Docetaxel-Loaded Nanoparticles Assembled from β-Cyclodextrin/Calixarene Giant Surfactants: Physicochemical Properties and Cytotoxic Effect in Prostate Cancer and Glioblastoma Cells

Abstract

Giant amphiphiles encompassing a hydrophilic β-cyclodextrin (βCD) component and a hydrophobic calix[4]arene (CA4) module undergo self-assembly in aqueous media to afford core-shell nanospheres or nanocapsules, depending on the nanoprecipitation protocol, with high docetaxel (DTX) loading capacity. The blank and loaded nanoparticles have been fully characterized by dynamic light scattering (DLS), ζ-potential measurements and cryo-transmission electron microscopy (cryo-TEM). The data are compatible with the distribution of the drug between the nanoparticle core and the shell, where it is probably anchored by inclusion of the DTX aromatic moieties in βCD cavities. Indeed, the release kinetics profiles evidenced an initial fast release of the drug, which likely accounts for the fraction hosted on the surface, followed by a slow and sustained release rate, corresponding to diffusion of DTX in the core, which can be finely tuned by modification of the giant amphiphile chemical structure. The ability of the docetaxel-loaded nanoparticles to induce cellular death in different prostate (human LnCap and PC3) and glioblastoma (human U87 and rat C6) cells was also explored. Giant amphiphile-based DTX formulations surpassing or matching the antitumoral activity of the free DTX formulation were identified in all cases with no need to employ any organic co-solvent, thus overcoming the DTX water solubility problems. Moreover, the presence of the βCD shell at the surface of the assemblies is intended to impart stealth properties against serum proteins while permitting nanoparticle surface decoration by supramolecular approaches, paving the way for a new generation of molecularly well-defined antitumoral drug delivery systems with improved specificity and efficiency. Altogether, the results provide a proof of concept of the suitability of the approach based on βCD-CA4 giant amphiphiles to access DTX carriers with tunable properties.

Cyclodextrin Based Nanoparticles for Drug Delivery and Theranostics

“…106 Docetaxel-loaded NPs assembled from β-CD/calixarene giant surfactants shows initial burst release followed by longer drug release for about 30 to 60 hours. 107 Insert therapeutics-101, a linear CD-containing polymer conjugate of CPT formulated in NPs is under clinical trial showing prolonged release. 108 Docetaxel loaded in heptakis (2-O-oligo (ethyleneoxide)-6hexadecylthio-)-beta-CD has shown slow release allowing prolonged cell arrest in mitosis.…”

<p>Targeted Treatment of Colon Cancer with Aptamer-Guided Albumin Nanoparticles Loaded with Docetaxel</p>

“…Sustained release of drug from NP influences pharmacokinetics and therapeutic efficacy. 36 The drug release profiles from NPs-DTX or Apt-NPs-DTX were evaluated using a dialysis bag with cutoff limit of 1000 Da. As shown in Figure 2 , NP-encapsulated DTX was released relatively slowly, and there was no obvious difference in release profile between Apt-NPs-DTX and NPs-DTX.…”

Multivalent and Multifunctional Calixarenes in Bionanotechnology

“…Compared to other multivalent scaffolds, calixarenes offer the possibility to shape the size, the valency and the stereochemical disposition in the space of the multiple ligating units. Moreover, the introduction of proper aliphatic chains and the presence itself of the lipophilic aromatic external walls of the macrocycle ensure the possibility to tune the amphiphilic character of the multivalent ligand [115] so that they can be noncovalently included in the lipophilic monolayers of nanoparticles [71] and nanocapsules [116] or in the double layers of liposomes [70,117] to address specific biological targets. Playing with this palette of instruments, organic chemists might design proper systems, based on calixarenes, able to interact with proteins, nucleic acids or even biomacromolecules present on the surface of cells/bacteria/viruses.…”