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. 2021 Sep 14:16:6281-6295.
doi: 10.2147/IJN.S326629. eCollection 2021.

TPGS-Modified Long-Circulating Liposomes Loading Ziyuglycoside I for Enhanced Therapy of Myelosuppression

Affiliations

TPGS-Modified Long-Circulating Liposomes Loading Ziyuglycoside I for Enhanced Therapy of Myelosuppression

Tingting Song et al. Int J Nanomedicine. .

Abstract

Background: Ziyuglycoside I (ZgI), an active ingredient isolated from traditional Chinese medicine Sanguisorba officinalis L, has been demonstrated to increase the leucocytes and protect hematopoietic stem cells. However, the poor solubility and a short half-life of ZgI limit its bioavailability and efficacy. The D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) has been widely used to increase the solubility, improve the encapsulation rate, and extend the half-life of drugs.

Methods: Here, we formulated the TPGS-modified long-circulating liposomes loading ZgI with a sustained drug release and enhanced therapy for myelosuppression. ZgI-TPGS-liposomes were manufactured using a thin-film hydration technique, followed by characterizations of physicochemical properties, including the particle size, zeta potential, TEM, SEM, FTIR, XRD, stability, drug loading (DL), encapsulation efficiency (EE). The in vitro and in vivo delivery efficiency were further evaluated by cellular uptake, in vitro drug release and in vivo pharmacokinetics. Finally, therapeutic effect on myelosuppression was investigated.

Results: The ZgI-TPGS-liposomes had an particle size of 97.89 ± 1.42 nm and ZP of -28.65 ± 0.16 mV. It exhibited DL of 9.06 ± 0.76% and EE of 92.34 ± 3.83%, along with excellent storage stability, cellular uptake and sustained drug release to free ZgI and liposomes without TPGS. Additionally, the TPGS modified liposomes significantly enhanced the therapeutic effect of ZgI on CTX induced myelosuppression, which can be confirmed in the apoptosis inhibition and cell viability promotion of CTX injured HSPC-1 cells. Also, the mice in vivo pharmacodynamics demonstrated that TPGS liposomes promoted ZgI increasing the numbers of leucocytes and neutrophils in myelosuppression mice induced by CTX.

Conclusion: Our research suggest that TPGS-modified long-circulating liposomes loading ziyuglycoside I has potential application in myelosuppression therapy.

Keywords: TPGS; long-circulating liposomes; myelosuppression; therapy; ziyuglycoside I.

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Conflict of interest statement

The authors report no conflicts of interest for this work.

Figures

Figure 1
Figure 1
The Sanguisorba officinalis and the molecule structure of ZiyuglycosideI.
Figure 2
Figure 2
Preparation scheme of ZgI-TPGS-liposomes.
Figure 3
Figure 3
Schematic illustration of in vivo and in vitro pharmacodynamics study of ZgI-TPGS-liposomes.
Figure 4
Figure 4
Chromatograms of ZgI in liposomes. (A) negative control (blank liposomes); (B) ZgI standard substance; (C) sample for test (ZgI-liposomes).
Figure 5
Figure 5
The preparation and characterization of ZgI-TPGS-liposomes. (A) The brief illustration of ZgI-TPGS-liposomes preparation. (B) Actual sample of ZgI-TPGS-liposomes. (C) Size distribution. (D) TEM image. (E) SEM image. (F) FTIR spectrum: (a) ZgI. (b) Physical mixture. (c) ZgI-liposomes. (d) ZgI-TPGS-liposomes. (G) XRD spectrum: (a) ZgI. (b) Physical mixture. (c) ZgI-liposomes. (d) ZgI-TPGS-liposomes.
Figure 6
Figure 6
Cellular uptake of coumarin-6-liposomes and TPGS-liposomes in RAW 264.7 cells. (A) Fluorescent images of each group. (B) Comparison of relative fluorescence intensity of each group. Data are presented as mean ± SD from five independent experiments (vs coumarin-6, *P<0.05; vs coumarin-6-lip, ΔP<0.05).
Figure 7
Figure 7
The test result of cumulative ZgI release. Data are presented as mean ± SD from three independent experiments vs ZgI, *P < 0.05, **P < 0.01; vs ZgI-liposomes, ΔP < 0.05, ΔΔP < 0.01.
Figure 8
Figure 8
Mean plasma concentration-time curves of ZgI after i.v of a single dose of 20 mg/kg of ZgI/TPGS. Picture on the top right corner was the plasma concentration-time curves for 0–4 h duration (mean ± SD, n = 6).
Figure 9
Figure 9
The in vitro study of ZgI-TPGS-liposomes protecting HSPC-1 from CTX induced injury. (A). The cytotoxicity of ZgI-TPGS-liposomes in normal HSPC-1 cells (n = 3). (B). The viability of HSPC-1 cells. (C). The apoptosis rate of HSPC-1 cells. (D). The green fluorescence of apoptosis photographed by fluorescence microscope; (E). Flow cytometric detection of HSPC-1 apoptosis: (a) Normal control group. (b)CTX group. (c) ZgI treatment group. (d) ZgI- liposomes treatment group. (e) ZgI-TPGS-liposomes treatment group.Data are presented as mean ± SD from six independent experiments (vs CXT, *P<0.05, **P<0.05; vs ZgI, ΔP < 0.05, ΔΔP < 0.01; vs ZgI-liposomes, #P < 0.05.).
Figure 10
Figure 10
The in vivo treatment of ZgI-TPGS-liposomes on CTX induced myelosuppression. (A). The body weight changes of CTX treated mice after ZgI-TPGS-liposomes treatment. (B). The leucocyte count of CTX treated mice after ZgI-TPGS-liposomes treatment. (C). The neutrophils count of CTX treated mice after ZgI-TPGS-liposomes treatment. Data are presented as mean ± SD from eight independent experiments (vs CXT, *P<0.05, **P<0.05; vs ZgI, ΔP < 0.05; vs ZgI-liposomes, #P < 0.051.).

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