Amphiphilic Phospholipid-Based Riboflavin Derivatives for Tumor Targeting Nanomedicines

N. Beztsinna, Y. Tsvetkova, M. Bartneck, Twan Gerardus Gertudis Maria Lammers, F. Kiessling, I. Bestel

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)

Abstract

Riboflavin (RF) is an essential vitamin for cellular metabolism. Recent studies have shown that RF is internalized through RF transporters, which are highly overexpressed by prostate and breast cancer cells, as well as by angiogenic endothelium. Here, we present an optimized synthesis protocol for preparing tailor-made amphiphilic phospholipid-based RF derivatives using phosphoramidite chemistry. The prepared RF amphiphile—RfdiC14—can be inserted into liposome formulations for targeted drug delivery. The obtained liposomes had a hydrodynamic size of 115 ± 5 nm with narrow size distribution (PDI 0.06) and a zeta potential of −52 ± 3 mV. In vitro uptake studies showed that RfdiC14-containing liposomes were strongly internalized in HUVEC, PC3, and A431 cells, in a specific and transporter-mediated manner. To assess the RF targeting potential in vivo, an amphiphile containing PEG spacer between RF and a lipid was prepared—DSPE-PEG-RF. The latter was successfully incorporated into long-circulating near-infrared-labeled liposomes (141 ± 1 nm in diameter, PDI 0.07, zeta potential of −33 ± 1 mV). The longitudinal μCT/FMT biodistribution studies in PC3 xenograft bearing mice demonstrated similar pharmacokinetics profile of DSPE-PEG-RF-functionalized liposomes compared to control. The subsequent histological evaluation of resected tumors revealed higher degree of tumor retention as well as colocalization of targeted liposomes with endothelial cells emphasizing the targeting potential of RF amphiphiles and their utility for the lipid-containing drug delivery systems.
Original languageEnglish
Pages (from-to)2048-2061
JournalBioconjugate chemistry
Volume27
Issue number9
DOIs
Publication statusPublished - 2016

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Nanomedicine
Medical nanotechnology
Riboflavin
Liposomes
Phospholipids
Tumors
Derivatives
Polyethylene glycols
Neoplasms
Amphiphiles
Zeta potential
Lipids
Bearings (structural)
Pharmacokinetics
Vitamins
Endothelial cells
Metabolism
Hydrodynamics
Drug Compounding
Cells

Keywords

  • METIS-321014
  • IR-103415

Cite this

Beztsinna, N. ; Tsvetkova, Y. ; Bartneck, M. ; Lammers, Twan Gerardus Gertudis Maria ; Kiessling, F. ; Bestel, I. / Amphiphilic Phospholipid-Based Riboflavin Derivatives for Tumor Targeting Nanomedicines. In: Bioconjugate chemistry. 2016 ; Vol. 27, No. 9. pp. 2048-2061.
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abstract = "Riboflavin (RF) is an essential vitamin for cellular metabolism. Recent studies have shown that RF is internalized through RF transporters, which are highly overexpressed by prostate and breast cancer cells, as well as by angiogenic endothelium. Here, we present an optimized synthesis protocol for preparing tailor-made amphiphilic phospholipid-based RF derivatives using phosphoramidite chemistry. The prepared RF amphiphile—RfdiC14—can be inserted into liposome formulations for targeted drug delivery. The obtained liposomes had a hydrodynamic size of 115 ± 5 nm with narrow size distribution (PDI 0.06) and a zeta potential of −52 ± 3 mV. In vitro uptake studies showed that RfdiC14-containing liposomes were strongly internalized in HUVEC, PC3, and A431 cells, in a specific and transporter-mediated manner. To assess the RF targeting potential in vivo, an amphiphile containing PEG spacer between RF and a lipid was prepared—DSPE-PEG-RF. The latter was successfully incorporated into long-circulating near-infrared-labeled liposomes (141 ± 1 nm in diameter, PDI 0.07, zeta potential of −33 ± 1 mV). The longitudinal μCT/FMT biodistribution studies in PC3 xenograft bearing mice demonstrated similar pharmacokinetics profile of DSPE-PEG-RF-functionalized liposomes compared to control. The subsequent histological evaluation of resected tumors revealed higher degree of tumor retention as well as colocalization of targeted liposomes with endothelial cells emphasizing the targeting potential of RF amphiphiles and their utility for the lipid-containing drug delivery systems.",
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Amphiphilic Phospholipid-Based Riboflavin Derivatives for Tumor Targeting Nanomedicines. / Beztsinna, N.; Tsvetkova, Y.; Bartneck, M.; Lammers, Twan Gerardus Gertudis Maria; Kiessling, F.; Bestel, I.

