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International Journal of Nanomedicine Volume 10, 2015 - Issue
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Original Research

Multi-small molecule conjugations as new targeted delivery carriers for tumor therapy

Lingling Shan1 Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People’s Republic of China
,
Ming Liu2 Department of Biology, University of South Dakota, Vermillion, SD, USA
,
Chao Wu1 Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People’s Republic of China
,
Liang Zhao1 Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People’s Republic of China
,
Siwen Li3 Department of Biomedical Engineering, School of Life Science and Technology, China Pharmaceutical University, Nanjing, People’s Republic of China
,
Lisheng Xu1 Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People’s Republic of China
,
Wengen Cao1 Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People’s Republic of China
,
Guizhen Gao1 Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People’s Republic of China
&
Yueqing Gu3 Department of Biomedical Engineering, School of Life Science and Technology, China Pharmaceutical University, Nanjing, People’s Republic of ChinaCorrespondence[email protected]
 show all
Pages 5571-5591 | Published online: 01 Sep 2015

Figures & data

Figure 1 Synthetic scheme and structures of FA-FITC-Arg-PTX (A) and FA-5AF-Glu-PTX (B).

Notes: (A) a, Fmoc-Arg(Pbf)-PTX; b, FA-NHS; c, NH2- Arg(Pbf)-PTX; d, FA- Arg(Pbf)-PTX; e, FA- (NH2)Arg-PTX; f, FA-FITC-Arg-PTX. (B) a, Fmoc-Glu(tBu)-PTX; b, FA-NHS; c, NH2-Glu(tBu)-PTX; d, FA- Glu(tBu)-PTX; e, FA-(COOH) Glu-PTX; f, FA-5AF-Glu-PTX.

Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; h, hour; min, minute; RT, room temperature.

Figure 1 Synthetic scheme and structures of FA-FITC-Arg-PTX (A) and FA-5AF-Glu-PTX (B).Notes: (A) a, Fmoc-Arg(Pbf)-PTX; b, FA-NHS; c, NH2- Arg(Pbf)-PTX; d, FA- Arg(Pbf)-PTX; e, FA- (NH2)Arg-PTX; f, FA-FITC-Arg-PTX. (B) a, Fmoc-Glu(tBu)-PTX; b, FA-NHS; c, NH2-Glu(tBu)-PTX; d, FA- Glu(tBu)-PTX; e, FA-(COOH) Glu-PTX; f, FA-5AF-Glu-PTX.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; h, hour; min, minute; RT, room temperature.
Figure 1 Synthetic scheme and structures of FA-FITC-Arg-PTX (A) and FA-5AF-Glu-PTX (B).Notes: (A) a, Fmoc-Arg(Pbf)-PTX; b, FA-NHS; c, NH2- Arg(Pbf)-PTX; d, FA- Arg(Pbf)-PTX; e, FA- (NH2)Arg-PTX; f, FA-FITC-Arg-PTX. (B) a, Fmoc-Glu(tBu)-PTX; b, FA-NHS; c, NH2-Glu(tBu)-PTX; d, FA- Glu(tBu)-PTX; e, FA-(COOH) Glu-PTX; f, FA-5AF-Glu-PTX.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; h, hour; min, minute; RT, room temperature.

Figure 2 Characterization of multi-small molecule-conjugated paclitaxel prodrugs.

Notes: (A) Absorption peaks of FA-FITC-Arg-PTX prodrug formulation overlaps the peaks of FA, Arg, PTX, and FITC at 365 nm, 220 nm, 227 nm, 375 nm, and 780 nm, respectively. (B) Absorption spectra for the FA-5AF-Glu-PTX formulation. The absorption peaks at 365 nm, 220 nm, 227 nm, and 465 nm represent absorption of FA, Glu, PTX, and 5AF, respectively. (C) Absorption spectra of ICG02-(NH2)Arg-PTX formulation at 220 nm, 227 nm, and 780 nm represent absorption of Arg, FA, and ICG-Der-02, respectively. (D) Absorption peaks of FA-ICG02-Arg-PTX formulation at 365 nm, 220 nm, 227 nm, and 780 nm represent absorption of FA, Arg, PTX, and ICG-Der-02, respectively. (E) Release of free PTX from FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in phosphate-buffered saline. (F) Release of free PTX from FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in human plasma.

Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; Arg, arginine; Glu, glutamic acid.

