T908 Polymeric Micelles Improved the Uptake of Sgc8-c Aptamer Probe in Tumor-Bearing Mice: A Co-Association Study between the Probe and Preformed Nanostructures.

Romina Castelli,Manuel Ibarra,Ricardo Faccio,Albertina Moglioni,Pablo Cabral,Romina J Glisoni,Victoria Calzada,Hugo Cerecetto,Marcelo Fernández,Iris Miraballes

doi:10.3390/ph15010015

Romina Castelli, Manuel Ibarra + Show 8 more

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https://doi.org/10.3390/ph15010015

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Aptamers are oligonucleotides that have the characteristic of recognizing a target with high affinity and specificity. Based on our previous studies, the aptamer probe Sgc8-c-Alexa647 is a promising tool for molecular imaging of PTK7, which is an interesting biomarker in cancer. In order to improve the delivery of this probe as well as create a novel drug delivery nanosystem targeted to the PTK7 receptor, we evaluate the co-association between the probe and preformed nanostructures. In this work, preformed pegylated liposomes (PPL) and linear and branched pristine polymeric micelles (PMs), based on PEO–PPO–PEO triblock copolymers were used: poloxamer F127® and poloxamines T1307® and T908®. For it, Sgc8-c-Alexa647 and its co-association with the different nanostructures was exhaustively analyzed. DLS analysis showed nanometric sizes, and TEM and AFM showed notable differences between free- and co-associated probe. Likewise, all nanosystems were evaluated on A20 lymphoma cell line overexpressing PTK7, and the confocal microscopy images showed distinctness in cellular uptake. Finally, the biodistribution in BALB/c mice bearing lymphoma-tumor and pharmacokinetic study revealed an encouraging profile for T908-probe. All data obtained from this work suggested that PMs and, more specifically T908 ones, are good candidates to improve the pharmacokinetics and the tumor uptake of aptamer-based probes.

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The novel probe (Sgc8c-Alexa647, Figure S1A) with high affinity to the PTK7 receptor has the following in its structure: (i) a principal domain with hydrophobic characteristics from the fluorophore-portion Alexa647 and (ii) a purely hydrophilic domain from the main oligonucleotide structure; in this work, we propose to exhaustively investigate its co-association with two structurally different types of nanostructures
polymeric micelles (PMs) would increase its in vivo mean residence time (MRT) and favor the accumulation into tumors due to the enhanced permeation and retention effect (EPR effect) and the cellular uptake by the active targeting through the PTK7 receptor overexpressed on lymphoma tumors
To further study the existence of probe non-co-associated to the nanosystems, we proceeded to evaluate after the appropriate incubation, the elution of preformed pegylated liposomes (PPL)-probe (50 μg/mL)

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Introduction

Single-strain oligonucleotides that can bind a wide range of ligands with high affinity and specificity [1]. The dissociation constant (Kd) for aptamer–target complexes is in the high pico-molar to low nano-molar range [2,3]. Aptamers can be selected against proteins, peptides, dyes, metal ions, viruses, bacteria, toxins, and whole cells, even against non-immunogenic molecules. Aptamers are similar to antibodies; aptamers have an ease of synthesis and easy chemical modification that allows conjugation with a variety of molecules and stability at a higher

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