64Cu-labeled folate-conjugated shell cross-linked nanoparticles for tumor imaging and radiotherapy: Synthesis, radiolabeling, and biologic evaluation

Raffaella Rossin, Dipanjan Pan, Kai Qi, Jeffrey L. Turner, Xiankai Sun, Karen L. Wooley, Michael J. Welch

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

Long-circulating nanoparticles functionalized with ligands for receptors overexpressed by tumor cells have promising applications for active and passive tumor targeting. The purpose of this study was to evaluate 64Cu- radiolabeled folate-conjugated shell cross linked nanoparticles (SCKs) as candidate agents to shuttle radionuclides and drugs into tumors overexpressing the folate receptor (FR). Methods: SCKs were obtained by cross-linking the shell of micelles obtained from amphiphilic diblock copolymers. SCKs were then functionalized with folate, fluorescein thiosemicarbazide (FTSC), and 1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N‴-tetraacetic acid (TETA). The specific interaction of SCK-folate with the FR was investigated on KB cells. The biodistributions of 64Cu-TETA-SCK and 64Cu-TETA-SCK-folate were evaluated in athymic mice bearing small-size KB cell xenografts (10-100 mg), whereas the intratumor distributions were investigated by autoradiography in 0.3 to 0.6-g KB cell xenogratts. Results: A global solution-state functionalization strategy has been introduced for attaching optimum numbers of targeting and imaging agents onto the SCKs for increasing the efficiency of interaction with cell-surface receptors. Epifluorescence microscopy confirmed the specific interaction of FTSC-SCK-folate with the FR in vitro. 64Cu labeling of TETA-SCKs led to the radiolabeled compounds with 15%-20% yield and >95% radiochemical purity. The biodistribution results demonstrated high accumulation of 64Cu- labeled SCKs in organs of the reticuloendothelial system (RES) (56.0 ± 7.1%ID/g and 45.7 ± 3.5 %ID/g [percentage injected dose per gram] in liver at 10 min after injection for folated and nonfolated SCKs, respectively) and a prolonged blood circulation. No increase of SCK tumor uptake deriving from folate conjugation was observed (5.9 ± 2.8 %ID/g and 6.0 ± 1.9%ID/g at 4 h after injection for folated and nonfolated SCKs, respectively). However, tumor accumulation was higher in small-size tumors, where competitive block of SCK-folate uptake with excess folate was observed. Autoradiography results confirmed the extravasation of radiolabeled SCKs in vascularized areas of the tumor, whereas no diffusion was observed in necrotic regions. Conclusion: Despite high RES uptake, the evaluated 64Cu-labeled SCKs exhibited long circulation in blood and were able to passively accumulate in tumors. Furthermore, SCK-folate uptake was competitively blocked by excess folate in small-size solid tumors, suggesting interaction with the FR. For these reasons, functionalized SCKs are promising drug-delivery agents for imaging and therapy of early stage solid tumors.

Original languageEnglish (US)
Pages (from-to)1210-1218
Number of pages9
JournalJournal of Nuclear Medicine
Volume46
Issue number7
StatePublished - 2005

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Folic Acid
Nanoparticles
Radiotherapy
Neoplasms
KB Cells
Mononuclear Phagocyte System
Acids
Blood Circulation
Autoradiography
Injections
Cell Surface Receptors
Micelles
Heterografts
Nude Mice
Radioisotopes
Pharmaceutical Preparations
Microscopy

Keywords

  • Cu
  • Enhanced permeability and retention effect
  • Folate nanoparticles
  • Folate receptor
  • Radiolabeling

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

64Cu-labeled folate-conjugated shell cross-linked nanoparticles for tumor imaging and radiotherapy : Synthesis, radiolabeling, and biologic evaluation. / Rossin, Raffaella; Pan, Dipanjan; Qi, Kai; Turner, Jeffrey L.; Sun, Xiankai; Wooley, Karen L.; Welch, Michael J.

In: Journal of Nuclear Medicine, Vol. 46, No. 7, 2005, p. 1210-1218.