Figure 2 Characterization of multi-small molecule-conjugated paclitaxel prodrugs.Notes: (A) Absorption peaks of FA-FITC-Arg-PTX prodrug formulation overlaps the peaks of FA, Arg, PTX, and FITC at 365 nm, 220 nm, 227 nm, 375 nm, and 780 nm, respectively. (B) Absorption spectra for the FA-5AF-Glu-PTX formulation. The absorption peaks at 365 nm, 220 nm, 227 nm, and 465 nm represent absorption of FA, Glu, PTX, and 5AF, respectively. (C) Absorption spectra of ICG02-(NH2)Arg-PTX formulation at 220 nm, 227 nm, and 780 nm represent absorption of Arg, FA, and ICG-Der-02, respectively. (D) Absorption peaks of FA-ICG02-Arg-PTX formulation at 365 nm, 220 nm, 227 nm, and 780 nm represent absorption of FA, Arg, PTX, and ICG-Der-02, respectively. (E) Release of free PTX from FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in phosphate-buffered saline. (F) Release of free PTX from FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in human plasma.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; Arg, arginine; Glu, glutamic acid.

Figure 3 Targeting capability of fluorescence dye-labeled PTX prodrug formulations in different tumor cell lines with different FA-α receptor expression levels.

Notes: (A) Protein levels of FR-α in the tumor and normal cell lines were determined by Western blot. (B) Targeting ability of PTX prodrug formulations in MDA-MB-231, MCF-7, A549, and HEK293 cells. Tumor cells show increased uptake of PTX prodrug compared with the normal cell lines with low expression of FR protein. (C) Flow cytometric analysis of FA-modified PTX prodrug formulation in MDA-MB-231, MCF-7, A549, and HEK293 cells. FA-FITC-Arg-PTX and FA-5AF-Glu-PTX prodrug formulations were taken up into the MDA-MB-231 cell lines at a rate of 89.6% and 85.9%, respectively, but at a rate of only 2.1% and 1.9% in HEK293 cells.

Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; FA-α, folate receptor alpha.

Figure 3 Targeting capability of fluorescence dye-labeled PTX prodrug formulations in different tumor cell lines with different FA-α receptor expression levels.Notes: (A) Protein levels of FR-α in the tumor and normal cell lines were determined by Western blot. (B) Targeting ability of PTX prodrug formulations in MDA-MB-231, MCF-7, A549, and HEK293 cells. Tumor cells show increased uptake of PTX prodrug compared with the normal cell lines with low expression of FR protein. (C) Flow cytometric analysis of FA-modified PTX prodrug formulation in MDA-MB-231, MCF-7, A549, and HEK293 cells. FA-FITC-Arg-PTX and FA-5AF-Glu-PTX prodrug formulations were taken up into the MDA-MB-231 cell lines at a rate of 89.6% and 85.9%, respectively, but at a rate of only 2.1% and 1.9% in HEK293 cells.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; FA-α, folate receptor alpha.

Figure 4 In vitro antitumor effects of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX.

Notes: (A) A cell viability ratio assay was used to qualitatively display the antitumor activity and cytotoxicity of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in the tumor cell lines and normal HEK293 cell line (MTT assay, n=6). (B) The cells were then incubated in the free PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX drug formulations. One day later, the morphology of cell apoptosis was observed by fluorescence microscopy. (C) The number of late apoptosis/necrotic value (Q4) of the three cell lines (MDA-MB-231, MCF-7, and A549) was 25.8%/36.5%/34.1%, 19.9%/26.7%/27.9%, and 14.6%/16.8%/16.3%, respectively.

Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.

Figure 4 In vitro antitumor effects of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX.Notes: (A) A cell viability ratio assay was used to qualitatively display the antitumor activity and cytotoxicity of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in the tumor cell lines and normal HEK293 cell line (MTT assay, n=6). (B) The cells were then incubated in the free PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX drug formulations. One day later, the morphology of cell apoptosis was observed by fluorescence microscopy. (C) The number of late apoptosis/necrotic value (Q4) of the three cell lines (MDA-MB-231, MCF-7, and A549) was 25.8%/36.5%/34.1%, 19.9%/26.7%/27.9%, and 14.6%/16.8%/16.3%, respectively.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.

Figure 5 Acute toxicity of PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX assessed by LD50.