In: Bioconjugate chemistry, Vol. 27, No. 9, 2016, p. 2048-2061.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Amphiphilic Phospholipid-Based Riboflavin Derivatives for Tumor Targeting Nanomedicines

AU - Beztsinna, N.

AU - Tsvetkova, Y.

AU - Bartneck, M.

AU - Lammers, Twan Gerardus Gertudis Maria

AU - Kiessling, F.

AU - Bestel, I.

PY - 2016

Y1 - 2016

N2 - Riboflavin (RF) is an essential vitamin for cellular metabolism. Recent studies have shown that RF is internalized through RF transporters, which are highly overexpressed by prostate and breast cancer cells, as well as by angiogenic endothelium. Here, we present an optimized synthesis protocol for preparing tailor-made amphiphilic phospholipid-based RF derivatives using phosphoramidite chemistry. The prepared RF amphiphile—RfdiC14—can be inserted into liposome formulations for targeted drug delivery. The obtained liposomes had a hydrodynamic size of 115 ± 5 nm with narrow size distribution (PDI 0.06) and a zeta potential of −52 ± 3 mV. In vitro uptake studies showed that RfdiC14-containing liposomes were strongly internalized in HUVEC, PC3, and A431 cells, in a specific and transporter-mediated manner. To assess the RF targeting potential in vivo, an amphiphile containing PEG spacer between RF and a lipid was prepared—DSPE-PEG-RF. The latter was successfully incorporated into long-circulating near-infrared-labeled liposomes (141 ± 1 nm in diameter, PDI 0.07, zeta potential of −33 ± 1 mV). The longitudinal μCT/FMT biodistribution studies in PC3 xenograft bearing mice demonstrated similar pharmacokinetics profile of DSPE-PEG-RF-functionalized liposomes compared to control. The subsequent histological evaluation of resected tumors revealed higher degree of tumor retention as well as colocalization of targeted liposomes with endothelial cells emphasizing the targeting potential of RF amphiphiles and their utility for the lipid-containing drug delivery systems.

AB - Riboflavin (RF) is an essential vitamin for cellular metabolism. Recent studies have shown that RF is internalized through RF transporters, which are highly overexpressed by prostate and breast cancer cells, as well as by angiogenic endothelium. Here, we present an optimized synthesis protocol for preparing tailor-made amphiphilic phospholipid-based RF derivatives using phosphoramidite chemistry. The prepared RF amphiphile—RfdiC14—can be inserted into liposome formulations for targeted drug delivery. The obtained liposomes had a hydrodynamic size of 115 ± 5 nm with narrow size distribution (PDI 0.06) and a zeta potential of −52 ± 3 mV. In vitro uptake studies showed that RfdiC14-containing liposomes were strongly internalized in HUVEC, PC3, and A431 cells, in a specific and transporter-mediated manner. To assess the RF targeting potential in vivo, an amphiphile containing PEG spacer between RF and a lipid was prepared—DSPE-PEG-RF. The latter was successfully incorporated into long-circulating near-infrared-labeled liposomes (141 ± 1 nm in diameter, PDI 0.07, zeta potential of −33 ± 1 mV). The longitudinal μCT/FMT biodistribution studies in PC3 xenograft bearing mice demonstrated similar pharmacokinetics profile of DSPE-PEG-RF-functionalized liposomes compared to control. The subsequent histological evaluation of resected tumors revealed higher degree of tumor retention as well as colocalization of targeted liposomes with endothelial cells emphasizing the targeting potential of RF amphiphiles and their utility for the lipid-containing drug delivery systems.

KW - METIS-321014

KW - IR-103415

U2 - 10.1021/acs.bioconjchem.6b00317

DO - 10.1021/acs.bioconjchem.6b00317

M3 - Article

VL - 27

SP - 2048

EP - 2061

JO - Bioconjugate chemistry

JF - Bioconjugate chemistry

SN - 1043-1802

IS - 9

ER -