Delivery of P-glycoprotein substrates using chemosensitizers and nanotechnology for selective and efficient therapeutic outcomes

Abstract

As a result of its broad substrate specificity and critical localization in excretory and barrier function tissues, P-glycoprotein (P-gp) plays major roles in the pharmacokinetics, safety and efficacy profiles of numerous drugs. P-gp is often responsible for the failure of many chemical treatments against cancer, immunosuppressive, infectious and neurodegenerative diseases. Among the therapeutic approaches to circumvent P-gp function, advances in the design of new chemical P-gp modulators to interact specifically with P-gp have yielded few clinical successful reports. Members of a class of components that were initially developed as surface active agents showed promising results with regard to the modulation of P-gp. These components include surfactants and amphiphilic co-polymers. Alternatively, colloidal systems were developed to facilitate drug uptake in resistant cells. This approach is based on the encapsulation of drugs, which masks them from the biological environment and prevents their transport by P-gp using the surfactants released from the nanocarrier. Likewise, a novel and synergistic strategy is currently being explored and involves nanocarrier-mediated transport and controlled release of both P-gp substrates and P-gp modulators. In this review, we discuss recent results obtained by direct modulation with chemosensitizers and the available nanotechnology to modulate P-gp function. In this manuscript, we also discuss unexplored pathways for future therapies.

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.