Notes: (A) Compared with PTX (15, 20, 25, 35, and 45 mg/kg), FA-Arg-PTX-FITC (80, 160, 200, 280, and 320 mg/kg) increased the survival rate in in normal mice. The survival rate of FA-Arg-PTX-FITC was 100% with different dose, LD50 >320 mg/kg. (B) Compared with PTX (15, 20, 25, 35, and 45 mg/kg), FA-5AF-Glu-PTX (80, 160, 200, 280, 320 mg/kg) increased the survival rate in in normal mice. The survival rate of FA-5AF-Glu-PTX was 100% with different dose, LD50 >320 mg/kg (n=10 per group).

Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.

Figure 5 Acute toxicity of PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX assessed by LD50.Notes: (A) Compared with PTX (15, 20, 25, 35, and 45 mg/kg), FA-Arg-PTX-FITC (80, 160, 200, 280, and 320 mg/kg) increased the survival rate in in normal mice. The survival rate of FA-Arg-PTX-FITC was 100% with different dose, LD50 >320 mg/kg. (B) Compared with PTX (15, 20, 25, 35, and 45 mg/kg), FA-5AF-Glu-PTX (80, 160, 200, 280, 320 mg/kg) increased the survival rate in in normal mice. The survival rate of FA-5AF-Glu-PTX was 100% with different dose, LD50 >320 mg/kg (n=10 per group).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.

Figure 6 Dynamic behavior and targeting capability of the PTX prodrug formulations in MDA-MB-231 tumor-bearing mice.

Notes: (A) Images of the tumor-bearing mice after administration of ICG02-(NH2)Arg-PTX within 48 hours. (B) Images of the tumor-bearing mice after administration of FA-ICG02-Arg-PTX within 48 hours. (C) The T/N ratio in MDA-MB-231 tumor tissues for ICG02-(NH2)Arg-PTX and FA-ICG02-Arg-PTX prodrug formulations. (D) Based on the targeting ability of PTX prodrugs, we euthanized the mice bearing MDA-MB-231 tumor xenografts at 4 hours post-injection of FA-FITC-Arg-PTX or FA-5AF-Glu-PTX and all tissues were immediately excised for sectioning and were visualized by fluorescence microscopy. *Statistical analysis indicated that there was a significant difference in the T/N ratio in the MDA-MB-231 tumor tissues between the two prodrug formulations (P<0.05). The data are shown as the mean ± standard deviation (n=5 per group).

Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; T/N, tumor-to-normal tissue; h, hour; m, minutes.

Figure 6 Dynamic behavior and targeting capability of the PTX prodrug formulations in MDA-MB-231 tumor-bearing mice.Notes: (A) Images of the tumor-bearing mice after administration of ICG02-(NH2)Arg-PTX within 48 hours. (B) Images of the tumor-bearing mice after administration of FA-ICG02-Arg-PTX within 48 hours. (C) The T/N ratio in MDA-MB-231 tumor tissues for ICG02-(NH2)Arg-PTX and FA-ICG02-Arg-PTX prodrug formulations. (D) Based on the targeting ability of PTX prodrugs, we euthanized the mice bearing MDA-MB-231 tumor xenografts at 4 hours post-injection of FA-FITC-Arg-PTX or FA-5AF-Glu-PTX and all tissues were immediately excised for sectioning and were visualized by fluorescence microscopy. *Statistical analysis indicated that there was a significant difference in the T/N ratio in the MDA-MB-231 tumor tissues between the two prodrug formulations (P<0.05). The data are shown as the mean ± standard deviation (n=5 per group).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; T/N, tumor-to-normal tissue; h, hour; m, minutes.

Figure 7 In vivo therapeutic experiment.

Notes: (A) Tumor volumes for MCF-7-bearing mice as a function of time (days). (B) Animal weights of MCF-7-bearing mice as a function of time (days). Data are shown as the mean (n=6). (C) Tumor volumes for A549-bearing mice as a function of time (days). (D) Animal weights of A549-bearing mice as a function of time (days). Data are shown as the mean (n=6). (E) Tissue sections of tumor excised from MCF-7-bearing nude mice 15 days after administration of PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX. More than 98% of mice in the groups treated with PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX showed tumor tissue with spotty necrosis, spherical cells, and loose order under higher than normal doses. (Magnification 400×).

Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.

