Vitamin E TPGS-Based Nanomedicine, Nanotheranostics, and Targeted Drug Delivery: Past, Present, and Future

It has been seventy years since a water-soluble version of vitamin E called tocophersolan (also known as TPGS) was produced; it was approved by USFDA in 1998 as an inactive ingredient. Drug formulation developers were initially intrigued by its surfactant qualities, and gradually it made its way into the toolkit of pharmaceutical drug delivery. Since then, four drugs with TPGS in their formulation have been approved for sale in the United States and Europe including ibuprofen, tipranavir, amprenavir, and tocophersolan. Improvement and implementation of novel diagnostic and therapeutic techniques for disease are goals of nanomedicine and the succeeding field of nanotheranostics.

Specifically, imaging and treating tumors with nanohybrid theranostics shows promising potential. Docetaxel, paclitaxel, and doxorubicin are examples of poorly bioavailable therapeutic agents; hence, much effort is applied for developing TPGS-based nanomedicine, nanotheranostics, and targeted drug delivery systems to increase circulation time and promote the reticular endothelial escape of these drug delivery systems. TPGS has been used in a number of ways for improving drug solubility, bioavailability improvement, and prevention of drug efflux from the targeted cells, which makes it an excellent candidate for therapeutic delivery.

Through the downregulation of P-gp expression and modulation of efflux pump activity, TPGS can also mitigate multidrug resistance (MDR). Novel materials such as TPGS-based copolymers are being studied for their potential use in various diseases. In recent clinical trials, TPGS has been utilized in a huge number of Phase I, II, and III studies. Additionally, numerous TPGS-based nanomedicine and nanotheranostic applications are reported in the literature which are in their preclinical stage. However, various randomized or human clinical trials have been underway for TPGS-based drug delivery systems for multiple diseases such as pneumonia, malaria, ocular disease, keratoconus, etc. In this review, we have emphasized in detail the review of the nanotheranostics and targeted drug delivery approaches premised on TPGS. In addition, we have covered various therapeutic systems involving TPGS and its analogs with special references to its patent and clinical trials.

1. Introduction

Nanotechnology for the specific imaging and treatment of various illnesses, including cancer, has recently made extensive use of vitamin E TPGS or TPGS [1]. TPGS has been recognized by the FDA as a safe pharmaceutical excipient with the added advantages of its excellent biocompatibility, enhanced drug solubilization, and selectively improved permeability of the anticancer drug across tumor cells [2]. TPGS has demonstrated its key role in inhibiting ATP dependent P-glycoprotein and hence overcoming multidrug resistance during cancer therapy [3]. Combining nanotechnology with TPGS creates a solid foundation for the study and advancement of targeted nanomedicine and nanotheranostics, both of which have great promise for enhancing cancer diagnosis and treatment [4,5]. The nanotheranostics platform with integrated TPGS has depicted promising outcomes in preclinical studies along with enhanced solubility and stability of the loaded drug and diagnostic agents. Numerous studies have suggested that TPGS can avert tumor invasion and metastasis; however, their underlying mechanism remains unexplored [6]. Additionally, the immunological aspects of TPGS require rigorous investigation to develop safe and effective theranostic nanomedicine without any immunological side effects.

Currently developed TPGS-based targeted nanomedicine and nanotheranostics are still at the laboratory scale with limited preclinical evaluation; however, progress in developing advanced nanotheranostics remains comparatively slow, hindering its translation into clinical practices [7]. It can be accelerated by optimizing the industrial scale-up process and selecting competent models to eliminate the physiological variation between animals and humans. Further, advancement in nanotheranostics provides a disease prognosis with personalized therapy that enables fatal diseases to be curable or at least treatable at the primary stage [6]. TPGS is a vitamin E derivative that can dissolve in water, and its developmental history goes back 70 years. Its surfactant features caught the attention of drug formulation designers, and it gradually made its way into the toolbox of pharmaceutical drug delivery innovators. Recently, in a study, Liu et al. developed Soluplus^® and TPGS-based novel polymeric formulation of curcumin for enhancing its cellular uptake and permeability across the cellular membrane. Additionally, in vitro studies demonstrated that TPGS has successfully improved the water solubility of curcumin and increased its cellular permeability across Caco-2 cells [8]. It was noted that TPGS has antineoplastic action towards breast cancer cells by downregulation of the anti-apoptotic proteins [9].

The surfactant property of the TPGS enables its application in a wide variety of formulation development, including the development of PLGA nanoparticles for DNA labeling, provides uniformly sized nanoparticles with high drug loading, improves their hydrophilicity, and suppresses their tendency to aggregate [10]. Additionally, vitamin E or tocopherols are organic compounds preferentially soluble in lipids with antioxidant properties. Apart from drug delivery, in a recent study, Bi et al. explored incorporation of TPGS in a film of the chitosan along with silicon dioxide nanoparticles, which significantly improved the antioxidant and antimicrobial properties of chitosan film for the packaging [11]. TPGS has been widely used to prepare biocompatible polymer conjugates for drug delivery and targeting [12]. Drug delivery systems for a wide range of ailments, including cancer, tuberculosis, ophthalmic diseases, inflammatory diseases, etc., have been developed using TPGS, demonstrating the technology’s value [13].

