PEO-PPO Block Copolymers for Passive Micellar Targeting and Overcoming Multidrug Resistance in Cancer Therapy

Abstract

Drug carriers tailored to fit the physicochemical properties of anticancer agents and the therapeutic peculiarities of tumor management are envisioned for improving the effectiveness/toxicity ratio of the current treatments. Polymeric micelles are attracting much attention owing to their unique beneficial features: i) core-shell structure capable to host hydrophobic drugs, raising the apparent solubility in aqueous medium; ii) size adequate for a preferential accumulation (passive targeting) within the tumor, exhibiting enhanced permeability and retention (EPR effect), and iii) unimers that modulate the activity of efflux pumps involved in multidrug resistance (MDR). This review focuses on amphiphilic poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) block copolymers, namely the linear poloxamers (Pluronic® or Lutrol®) and the X-shaped poloxamines (Tetronic®), as components of polymeric micelles able to play these three roles. Specific facets of poloxamers have been highlighted some years ago, but recently their wide range of possibilities is beginning to be fully elucidated and understood. Poloxamines are new excipients in the cancer arena and the comparison of their performance with that of poloxamers may enable to identify aspects of their architecture relevant for the optimization of micellar carriers. Clinical trials in progress indicate that drug-loaded polymeric micelles are beneficial regarding efficiency, safety, and compliance of the treatment and quality of life of the patients. The fact that some copolymers are already approved for internal use and several chemotherapy agents will be off patent soon may help to bring the clinical use of poloxamer- or poloxamine-based micelles into a reality in the coming years.

Polymeric mixed micelles loaded mitoxantrone for overcoming multidrug resistance in breast cancer via photodynamic therapy

“…13,14 In our previous study, a mixed micelle system, formed by poly(ε-caprolactone)-pluronic F68-poly(ε-caprolactone) (PFP) and poly(d,l-lactide-co-glycolide)-poly(ethylene glycol)-poly (d,l-lactide-co-glycolide) (PPP), has been designed to efficiently deliver the anticancer agent MIT, while reversing MDR in breast cancer. 15 As mentioned above, the application of PDT could reverse the MDR effect in cancer cells.…”

Peptides and proteins used to enhance gold nanoparticle delivery to the brain: preclinical approaches

“…83,84 In addition, RMT mechanisms allow for the delivery of particles, such as transferrin and insulin receptors, to the brain. 85,86 As discussed by Kreuter 87 other mechanisms for nanoparticles to cross the BBB under physiological conditions can include the inhibition of the P-gp efflux system using polysorbate 80 or pluronic acids, 88 the increased retention of nanoparticles in the BBB capillaries combined with adsorption on the capillary walls, the presence of a surfactant that fluidizes the membrane, the temporal opening of tight junctions between the brain blood vessel endothelial cells, a general toxic effect in the BBB, or the combination of all of these mechanisms. 87 …”

Micelas poliméricas para encapsulación, vectorización y cesión de fármacos

“…Sin embargo, y a pesar de sus aplicaciones potenciales en el desarrollo de medicamentos innovadores, todavía son escasamente utilizadas y sólo unos pocos productos han alcanzado las etapas clínicas avanzadas [31]. Este capítulo se inicia con la descripción de los aspectos fundamentales de producción y caracterización de micelas poliméricas, señalando sus principales ventajas e inconvenientes.…”

“…Además, el pequeño tamaño de las micelas poliméricas determina que se acumulen en tumores altamente vascularizados por el efecto EPR (vectorización pasiva) [31]. La superficie de la micela se puede "decorar" con ligandos con el fin de que puedan ser reconocidas por receptores celulares específicos y captadas selectivamente por células concretas.…”

“…Actualmente existen seis medicamentos a base de micelas poliméricas comercializados o en fases avanzadas de evaluación clínica, todos ellos para el tratamiento del cáncer por vía intravenosa [31]. La mayor parte de estos medicamentos explotan el efecto EPR, aunque las micelas poliméricas cumplen también la función de incrementar la solubilidad de fármacos pobremente solubles, como paclitaxel, o de inhibir la actividad de la ABC glicoproteína P para evitar o revertir MDR.…”