Synthesis of a New pH-Sensitive Folate–Doxorubicin Conjugate and its Antitumor Activity In Vitro

Ye, Wei-Liang; Teng, Zhaogang; Liu, Dao-Zhou; Han, Chunchun; Liu, Miao; Cheng, Ying; Yang, Tiehong; Mei, Qibing; Zhou, Siyuan

doi:10.1002/jps.23381

Cited by 15 publications

(22 citation statements)

References 29 publications

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“…In our lab, we previously synthesized FA-AMA-DOX and DOX-hyd-PEG conjugate to deliver DOX to tumor cell [18], [20]. The IC 50 of FA-AMA-DOX and DOX-hyd-PEG conjugate on HepG2 cells was 5.0±0.8 mol/L and 7.6±0.9 µM respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Second, the Boc group in the polymer was removed in 10% trifluoroacetic acid for 20 min to obtain FA-PEG-Hyd. For DOX conjugation, FA-PEG-Hyd (100 mg) was dissolved in 40 mL of DMSO, 20 mg of DOX dissolved in 10 mL of DMSO was then added with trifluoroacetic acid (0.1 mL TFA) as an acid catalyst [18]. The reaction mixture was stirred under nitrogen at room temperature for 48 h and was protected from light.…”

Section: Methodsmentioning

confidence: 99%

“…AMA was conjugated to the targeting moiety FA via an amide bond, and to the antitumor drug DOX via a hydrazone bond. Although FA-AMA-DOX can deliver DOX to folate over-expressed tumor cells, it is a small molecular conjugate and its drug delivery efficiency in vivo needs further evaluation [18].…”

Section: Introductionmentioning

confidence: 99%

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Cellular Uptake and Antitumor Activity of DOX-hyd-PEG-FA Nanoparticles

Zhang

et al. 2014

PLoS ONE

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A PEG-based, folate mediated, active tumor targeting drug delivery system using DOX-hyd-PEG-FA nanoparticles (NPs) were prepared. DOX-hyd-PEG-FA NPs showed a significantly faster DOX release in pH 5.0 medium than in pH 7.4 medium. Compared with DOX-hyd-PEG NPs, DOX-hyd-PEG-FA NPs increased the intracellular accumulation of DOX and showed a DOX translocation from lysosomes to nucleus. The cytotoxicity of DOX-hyd-PEG-FA NPs on KB cells was much higher than that of free DOX, DOX-ami-PEG-FA NPs and DOX-hyd-PEG NPs. The cytotoxicity of DOX-hyd-PEG-FA NPs on KB cells was attenuated in the presence of exogenous folic acid. The IC50 of DOX-hyd-PEG-FA NPs and DOX-hyd-PEG NPs on A549 cells showed no significant difference. After DOX-hyd-PEG-FA NPs were intravenously administered, the amount of DOX distributed in tumor tissue was significantly increased, while the amount of DOX distributed in heart was greatly decreased as compared with free DOX. Compared with free DOX, NPs yielded improved survival rate, prolonged life span, delayed tumor growth and reduced the cardiotoxicity in tumor bearing mice model. These results indicated that the acid sensitivity, passive and active tumor targeting abilities were likely to act synergistically to enhance the drug delivery efficiency of DOX-hyd-PEG-FA NPs. Therefore, DOX-hyd-PEG-FA NPs are a promising drug delivery system for targeted cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Cellular Uptake and Antitumor Activity of DOX-hyd-PEG-FA Nanoparticles

Zhang

et al. 2014

PLoS ONE

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“…Cellular uptake of free DOX and Asp-DOX was investigated using a fluorescence microscope (Nikon, Tokyo, Japan) with an excitation wavelength of 475 nm and absorption wavelength of 580 nm to observe the accumulation in the intracellular distribution of DOX as previously described. (10) Cancer cell lines HepG2 and H1299 were selected as two different models and seeded into 24-well plates at 1.5 9 10 5 ⁄ well. After 48 h, either free DOX or Asp-DOX at concentrations of 0, 10, 20, or 50 lg ⁄ mL, dissolved in serum-free medium, were added (500 lL ⁄ well).…”