The term “theranostics” describes the practice of combining diagnosis and treatment at the same time [14,15,16]. One of the main goals of nanomedicine methods for advanced theranostics is to use and develop nanocarriers like micelles, liposomes, polymeric nanomaterials, quantum dots, etc. The goal is to detect and treat diseases while they are still relatively easy to treat or perhaps completely reverse them if caught early enough. Even for deadly diseases like cancer, cardiovascular disease, and AIDS, nanodiagnostics show promise, offering the possibility of making treatment considerably less bothersome and the prognosis better, reducing healthcare costs, and improving patients’ quality of life [17]. Nanomedicine, for medical purposes, has the potential to be an effective tool in the creation of theranostic candidates, which can be used to diagnose and treat diseases at the same time [18]. Perhaps the most cutting-edge advancement in nanomedicine, the search for combined therapeutic and diagnostic qualities in a single delivery platform is driving the discipline of nanotheranostics. Resveratrol is widely present in grapes and red wine and has been found to have antioxidant and anticancer properties.

Although resveratrol’s oral absorption is about 75%, its bioavailability falls below 1% due to its extensive metabolism in the liver and intestine. To overcome such problems, a TPGS and poly-lactide (PLA)-based drug delivery system has been developed for resveratrol [19]. The advanced field of nanomedicine with diagnostic and therapeutic qualities integrated into a single platform is known as nanotheranostics [20]. To transfer several capabilities to a single delivery platform, nanodiagnostics is commonly created using complicated synthetic procedures. To enhance the permeability and retention (EPR) effect and permit the passive accumulation of particles in diseased tissue, nanotheranostics typically employ surface modifications [21].

However, the “responsiveness” of the carriers to external stimulation can provide further selectivity for the diseased area that can be used in nanotheranostics testing. This “activation trigger” is applied non-invasively and remotely to the target location [22]. The vast majority of carriers used for diagnostic or therapeutic purposes are always “on”, with detection and payload release beginning at the point of delivery. Alternatively, carriers having “off–on” theranostic qualities can be designed, which can provide individual assessment of medication delivery to the diseased tissue. Therefore, there may be new opportunities for adjusting the dosage and frequency of treatments made possible by responsive nanotheranostics [23,24]. Under these conditions, it appears difficult to further expand the complexity of these technologies. Numerous current theranostics allow for multimodal imaging and therapy, which improves both diagnostic precision and therapeutic efficacy. However, recent developments in nanomedicine are focusing on making carriers that can adapt to their biological surroundings. In other words, in vivo nanotheranostics can be “triggered” by the physiological changes that distinguish diseased from healthy tissue [25]. These ideas also demonstrate promise for enhancing standard experimental methods.

Background noise difficulties associated with imaging of fluorescently modified carriers, for instance, could be alleviated by using nano theranostics that, in accordance with very specific biological inputs, can improve their detection signal [26]. In a recent study, Jasim et al. reviewed the pharmaceutical applications of TPGS, including its surfactant property, synergistic anticancer activity, and induction of programmed cell death in cancer cells. Additionally, they discussed TPGS based prodrugs and their drug delivery systems but were not limited to enhancement of oral bioavailability of the drugs [27]. In this review, we have covered the various developments in the field of TPGS-based drug delivery systems from the past to the present. Additionally, we have discussed novel properties of TPGS, cellular and molecular mechanisms, TPGS-based multifunctional co-polymeric nanomedicine, nanotheranostics, and their chemical modification and conjugation with drugs for improving and advancing the therapeutic properties of the loaded therapeutic agents. Further, we have briefly discussed the pharmacokinetic and the safety assessment of TPGS to be used as suitable carriers for drug delivery but not limited to their role in the enhancement of the diagnostic and therapeutic properties of TPGS-based nanotheranostics systems. Finally, we have limited our discussion to clinical trials, regulatory status, and TPGS-based marketed formulations for numerous diseases.

Download the full review as PDF here: Vitamin E TPGS-Based Nanomedicine, Nanotheranostics, and Targeted Drug Delivery: Past, Present, and Future

or read it here

Mehata, A.K.; Setia, A.; Vikas; Malik, A.K.; Hassani, R.; Dailah, H.G.; Alhazmi, H.A.; Albarraq, A.A.; Mohan, S.; Muthu, M.S. Vitamin E TPGS-Based Nanomedicine, Nanotheranostics, and Targeted Drug Delivery: Past, Present, and Future. Pharmaceutics 2023, 15, 722.
https://doi.org/10.3390/pharmaceutics15030722

excipients formulation