Figure 7 In vivo therapeutic experiment.Notes: (A) Tumor volumes for MCF-7-bearing mice as a function of time (days). (B) Animal weights of MCF-7-bearing mice as a function of time (days). Data are shown as the mean (n=6). (C) Tumor volumes for A549-bearing mice as a function of time (days). (D) Animal weights of A549-bearing mice as a function of time (days). Data are shown as the mean (n=6). (E) Tissue sections of tumor excised from MCF-7-bearing nude mice 15 days after administration of PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX. More than 98% of mice in the groups treated with PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX showed tumor tissue with spotty necrosis, spherical cells, and loose order under higher than normal doses. (Magnification 400×).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.

Figure S1 Characterization of nanocarrier-conjugated intermediate compound.

Notes: (A) NH2-Arg(Pbf)-PTX (theoretically calculated molecular weight 1,280.43): MS (ESI, m/z) 1,279.43 ([M + H]+. (B) FA-Arg(NH2)-PTX (theoretically calculated molecular weight 1,469.51): MS (ESI, m/z) 1,468.51 ([M + H]+). (C) NH2-Glu(tBut)-PTX (theoretically calculated molecular weight 1,057.15): MS (ESI, m/z) 1,056.15 ([M +H]+). (D) FA-Glu(COOH)-PTX (theoretically calculated molecular weight 1,442.44): MS (ESI, m/z) 1,441.44 ([M + H]+).

Abbreviations: ESI, electrospray ionization; FA, folic acid; MS, mass spectrometry; PTX, paclitaxel; TOF, time of flight.

Figure S1 Characterization of nanocarrier-conjugated intermediate compound.Notes: (A) NH2-Arg(Pbf)-PTX (theoretically calculated molecular weight 1,280.43): MS (ESI, m/z) 1,279.43 ([M + H]+. (B) FA-Arg(NH2)-PTX (theoretically calculated molecular weight 1,469.51): MS (ESI, m/z) 1,468.51 ([M + H]+). (C) NH2-Glu(tBut)-PTX (theoretically calculated molecular weight 1,057.15): MS (ESI, m/z) 1,056.15 ([M +H]+). (D) FA-Glu(COOH)-PTX (theoretically calculated molecular weight 1,442.44): MS (ESI, m/z) 1,441.44 ([M + H]+).Abbreviations: ESI, electrospray ionization; FA, folic acid; MS, mass spectrometry; PTX, paclitaxel; TOF, time of flight.
Figure S1 Characterization of nanocarrier-conjugated intermediate compound.Notes: (A) NH2-Arg(Pbf)-PTX (theoretically calculated molecular weight 1,280.43): MS (ESI, m/z) 1,279.43 ([M + H]+. (B) FA-Arg(NH2)-PTX (theoretically calculated molecular weight 1,469.51): MS (ESI, m/z) 1,468.51 ([M + H]+). (C) NH2-Glu(tBut)-PTX (theoretically calculated molecular weight 1,057.15): MS (ESI, m/z) 1,056.15 ([M +H]+). (D) FA-Glu(COOH)-PTX (theoretically calculated molecular weight 1,442.44): MS (ESI, m/z) 1,441.44 ([M + H]+).Abbreviations: ESI, electrospray ionization; FA, folic acid; MS, mass spectrometry; PTX, paclitaxel; TOF, time of flight.

Figure S2 Characterization of nanocarrier-conjugated paclitaxel prodrugs.

Notes: (A) Fluorescence of FITC/5AF can be observed from thin layer chromatography of purified FA-FITC-Arg-PTX/FA-5AF-Glu-PTX using a fluorescence imaging system. (B) FA-FITC-Arg-PTX (theoretically calculated molecular weight 1,859.88): MS (ESI, m/z) 1,858.88 ([M + H]+). FA-5AF-Glu-PTX (theoretically calculated molecular weight 1,790.75): MS (ESI, m/z) 1,789.75 ([M + H]+). (C) High-performance liquid chromatography of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX prodrugs. (D) Fluorescence of ICG02 can be observed from the band of purified ICG02-(NH2)Arg-PTX using a near-infrared imaging system. Fluorescence of ICG02 can be observed from the band of purified FA-ICG02-Arg-PTX using the near-infrared imaging system.

Abbreviations: 5AF, 5-aminofluorescein; ESI, electrospray ionization; FA, folic acid; FITC, fluorescein isothiocyanate; MS, mass spectrometry; PTX, paclitaxel.

