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Biocompatible and biodegradable fibrinogen microspheres for tumor-targeted doxorubicin delivery.

Joo JY, Park GY, An SS - Int J Nanomedicine (2015)

Bottom Line: Doxorubicin (DOX), a chemotherapeutic agent, was covalently conjugated to Fbg, and the microspheres were prepared.In vitro cytotoxicity tests confirmed low cytotoxicity in normal cells and high antitumor effect toward cancer cells.Therefore, DOX-linker-Fbg microspheres could be a suitable drug carrier for safer and effective drug delivery.

View Article: PubMed Central - PubMed

Affiliation: Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, Seongnam-si, Republic of Korea.

ABSTRACT
In the development of effective drug delivery carriers, many researchers have focused on the usage of nontoxic and biocompatible materials and surface modification with targeting molecules for tumor-specific drug delivery. Fibrinogen (Fbg), an abundant glycoprotein in plasma, could be a potential candidate for developing drug carriers because of its biocompatibility and tumor-targeting property via arginine-glycine-aspartate (RGD) peptide sequences. Doxorubicin (DOX), a chemotherapeutic agent, was covalently conjugated to Fbg, and the microspheres were prepared. Acid-labile and non-cleavable linkers were used for the conjugation of DOX to Fbg, resulting in an acid-triggered drug release under a mild acidic condition and a slow-controlled drug release, respectively. In vitro cytotoxicity tests confirmed low cytotoxicity in normal cells and high antitumor effect toward cancer cells. In addition, it was discovered that a longer linker could make the binding of cells to Fbg drug carriers easier. Therefore, DOX-linker-Fbg microspheres could be a suitable drug carrier for safer and effective drug delivery.

No MeSH data available.


Related in: MedlinePlus

Synthesis of DOX–linker–Fbg conjugates using (A) acid-labile linkers (3-MAH; and KMUH) and (B) non-cleavable linkers (SM(PEG)4, SM(PEG)12).Abbreviations: DOX, doxorubicin; Fbg, fibrinogen; 2-IT, 2-iminothiolane; 3-MAH, 3-maleimidopropionic acid hydrazonium trifluoroacetic acid; KMUH, N-(k-maleimidoundecanoic acid; SM(PEG)4, succinimidyl-[(N-maleimidopropionamido)-tetraethylene glycol] ester; SM(PEG)12, succinimidyl-[(N-maleimidopropionamido)-dodecaethylene glycol] ester.
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f1-ijn-10-101: Synthesis of DOX–linker–Fbg conjugates using (A) acid-labile linkers (3-MAH; and KMUH) and (B) non-cleavable linkers (SM(PEG)4, SM(PEG)12).Abbreviations: DOX, doxorubicin; Fbg, fibrinogen; 2-IT, 2-iminothiolane; 3-MAH, 3-maleimidopropionic acid hydrazonium trifluoroacetic acid; KMUH, N-(k-maleimidoundecanoic acid; SM(PEG)4, succinimidyl-[(N-maleimidopropionamido)-tetraethylene glycol] ester; SM(PEG)12, succinimidyl-[(N-maleimidopropionamido)-dodecaethylene glycol] ester.

Mentions: DOX was conjugated to Fbg using acid-labile cross-linkers;18 3-MAH (L1, n=1) for acid-triggered drug release, and each conjugation concept was described in Figure 1A. DOX (1.5 mg, 2.76 µmol) was mixed with 3-MAH (0.88 mg, 2.97 µmol) in 1 mL of phosphate-buffered saline (PBS) (pH 7.2), and stirred with an orbital shaker (250 rpm) at 25°C in the dark for 24 hours. The resultant reaction produced DOX–linker [DOX–(3-MAH)] complexes through a hydrazone bond. To introduce thiol (–SH) groups on the Fbg molecules, Fbg (100 mg, 0.294 µmol) was dissolved in 2 mL of PBS (pH 7.2) containing 5 mM ethylenediaminetetraacetic acid, mixed with 2-IT (0.4 mg, 2.91 µmol), and stirred at 25°C for 1 hour. The DOX–linker solution was added to the thiolated-Fbg solution, and the reaction mixture was shaken at 25°C in the dark for 48 hours. After that, the DOX–linker–Fbg solution was purified using a size-exclusive Zeba™ Spin Desalting Column with 7 kDa molecular weight cut-off (MWCO) Thermo Fisher Scientific (Seoul, Republic of Korea) at 2,400 rpm for 2 minutes to remove the unconjugated DOX and linkers. Absorbance of the collected DOX–linker–Fbg solution was measured with micro-plate reader (Victor 3 Multilabel Counter, PerkinElmer Inc., Waltham, MA, USA) at 490 nm, and the conjugation efficacy was calculated from a standard curve of DOX concentration gradient.