Section: Doxorubicinmentioning

confidence: 99%

Aspartate‐modified doxorubicin on its N‐terminal increases drug accumulation in LAT1‐overexpressing tumors

Dong

Gao

et al. 2015

Cancer Science

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L-type amino acid transporter 1 (LAT1), overexpressed on the membrane of various tumor cells, is a potential target for tumor-targeting therapy. This study aimed to develop a LAT1-mediated chemotherapeutic agent. We screened doxorubicin modified by seven different large neutral amino acids. The aspartate-modified doxorubicin (Asp-DOX) showed the highest affinity (Km = 41.423 μmol/L) to LAT1. Aspartate was attached to the N-terminal of DOX by the amide bond with a free carboxyl and a free amino group on the α-carbon atom of the Asp residue. The product Asp-DOX was characterized by HPLC/MS. In vitro, Asp-DOX exerted stronger inhibition on the cancer cells overexpressing LAT1 and the uptake of Asp-DOX was approximately 3.5-fold higher than that of DOX in HepG2 cells. Pharmacokinetic data also showed that Asp-DOX was expressed over a longer circulation time (t1/2 = 49.14 min) in the blood compared to DOX alone (t1/2 = 15.12 min). In HepG2 and HCT116 tumor-bearing mice, Asp-DOX achieved 3.1-fold and 6.4-fold accumulation of drugs in tumor tissue, respectively, than those of the unmodified DOX. More importantly, treatment of tumor-bearing mice with Asp-DOX showed a significantly stronger inhibition of tumor growth than mice treated with free DOX in HepG2 tumor models. Furthermore, after Asp modification, Asp-DOX avoided MDR mediated by P-glycoprotein. These results suggested that the Asp-DOX modified drug may provide a new treatment strategy for tumors that overexpress LAT1 and MDR1.

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“…The conjugates can still be recognized and transported by the FR, and FR‐expressing cells can still selectively concentrate such folate conjugates. Many folate‐conjugated nanomaterials have been developed and used in tumor‐targeted imaging, drug delivery, and chemotherapy . In this study, we report the synthesis of folate‐conjugated oligomeric nanoparticles (NPs) radiolabeled with 99m Tc as FR‐mediated cell targeting.…”

Section: Introdrctionmentioning

confidence: 99%

^99mTc‐labeled oligomeric nanoparticles as potential agents for folate receptor‐positive tumor targeting

Liang

Zhang

et al. 2018

Labelled Comp Radiopharmac

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One type of biocompatible nanoparticles functionalized with folate and Tc was successfully synthesized. Maleimide-folic acid (Mal-FA) was selected to covalently conjugate with -SH of the nanoparticles (NPs) to prepare NPs-FA for targeting. Tc was selected to conjugate with -NH and -SH groups of cysteine residues on the surface of NPs to prepare NPs-FA- Tc for radioactive counting. The ability to target folate receptors of NPs-FA- Tc was assessed in uptake studies with folate-receptor-positive human HepG2 cells. The results showed that the as-prepared NPs can selectively uptake by folate receptor-overexpressing HepG2 tumor cells in vitro. The oligomeric hybrid NPs radiolabeled with Tc may develop to be SPECT/CT imaging biomaterials with high selectivity.

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Synthesis of a New pH-Sensitive Folate–Doxorubicin Conjugate and its Antitumor Activity In Vitro

Cited by 15 publications

References 29 publications

Cellular Uptake and Antitumor Activity of DOX-hyd-PEG-FA Nanoparticles

Cellular Uptake and Antitumor Activity of DOX-hyd-PEG-FA Nanoparticles

Aspartate‐modified doxorubicin on its N‐terminal increases drug accumulation in LAT1‐overexpressing tumors

^99mTc‐labeled oligomeric nanoparticles as potential agents for folate receptor‐positive tumor targeting

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