoneally. This study investigated the impact of liposome surface properties (charge and PEGylation) on absorption into lymph and blood, and lymphatic disposition patterns, following IP administration. To achieve this, stable 3H-dipalmitoyl-phosphatidylcholine (DPPC) and 14C-sucrose-radiolabeled liposomes of 100-150 nm diameter with negative, neutral, or positive surface charge, or a PEGylated surface, were prepared and administered intraperitoneally to rats. Radiolabel concentrations were measured in lymph, blood, and lymph nodes (LNs). Lymph was collected from the thoracic lymph duct at either the abdomen (ABD) or the jugular-subclavian junction (JSJ). The lymphatic recovery of the radiolabels was substantially lower after administration in positively charged compared to the neutral, negative, or PEGylated liposomes. Radiolabel recovery was substantially greater (up to 18-fold) in the thoracic lymph collected at the JSJ when compared to that at the ABD, suggesting that liposomes entered the lymphatics at the diaphragm. Consistent with this, the concentration of the liposome labels was substantially higher (up to seven-fold) in mediastinal than in mesenteric LNs. Overall, this study shows how the peritoneal absorption and lymphatic disposition of drugs administered intraperitoneally can be manipulated through a careful selection of the drug delivery system and may thus be optimized to treat localized conditions such as cancers, infections, inflammatory diseases, and acute and critical illness. {\circledC}",
keywords = "drug delivery, intraperitoneal administration, liposome, lymphatic uptake, peritoneum",
author = "Given Lee and Sifei Han and Iasmin Inocencio and Enyuan Cao and Jiwon Hong and Phillips, {Anthony R.J.} and Windsor, {John A.} and Christopher Porter and Natalie Trevaskis",
year = "2019",
doi = "10.1021/acs.molpharmaceut.9b00855",
language = "English",
journal = "Molecular Pharmaceutics",
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Lymphatic Uptake of Liposomes after Intraperitoneal Administration Primarily Occurs via the Diaphragmatic Lymphatics and is Dependent on Liposome Surface Properties. / Lee, Given; Han, Sifei; Inocencio, Iasmin; Cao, Enyuan; Hong, Jiwon; Phillips, Anthony R.J.; Windsor, John A.; Porter, Christopher; Trevaskis, Natalie.

In: Molecular Pharmaceutics, 2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Lymphatic Uptake of Liposomes after Intraperitoneal Administration Primarily Occurs via the Diaphragmatic Lymphatics and is Dependent on Liposome Surface Properties

AU - Lee, Given

AU - Han, Sifei

AU - Inocencio, Iasmin

AU - Cao, Enyuan

AU - Hong, Jiwon

AU - Phillips, Anthony R.J.

AU - Windsor, John A.

AU - Porter, Christopher

AU - Trevaskis, Natalie

PY - 2019

Y1 - 2019

N2 - Drugs are commonly administered via the intraperitoneal (IP) route to treat localized infections and cancers in patients and to test drug efficacy and toxicity in preclinical studies. Despite this, there remain large gaps in our understanding of drug absorption routes (lymph vs blood) and pharmacokinetics following IP administration. This is particularly true when drugs are administered in complex delivery systems such as liposomes which are the main marketed formulation for several drugs that are administered intraperitoneally. This study investigated the impact of liposome surface properties (charge and PEGylation) on absorption into lymph and blood, and lymphatic disposition patterns, following IP administration. To achieve this, stable 3H-dipalmitoyl-phosphatidylcholine (DPPC) and 14C-sucrose-radiolabeled liposomes of 100-150 nm diameter with negative, neutral, or positive surface charge, or a PEGylated surface, were prepared and administered intraperitoneally to rats. Radiolabel concentrations were measured in lymph, blood, and lymph nodes (LNs). Lymph was collected from the thoracic lymph duct at either the abdomen (ABD) or the jugular-subclavian junction (JSJ). The lymphatic recovery of the radiolabels was substantially lower after administration in positively charged compared to the neutral, negative, or PEGylated liposomes. Radiolabel recovery was substantially greater (up to 18-fold) in the thoracic lymph collected at the JSJ when compared to that at the ABD, suggesting that liposomes entered the lymphatics at the diaphragm. Consistent with this, the concentration of the liposome labels was substantially higher (up to seven-fold) in mediastinal than in mesenteric LNs. Overall, this study shows how the peritoneal absorption and lymphatic disposition of drugs administered intraperitoneally can be manipulated through a careful selection of the drug delivery system and may thus be optimized to treat localized conditions such as cancers, infections, inflammatory diseases, and acute and critical illness. ©

AB - Drugs are commonly administered via the intraperitoneal (IP) route to treat localized infections and cancers in patients and to test drug efficacy and toxicity in preclinical studies. Despite this, there remain large gaps in our understanding of drug absorption routes (lymph vs blood) and pharmacokinetics following IP administration. This is particularly true when drugs are administered in complex delivery systems such as liposomes which are the main marketed formulation for several drugs that are administered intraperitoneally. This study investigated the impact of liposome surface properties (charge and PEGylation) on absorption into lymph and blood, and lymphatic disposition patterns, following IP administration. To achieve this, stable 3H-dipalmitoyl-phosphatidylcholine (DPPC) and 14C-sucrose-radiolabeled liposomes of 100-150 nm diameter with negative, neutral, or positive surface charge, or a PEGylated surface, were prepared and administered intraperitoneally to rats. Radiolabel concentrations were measured in lymph, blood, and lymph nodes (LNs). Lymph was collected from the thoracic lymph duct at either the abdomen (ABD) or the jugular-subclavian junction (JSJ). The lymphatic recovery of the radiolabels was substantially lower after administration in positively charged compared to the neutral, negative, or PEGylated liposomes. Radiolabel recovery was substantially greater (up to 18-fold) in the thoracic lymph collected at the JSJ when compared to that at the ABD, suggesting that liposomes entered the lymphatics at the diaphragm. Consistent with this, the concentration of the liposome labels was substantially higher (up to seven-fold) in mediastinal than in mesenteric LNs. Overall, this study shows how the peritoneal absorption and lymphatic disposition of drugs administered intraperitoneally can be manipulated through a careful selection of the drug delivery system and may thus be optimized to treat localized conditions such as cancers, infections, inflammatory diseases, and acute and critical illness. ©

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KW - intraperitoneal administration

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KW - lymphatic uptake

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DO - 10.1021/acs.molpharmaceut.9b00855

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SN - 1543-8384

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