Research output: Contribution to journalArticle

Rossin, Raffaella ; Pan, Dipanjan ; Qi, Kai ; Turner, Jeffrey L. ; Sun, Xiankai ; Wooley, Karen L. ; Welch, Michael J. / 64Cu-labeled folate-conjugated shell cross-linked nanoparticles for tumor imaging and radiotherapy : Synthesis, radiolabeling, and biologic evaluation. In: Journal of Nuclear Medicine. 2005 ; Vol. 46, No. 7. pp. 1210-1218.
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abstract = "Long-circulating nanoparticles functionalized with ligands for receptors overexpressed by tumor cells have promising applications for active and passive tumor targeting. The purpose of this study was to evaluate 64Cu- radiolabeled folate-conjugated shell cross linked nanoparticles (SCKs) as candidate agents to shuttle radionuclides and drugs into tumors overexpressing the folate receptor (FR). Methods: SCKs were obtained by cross-linking the shell of micelles obtained from amphiphilic diblock copolymers. SCKs were then functionalized with folate, fluorescein thiosemicarbazide (FTSC), and 1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N‴-tetraacetic acid (TETA). The specific interaction of SCK-folate with the FR was investigated on KB cells. The biodistributions of 64Cu-TETA-SCK and 64Cu-TETA-SCK-folate were evaluated in athymic mice bearing small-size KB cell xenografts (10-100 mg), whereas the intratumor distributions were investigated by autoradiography in 0.3 to 0.6-g KB cell xenogratts. Results: A global solution-state functionalization strategy has been introduced for attaching optimum numbers of targeting and imaging agents onto the SCKs for increasing the efficiency of interaction with cell-surface receptors. Epifluorescence microscopy confirmed the specific interaction of FTSC-SCK-folate with the FR in vitro. 64Cu labeling of TETA-SCKs led to the radiolabeled compounds with 15{\%}-20{\%} yield and >95{\%} radiochemical purity. The biodistribution results demonstrated high accumulation of 64Cu- labeled SCKs in organs of the reticuloendothelial system (RES) (56.0 ± 7.1{\%}ID/g and 45.7 ± 3.5 {\%}ID/g [percentage injected dose per gram] in liver at 10 min after injection for folated and nonfolated SCKs, respectively) and a prolonged blood circulation. No increase of SCK tumor uptake deriving from folate conjugation was observed (5.9 ± 2.8 {\%}ID/g and 6.0 ± 1.9{\%}ID/g at 4 h after injection for folated and nonfolated SCKs, respectively). However, tumor accumulation was higher in small-size tumors, where competitive block of SCK-folate uptake with excess folate was observed. Autoradiography results confirmed the extravasation of radiolabeled SCKs in vascularized areas of the tumor, whereas no diffusion was observed in necrotic regions. Conclusion: Despite high RES uptake, the evaluated 64Cu-labeled SCKs exhibited long circulation in blood and were able to passively accumulate in tumors. Furthermore, SCK-folate uptake was competitively blocked by excess folate in small-size solid tumors, suggesting interaction with the FR. For these reasons, functionalized SCKs are promising drug-delivery agents for imaging and therapy of early stage solid tumors.",
keywords = "Cu, Enhanced permeability and retention effect, Folate nanoparticles, Folate receptor, Radiolabeling",
author = "Raffaella Rossin and Dipanjan Pan and Kai Qi and Turner, {Jeffrey L.} and Xiankai Sun and Wooley, {Karen L.} and Welch, {Michael J.}",
year = "2005",
language = "English (US)",
volume = "46",
pages = "1210--1218",
journal = "Journal of Nuclear Medicine",
issn = "0161-5505",
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TY - JOUR

T1 - 64Cu-labeled folate-conjugated shell cross-linked nanoparticles for tumor imaging and radiotherapy

T2 - Synthesis, radiolabeling, and biologic evaluation

AU - Rossin, Raffaella

AU - Pan, Dipanjan

AU - Qi, Kai

AU - Turner, Jeffrey L.

AU - Sun, Xiankai

AU - Wooley, Karen L.

AU - Welch, Michael J.