Figure S2 Characterization of nanocarrier-conjugated paclitaxel prodrugs.Notes: (A) Fluorescence of FITC/5AF can be observed from thin layer chromatography of purified FA-FITC-Arg-PTX/FA-5AF-Glu-PTX using a fluorescence imaging system. (B) FA-FITC-Arg-PTX (theoretically calculated molecular weight 1,859.88): MS (ESI, m/z) 1,858.88 ([M + H]+). FA-5AF-Glu-PTX (theoretically calculated molecular weight 1,790.75): MS (ESI, m/z) 1,789.75 ([M + H]+). (C) High-performance liquid chromatography of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX prodrugs. (D) Fluorescence of ICG02 can be observed from the band of purified ICG02-(NH2)Arg-PTX using a near-infrared imaging system. Fluorescence of ICG02 can be observed from the band of purified FA-ICG02-Arg-PTX using the near-infrared imaging system.Abbreviations: 5AF, 5-aminofluorescein; ESI, electrospray ionization; FA, folic acid; FITC, fluorescein isothiocyanate; MS, mass spectrometry; PTX, paclitaxel.
Figure S2 Characterization of nanocarrier-conjugated paclitaxel prodrugs.Notes: (A) Fluorescence of FITC/5AF can be observed from thin layer chromatography of purified FA-FITC-Arg-PTX/FA-5AF-Glu-PTX using a fluorescence imaging system. (B) FA-FITC-Arg-PTX (theoretically calculated molecular weight 1,859.88): MS (ESI, m/z) 1,858.88 ([M + H]+). FA-5AF-Glu-PTX (theoretically calculated molecular weight 1,790.75): MS (ESI, m/z) 1,789.75 ([M + H]+). (C) High-performance liquid chromatography of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX prodrugs. (D) Fluorescence of ICG02 can be observed from the band of purified ICG02-(NH2)Arg-PTX using a near-infrared imaging system. Fluorescence of ICG02 can be observed from the band of purified FA-ICG02-Arg-PTX using the near-infrared imaging system.Abbreviations: 5AF, 5-aminofluorescein; ESI, electrospray ionization; FA, folic acid; FITC, fluorescein isothiocyanate; MS, mass spectrometry; PTX, paclitaxel.

Figure S3 Aqueous solubility of multi-small molecule-conjugated PTX prodrugs.

Notes: The direct observation methods were used in the solubility calculations for the PTX prodrugs, FA-FITC-Arg-PTX (6.45±0.15 mg/mL, n=4) and FA-5AF-Glu-PTX (6.41±0.18 mg/mL, n=4).

Abbreviations: FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.

Figure S3 Aqueous solubility of multi-small molecule-conjugated PTX prodrugs.Notes: The direct observation methods were used in the solubility calculations for the PTX prodrugs, FA-FITC-Arg-PTX (6.45±0.15 mg/mL, n=4) and FA-5AF-Glu-PTX (6.41±0.18 mg/mL, n=4).Abbreviations: FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.

Figure S4 Release of PTX from FA-FITC-Arg-PTX and FA-5AF-Glu-PTX according to incubation time in phosphate-buffered saline (pH 7.4) or human plasma at 37°C.

Notes: (A) HPLC for incubation of FA-FITC-Arg-PTX in human plasma at 37°C, showing the peak for free PTX at 4 hours. (B) HPLC for incubation of FA-5AF-Glu-PTX in human plasma, showing the peak for free PTX at 4 hours.

Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; HPLC, high-performance liquid chromatography; PTX, paclitaxel.

Figure S4 Release of PTX from FA-FITC-Arg-PTX and FA-5AF-Glu-PTX according to incubation time in phosphate-buffered saline (pH 7.4) or human plasma at 37°C.Notes: (A) HPLC for incubation of FA-FITC-Arg-PTX in human plasma at 37°C, showing the peak for free PTX at 4 hours. (B) HPLC for incubation of FA-5AF-Glu-PTX in human plasma, showing the peak for free PTX at 4 hours.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; HPLC, high-performance liquid chromatography; PTX, paclitaxel.

Figure S5 A cell viability ratio assay was used to qualitatively determine the cytotoxicity of FA-FITC-Arg and FA-5AF-Glu in a normal HEK293 cell line. (MTT assay, n=6).

Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.

Figure S5 A cell viability ratio assay was used to qualitatively determine the cytotoxicity of FA-FITC-Arg and FA-5AF-Glu in a normal HEK293 cell line. (MTT assay, n=6).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.

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