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Review
. 2018 Jan 1;8(2):464-485.
doi: 10.7150/thno.22711. eCollection 2018.

Recent Advances in the Application of Vitamin E TPGS for Drug Delivery

Conglian Yang  1 , Tingting Wu  1 , Yan Qi  1 , Zhiping Zhang  1   2   3
Affiliations
Review

Recent Advances in the Application of Vitamin E TPGS for Drug Delivery

Conglian Yang et al. Theranostics. .

Abstract

D-ɑ-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) has been approved by FDA as a safe adjuvant and widely used in drug delivery systems. The biological and physicochemical properties of TPGS provide multiple advantages for its applications in drug delivery like high biocompatibility, enhancement of drug solubility, improvement of drug permeation and selective antitumor activity. Notably, TPGS can inhibit the activity of ATP dependent P-glycoprotein and act as a potent excipient for overcoming multi-drug resistance (MDR) in tumor. In this review, we aim to discuss the recent advances of TPGS in drug delivery including TPGS based prodrugs, nitric oxide donor and polymers, and unmodified TPGS based formulations. These potential applications are focused on enhancing delivery efficiency as well as the therapeutic effect of agents, especially on overcoming MDR of tumors. It also demonstrates that the clinical translation of TPGS based nanomedicines is still faced with many challenges, which requires more detailed study on TPGS properties and based delivery system in the future.

Keywords: TPGS; Vitamin E; anticancer.; drug delivery; multi-drug resistance.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Scheme of TPGS for P-gp inhibition and selective antitumor effect in drug delivery. TPGS can be easily conjugated with polymers or therapeutic agents to form TPGS based polymers or prodrugs. The resultant structure can further self-assemble into nanoparticles. Unmodified TPGS can also cooperate with other materials to form nanoformulations. After internalization by cells, the nanoparticles can be degraded in response to the specific intracellular environment (e.g. pH, GSH and ROS) to release the therapeutic agents and TPGS. Without P-gp inhibition, the drugs can be rapidly pumped out to the extracellular environment. The dissociated TPGS can bind to the mitochondrial respiratory complex II and induce mitochondrial dysfunction, resulting in the decreased mitochondrial membrane potential and increased ROS generation for cell apoptosis, and reduced ATP level for P-gp inhibition. Besides, TPGS can also inhibit the substrate induced ATPase activity to further overcome MDR. With P-gp inhibition, the intracellular accumulation of therapeutic drugs can be significantly enhanced. Meanwhile, TPGS can inhibit Bcl-2 and Survivin to promote cell apoptosis.
Figure 2
Figure 2
(A). Scheme of TPGS-CH=N-DOX prodrug hybrid micelle in “Molecular Economy” way. Left, the P-gp inhibition in MCF-7/ADR cancer cells; Right, the receptor-mediated targeting and anti-metastatic effect in B16F10. (B). Intracellular ATP level depletion effect of TD micelles. (C). Tumor inhibition effect in MCF-7/ADR tumor bearing mice. Reprinted with permission from . Copyright 2016 Elsevier.
Figure 3
Figure 3
(A). Schematic representation of combinational therapy using TSP-TN for tumor angiogenesis and self-promoted drug accumulation. (B). Representative ultrasound images with single treatment of saline or TN. (C). Tumor angiogenesis index and drug penetration index of saline or TN pretreated. (D). Tumor inhibition efficacy against MCF-7/MDR tumor. Reprinted with permission from . Copyright 2017 Elsevier.
Figure 4
Figure 4
(A). Scheme of FRET-TBH assembly in water and disassembly in 1 mM H2O2. (B). The schematic presentation of ROS-triggered and regenerating antitumor nanosystem. A: TBH self-assembling nanosystem (DOX-TBH) and endocytosis mediated by HA through the overexpressed CD44 receptors; B: the breakage of arylboronic linkers by ROS, followed by DOX-TBH rapid disassembly and released DOX and TPGS; C: By acting on mitochondrial respiratory complex II, the released TPGS induced ROS generation for complete disassembly of DOX-TBH; D: TPGS as the inhibitor of P-gp efflux to overcome MDR; E: DOX and ROS induced cell death in nucleus. (C). Scheme of folate-modified redox/pH-sensitive hybrid micelles (PTX@PST-FA) for achieving targeted delivery and overcoming MDR. (D). Antitumor effect against MCF-7/ADR tumor model by hybrid micelles. A and B reprinted with permission from . Copyright 2014 Elsevier. C and D reprinted with permission from . Copyright 2017 Royal Society of Chemistry.
Figure 5
Figure 5
(A). Fabrication of iRGD mediated PTX and Survivin shRNA co-loaded complex nanoparticles. (B). Design of tLyp-1-conjugated PLA-TPGS nanoparticles as a dual-targeting delivery system for co-delivery of DOX and Ce6. The nanoparticles were internalized by NRP-1 mediated endocytosis and penetrated into the inner areas of the tumor to combat drug resistant cancer via chemo-photodynamic combination therapy. A reprinted with permission from . Copyright 2014 American Chemical Society. B reprinted with permission from . Copyright 2015 Royal Society of Chemistry.
Figure 6
Figure 6
(A). The tumor inhibition profile of PTX nanoemulsion in MCF-7/ADR tumor. (B). Scheme of the mitochondria-targeted pH-responsive PDPA/TPGS@DOX micelles for overcoming drug resistance in MCF-7/ADR tumor. (a) Cellular uptake; (b) pH-responsive dissociation of micelles in endo/lysosome; (c) the mitochondria targeting effect of TPGS; and (d) nuclear entry of DOX. (C). Schematic representation of mitochondria targeting liposomes. (D). Drug contents in mitochondrial detected by flow cytometry after 4 h incubating A549/cDDP cells. (D1) Blank control; (D2) Free Coumarin; (D3) Coumarin liposomes; (D4) Targeting Coumarin liposomes. (E). Antitumor efficiency in A549/cDDP xenografted tumor. A reprinted with permission from . Copyright 2014 Elsevier. B reprinted with permission from . Copyright 2015 Elsevier. C, D and E reprinted with permission from . Copyright 2013 Elsevier.
Figure 7
Figure 7
(A). Scheme of the TPGS and HA dual-functionalized liposome for PTX and LND co-delivery to overcome MDR. A. Preparation of PTX&LND-HA. From top to bottom: PTX&LND-CL, PTX&LND-TPGS-L, and PTX&LND-HA. B. MDR reversal mechanism of PTX&LND-HA. I: tumor cell accumulation by the passive and active targeting effects; II: CD44-mediated internalization and HA degradation by HAase overexpressed in the tumor extracellular matrix and endo-lysosomes; III: endo-lysosomal escape of the liposome; IV: release of PTX for cytotoxicity and inhibition on P-gp efflux by TPGS; V: mitochondrial targeting of the liposome and release of LND to act on the mitochondrial function for sensitizing the MDR cancer cells to PTX. The mitochondrial targeting effect (B) and tumor volume change (C) in MCF-7/MDR cells and MCF-7/MDR tumor-bearing nude mice, respectively. Reprinted with permission from . Copyright 2015 Elsevier.
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