PY - 2005

Y1 - 2005

N2 - Long-circulating nanoparticles functionalized with ligands for receptors overexpressed by tumor cells have promising applications for active and passive tumor targeting. The purpose of this study was to evaluate 64Cu- radiolabeled folate-conjugated shell cross linked nanoparticles (SCKs) as candidate agents to shuttle radionuclides and drugs into tumors overexpressing the folate receptor (FR). Methods: SCKs were obtained by cross-linking the shell of micelles obtained from amphiphilic diblock copolymers. SCKs were then functionalized with folate, fluorescein thiosemicarbazide (FTSC), and 1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N‴-tetraacetic acid (TETA). The specific interaction of SCK-folate with the FR was investigated on KB cells. The biodistributions of 64Cu-TETA-SCK and 64Cu-TETA-SCK-folate were evaluated in athymic mice bearing small-size KB cell xenografts (10-100 mg), whereas the intratumor distributions were investigated by autoradiography in 0.3 to 0.6-g KB cell xenogratts. Results: A global solution-state functionalization strategy has been introduced for attaching optimum numbers of targeting and imaging agents onto the SCKs for increasing the efficiency of interaction with cell-surface receptors. Epifluorescence microscopy confirmed the specific interaction of FTSC-SCK-folate with the FR in vitro. 64Cu labeling of TETA-SCKs led to the radiolabeled compounds with 15%-20% yield and >95% radiochemical purity. The biodistribution results demonstrated high accumulation of 64Cu- labeled SCKs in organs of the reticuloendothelial system (RES) (56.0 ± 7.1%ID/g and 45.7 ± 3.5 %ID/g [percentage injected dose per gram] in liver at 10 min after injection for folated and nonfolated SCKs, respectively) and a prolonged blood circulation. No increase of SCK tumor uptake deriving from folate conjugation was observed (5.9 ± 2.8 %ID/g and 6.0 ± 1.9%ID/g at 4 h after injection for folated and nonfolated SCKs, respectively). However, tumor accumulation was higher in small-size tumors, where competitive block of SCK-folate uptake with excess folate was observed. Autoradiography results confirmed the extravasation of radiolabeled SCKs in vascularized areas of the tumor, whereas no diffusion was observed in necrotic regions. Conclusion: Despite high RES uptake, the evaluated 64Cu-labeled SCKs exhibited long circulation in blood and were able to passively accumulate in tumors. Furthermore, SCK-folate uptake was competitively blocked by excess folate in small-size solid tumors, suggesting interaction with the FR. For these reasons, functionalized SCKs are promising drug-delivery agents for imaging and therapy of early stage solid tumors.

AB - Long-circulating nanoparticles functionalized with ligands for receptors overexpressed by tumor cells have promising applications for active and passive tumor targeting. The purpose of this study was to evaluate 64Cu- radiolabeled folate-conjugated shell cross linked nanoparticles (SCKs) as candidate agents to shuttle radionuclides and drugs into tumors overexpressing the folate receptor (FR). Methods: SCKs were obtained by cross-linking the shell of micelles obtained from amphiphilic diblock copolymers. SCKs were then functionalized with folate, fluorescein thiosemicarbazide (FTSC), and 1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N‴-tetraacetic acid (TETA). The specific interaction of SCK-folate with the FR was investigated on KB cells. The biodistributions of 64Cu-TETA-SCK and 64Cu-TETA-SCK-folate were evaluated in athymic mice bearing small-size KB cell xenografts (10-100 mg), whereas the intratumor distributions were investigated by autoradiography in 0.3 to 0.6-g KB cell xenogratts. Results: A global solution-state functionalization strategy has been introduced for attaching optimum numbers of targeting and imaging agents onto the SCKs for increasing the efficiency of interaction with cell-surface receptors. Epifluorescence microscopy confirmed the specific interaction of FTSC-SCK-folate with the FR in vitro. 64Cu labeling of TETA-SCKs led to the radiolabeled compounds with 15%-20% yield and >95% radiochemical purity. The biodistribution results demonstrated high accumulation of 64Cu- labeled SCKs in organs of the reticuloendothelial system (RES) (56.0 ± 7.1%ID/g and 45.7 ± 3.5 %ID/g [percentage injected dose per gram] in liver at 10 min after injection for folated and nonfolated SCKs, respectively) and a prolonged blood circulation. No increase of SCK tumor uptake deriving from folate conjugation was observed (5.9 ± 2.8 %ID/g and 6.0 ± 1.9%ID/g at 4 h after injection for folated and nonfolated SCKs, respectively). However, tumor accumulation was higher in small-size tumors, where competitive block of SCK-folate uptake with excess folate was observed. Autoradiography results confirmed the extravasation of radiolabeled SCKs in vascularized areas of the tumor, whereas no diffusion was observed in necrotic regions. Conclusion: Despite high RES uptake, the evaluated 64Cu-labeled SCKs exhibited long circulation in blood and were able to passively accumulate in tumors. Furthermore, SCK-folate uptake was competitively blocked by excess folate in small-size solid tumors, suggesting interaction with the FR. For these reasons, functionalized SCKs are promising drug-delivery agents for imaging and therapy of early stage solid tumors.

KW - Cu

KW - Enhanced permeability and retention effect

KW - Folate nanoparticles

KW - Folate receptor

KW - Radiolabeling

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