Biocompatible and biodegradable fibrinogen microspheres for tumor-targeted doxorubicin delivery.

Joo JY, Park GY, An SS - Int J Nanomedicine (2015)

Synthesis of DOX–linker–Fbg conjugates using (A) acid-labile linkers (3-MAH; and KMUH) and (B) non-cleavable linkers (SM(PEG)4, SM(PEG)12).Abbreviations: DOX, doxorubicin; Fbg, fibrinogen; 2-IT, 2-iminothiolane; 3-MAH, 3-maleimidopropionic acid hydrazonium trifluoroacetic acid; KMUH, N-(k-maleimidoundecanoic acid; SM(PEG)4, succinimidyl-[(N-maleimidopropionamido)-tetraethylene glycol] ester; SM(PEG)12, succinimidyl-[(N-maleimidopropionamido)-dodecaethylene glycol] ester.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562758&req=5

f1-ijn-10-101: Synthesis of DOX–linker–Fbg conjugates using (A) acid-labile linkers (3-MAH; and KMUH) and (B) non-cleavable linkers (SM(PEG)4, SM(PEG)12).Abbreviations: DOX, doxorubicin; Fbg, fibrinogen; 2-IT, 2-iminothiolane; 3-MAH, 3-maleimidopropionic acid hydrazonium trifluoroacetic acid; KMUH, N-(k-maleimidoundecanoic acid; SM(PEG)4, succinimidyl-[(N-maleimidopropionamido)-tetraethylene glycol] ester; SM(PEG)12, succinimidyl-[(N-maleimidopropionamido)-dodecaethylene glycol] ester.
Mentions: DOX was conjugated to Fbg using acid-labile cross-linkers;18 3-MAH (L1, n=1) for acid-triggered drug release, and each conjugation concept was described in Figure 1A. DOX (1.5 mg, 2.76 µmol) was mixed with 3-MAH (0.88 mg, 2.97 µmol) in 1 mL of phosphate-buffered saline (PBS) (pH 7.2), and stirred with an orbital shaker (250 rpm) at 25°C in the dark for 24 hours. The resultant reaction produced DOX–linker [DOX–(3-MAH)] complexes through a hydrazone bond. To introduce thiol (–SH) groups on the Fbg molecules, Fbg (100 mg, 0.294 µmol) was dissolved in 2 mL of PBS (pH 7.2) containing 5 mM ethylenediaminetetraacetic acid, mixed with 2-IT (0.4 mg, 2.91 µmol), and stirred at 25°C for 1 hour. The DOX–linker solution was added to the thiolated-Fbg solution, and the reaction mixture was shaken at 25°C in the dark for 48 hours. After that, the DOX–linker–Fbg solution was purified using a size-exclusive Zeba™ Spin Desalting Column with 7 kDa molecular weight cut-off (MWCO) Thermo Fisher Scientific (Seoul, Republic of Korea) at 2,400 rpm for 2 minutes to remove the unconjugated DOX and linkers. Absorbance of the collected DOX–linker–Fbg solution was measured with micro-plate reader (Victor 3 Multilabel Counter, PerkinElmer Inc., Waltham, MA, USA) at 490 nm, and the conjugation efficacy was calculated from a standard curve of DOX concentration gradient.

Bottom Line: Doxorubicin (DOX), a chemotherapeutic agent, was covalently conjugated to Fbg, and the microspheres were prepared.In vitro cytotoxicity tests confirmed low cytotoxicity in normal cells and high antitumor effect toward cancer cells.Therefore, DOX-linker-Fbg microspheres could be a suitable drug carrier for safer and effective drug delivery.

View Article: PubMed Central - PubMed

Affiliation: Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, Seongnam-si, Republic of Korea.

ABSTRACT
In the development of effective drug delivery carriers, many researchers have focused on the usage of nontoxic and biocompatible materials and surface modification with targeting molecules for tumor-specific drug delivery. Fibrinogen (Fbg), an abundant glycoprotein in plasma, could be a potential candidate for developing drug carriers because of its biocompatibility and tumor-targeting property via arginine-glycine-aspartate (RGD) peptide sequences. Doxorubicin (DOX), a chemotherapeutic agent, was covalently conjugated to Fbg, and the microspheres were prepared. Acid-labile and non-cleavable linkers were used for the conjugation of DOX to Fbg, resulting in an acid-triggered drug release under a mild acidic condition and a slow-controlled drug release, respectively. In vitro cytotoxicity tests confirmed low cytotoxicity in normal cells and high antitumor effect toward cancer cells. In addition, it was discovered that a longer linker could make the binding of cells to Fbg drug carriers easier. Therefore, DOX-linker-Fbg microspheres could be a suitable drug carrier for safer and effective drug delivery.

No MeSH data available.


Related in: MedlinePlus