Micelas poliméricas carreadoras de paclitaxel: potencial nanoplataforma teranóstica anticancer

Abstract

Polymeric micelles (PM) are nanostructured carriers used in the delivery of hydrophobic drugs and/or imaging agents to solid tumors by passive targeting, enabling an anti-cancer theranostic platform. From this, our research group developed a 99mTc- radiolabeled PM carrying PTX (PM-DTPA-99mTc/PTX), which showed high tumor uptake in a murine breast tumor model, being a promising strategy for improving cancer treatment and diagnosis. In this context, the purpose of this study was to evaluate the structural organization of this nanosystem, to propose a strategy to increase its stability and to conduct preclinical studies to evaluate toxicity and antitumor activity of PM carrying PTX (PM/PTX). The structural evaluation performed by SAXS showed that the drug leads to an increase in the micelle core radius, which was compensated by a reduction of the PEG radius (RPEG) and resulted in no change in PM diameter. These radius variations were proportional to the PTX concentration to a maximum close to 0.6 mg/mL. Possibly, the reduction in RPEG is due to the change in brush-to-mushroom conformation of this polymer and was reflected in in vivo blood clearance studies that showed a longer circulation time for blank PM compared to PM/PTX. A radiopharmaceutical lyophilized kit for reconstitution with Na99mTcO4 was developed and its storage stability was evaluated. No changes in physicochemical (diameter, zeta potential, PTX content) or biological (biodistribution profile and accumulation in the tumor region) parameters after 180 days of storage were observed. In vitro cell uptake studies showed that PM had greater ability (5.8%) in delivery PTX to 4T1 cells after 2 hours of incubation when compared to cremophor-prepared PTX (CrEL/EtOH/PTX) (2.7%). In the in vivo toxicity studies, after receiving PM/PTX in single or repeated doses (7 doses) mice did not show signs of peripheral neuropathy, which was observed in the CrEL/EtOH/PTX group. In addition, PM/PTX presented higher antitumor activity, with a tumor inhibition ratio 50% higher than CrEL/EtOH/PTX. Data from this study suggest the potentiality of PM as an effective and safe delivery system for PTX and 99mTc for solid tumors.