narrative_review·ophthalmology, oncology, pharmacology, nanomedicine, drug delivery·PMC10054265
Vitamin E TPGS-Based Nanomedicine, Nanotheranostics, and Targeted Drug Delivery: Past, Present, and Future
Pharmaceutics · 10 authors, 8 centres
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This comprehensive review details the history, properties, and applications of vitamin E TPGS in nanomedicine and nanotheranostics, highlighting its role as a safe FDA-approved excipient that enhances drug solubility, inhibits P-glycoprotein to overcome multidrug resistance, and enables targeted delivery for cancer and other diseases. The paper summarizes preclinical and clinical evidence showing TPGS-based formulations improve pharmacokinetics, cytotoxicity, and imaging capabilities, though translation to clinical practice remains limited. The clinical significance lies in TPGS's potential to improve therapeutic outcomes for cancer, ophthalmic, and infectious diseases by combining diagnosis and treatment in a single nanoplatform.
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**Background:** Vitamin E TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate) is an FDA-approved, water-soluble derivative of natural vitamin E with amphiphilic properties (HLB value of 13). It functions as a nonionic surfactant, solubilizer, emulsifier, and permeation enhancer. Critically, TPGS inhibits ATP-dependent P-glycoprotein (P-gp) efflux pumps, thereby overcoming multidrug resistance (MDR) in cancer therapy. This review covers the historical development, chemical modifications, pharmacokinetics, safety, and applications of TPGS in nanomedicine and nanotheranostics, including its use in micelles, liposomes, polymeric nanoparticles, quantum dots, and other platforms for simultaneous diagnosis and treatment.
**Methods:** The authors conducted a narrative review of the literature, summarizing historical milestones (from 1950 invention to FDA approval in 1998 and first marketed formulation in 1999), TPGS characteristics (CMC 0.02 wt%, melting point 37°C, viscosity 400 cps at 50°C), and its role in solubilization (e.g., increasing amprenavir solubility from 36 µg/mL to 720 µg/mL; paclitaxel from 1.34 µg/mL to 50 µg/mL). They reviewed pharmacokinetic data from rat studies (LD50 >7 g/kg; elimination half-life ~11 h; volume of distribution high; bioavailability after oral administration very low; rapid hydrolysis to PEG1000 by carboxyl esterase 1). The review also covers chemical modifications (TPGS-COOH, TPGS-SH, TPGS-NH2) and drug–TPGS conjugates (doxorubicin, paclitaxel, cisplatin). Preclinical studies of TPGS-based nanomedicines are summarized, including in vitro cytotoxicity (IC50 values), cellular uptake, and in vivo pharmacokinetic and biodistribution data. Clinical trials and patents are listed.
**Key Results:** TPGS-based formulations significantly improve drug solubility, stability, and cellular permeability. For example, doxorubicin–TPGS conjugate showed 1.5-fold lower IC50 than free doxorubicin in MCF-7 cells, 4.5-fold higher half-life, and 24-fold higher AUC in rats. TPGS–paclitaxel conjugate exhibited improved cytotoxicity in paclitaxel-resistant A2780/T cells and longer half-life with increased AUC in vivo. TPGS–cisplatin conjugate reduced IC50 by ~3-fold in HepG2 cells. In micellar formulations, TPGS–docetaxel micelles (12–14 nm) showed IC50 values 53–67% lower than Taxotere in C6 glioma cells. Transferrin-targeted TPGS micelles were 15.31- to 71.73-fold more potent than Taxotere in MDA-MB-231-luc cells. TPGS-coated liposomes (126–191 nm) had IC50 of 5.93 µg/mL vs. 37.04 µg/mL for Taxotere in C6 cells. Trastuzumab-targeted TPGS-chitosan nanoparticles showed IC50 223-fold lower than Docel in SK-BR-3 cells. In vivo, targeted TPGS formulations improved AUC by 2.82- to 4.10-fold and half-life by 3.48- to 5.94-fold compared to commercial formulations. TPGS also enhanced imaging: gold nanocluster-loaded TPGS micelles accumulated 18- to 42-fold more in tumors than free AuNC. TPGS-Cu3BiS3 nanocrystals enabled CT and photoacoustic imaging and improved radiotherapy. TPGS-based nanorods (Ts-TPGS/Cap/TIG) overcame tigecycline-resistant Klebsiella pneumoniae in a pneumonia model, reducing 18FDG uptake on PET-CT. Clinical trials include riboflavin-TPGS for corneal cross-linking (NCT05019768) and Coqun (CQ10 + TPGS) for pseudo-exfoliative glaucoma, which reduced aqueous humor superoxide dismutase levels.
**Clinical Implications:** TPGS is a versatile, safe excipient that enhances drug delivery by improving solubility, inhibiting P-gp-mediated MDR, and enabling targeted theranostics. Its use in marketed products (e.g., Agenerase, Vedrop) and numerous clinical trials supports its translational potential. However, most TPGS-based nanotheranostics remain at the preclinical stage, with challenges in industrial scale-up and physiological variation between animal models and humans. Future directions include optimizing formulations for personalized therapy, advancing responsive nanocarriers, and rigorous immunological safety assessment. TPGS holds promise for treating cancer, ophthalmic diseases, tuberculosis, inflammatory conditions, and neurodegenerative disorders.