ReviewDelivery of P-glycoprotein substrates using chemosensitizers and nanotechnology for selective and efficient therapeutic outcomes
Graphical abstract
Introduction
Over the last several years, a large body of literature has confirmed that drug efflux transporters play prominent roles in the pharmacological behavior of most clinically used drugs, thereby affecting drug absorption, disposition and elimination. Often this efflux of therapeutic compounds is mediated by the family of ATP-binding cassette (ABC) transporters. Among the ABC transporters, P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP) play significant roles in restricting the permeability of several pharmacological agents, including anti-cancer and anti-HIV agents [1], [2].
Because P-gp was the first member of the ABC transporter family to be described [3], it is currently the most recognized efflux protein. Two factors make P-gp the most critical efflux transporter: (1) its broad substrate specificity eliciting multidrug resistance (MDR) [4] and (2) the prominent presence of P-gp in most excretory and barrier function tissues [2]. As a result of these aspects, P-gp is a major obstacle for the treatment of cancer and several brain disorders, as well as immunosuppressive and infectious diseases.
Screening studies to identify P-gp substrates indicated that some of the substrates also have the ability to block P-gp efflux, which led to a new strategy to identify successful therapeutic treatments. Unfortunately, the association of these compounds, known as first- and second-generation P-gp modulators, with cytotoxic drugs failed in clinical trials due to toxic profiles. These limitations prompted the development of third-generation P-gp modulators that specifically and potently inhibit P-gp function without interfering with other ABC transporters [5].
In addition, members of a diverse group of structurally and functionally excipients, such as surfactants and amphiphilic polymers, which are used for the preparation of drug delivery systems (DDSs), have clearly demonstrated their abilities to modulate the P-gp-mediated efflux mechanisms [6], [7]. DDSs, also known as nanocarriers, range in size from 1 to 200 nm, thus allowing parenteral administration. Their major advantages reside in their ability to mask drugs from the host environment, especially the reticuloendothelial system and in the recognition of target tissues by passive or active pathways. A few promising DDSs, such as doxorubicin-loaded pluronic® micelles (SP1049C), were tested in clinical trials. This micellar nanocarrier has shown promising results in terms of efficiency and safety in a phase II clinical trial in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction [8].
To ensure selective delivery of P-gp substrates and P-gp modulators, a relevant strategy would be to utilize nanocarriers to target both compound types to cells affected by the disease and thereby improving the therapeutic effectiveness and safety profile
The present review is focused on the emerging strategies to modulate P-gp function. The main results and obstacles obtained by direct modulation of chemosensitizers will be described. We will also outline the characteristics of pharmaceutical excipients, with a focus on the most sophisticated DDSs. Modulation of P-gp is becoming a high imperative for the research medical community and the pharmaceutical industry. Thus, this manuscript will highlight a novel and synergistic strategy that engages the association of chemosensitizers and DDSs to provide unexplored pathways for selective and efficient therapeutic outcomes.
Section snippets
Role of P-glycoprotein in efflux mechanisms
The discovery of efflux transporters has helped to explain why the minimal effective concentrations of certain drugs are not attained and why chemotherapy and the treatment of several brain disorders, immunosuppressive and infectious diseases fail. This mechanism is mediated by a large list of efflux transporters, most of which belong to the ABC transporter family [2], [9].
ABC transporters are transmembrane proteins that use ATP hydrolysis to drive the efflux of endogenous substrates and also
Therapeutic approaches using P-gp modulators
The modulation of P-gp is complex and involves competition at the P-gp substrate-binding sites, as well as the blockage of the ATP hydrolysis necessary for efflux transport function [37]. Over the last two decades, several P-gp modulators have been thoroughly studied to achieve effective inhibition of P-gp with the fewest possible interactions. Early in the 1980s, the calcium channel blocker verapamil was recognized for its ability to module P-gp efflux activity [38]. This property was quickly
Therapeutic approaches with drug-loaded nanocarriers
Many studies emphasize the promising potential of nanocarriers to overcome drug efflux mechanisms [7]. These colloidal systems include polymeric micelles [91], nanoparticles (NPs) [92], lipid nanocapsules (LNCs) [93], liposomes [94] and microemulsions [95]. These DDSs have many advantages. First, they promote the partial solubilization of hydrophobic drugs. Second, the presence of high molecular weight hydrophilic polymers, including polyethylene glycol (PEG) or dextran, on the surface confers
Synergistic combination of P-gp modulators with nanocarriers
As previously discussed, DDSs may overcome MDR in many tumor types. However, effective therapeutic P-gp modulation is often limited to cells with high resistance levels [128]. Additionally, some nanocarriers that allow high drug loading can exhibit a reduced ability to modulate P-gp due to the type of surfactant used, the surfactant concentration and the amount of anchorage on the surface. Thus, an alternative approach is to associate nanocarriers with chemosensitizers to benefit from both of
Conclusion
In spite of exponential improvements and progress with the various strategies to circumvent P-gp, the efficacy and safety of these strategies in clinical trials are still a challenge for drug development programs. The attainment of the ideal modulator is not yet a reality. Although third-generation modulators have demonstrated high selectivity and efficacy in preclinical studies, the clinical trial results were more conflicting. The poor solubility of chemosensitizers and sometimes their short
Acknowledgments
The authors gratefully thank the region of Franche-Comté for financial support.
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