Drug resistance and toxicity constitute challenging hurdles for cancer therapy. The application of nanotechnology for anticancer drug delivery is expected to address these issues and bring new hope ...for cancer treatment. In this context, we established an original nanomicellar drug delivery system based on an amphiphilic dendrimer (AmDM), which could generate supramolecular micelles to effectively encapsulate the anticancer drug doxorubicin (DOX) with high drug-loading capacity (>40%), thanks to the unique dendritic structure creating large void space for drug accommodation. The resulting AmDM/DOX nanomicelles were able to enhance drug potency and combat doxorubicin resistance in breast cancer models by significantly enhancing cellular uptake while considerably decreasing efflux of the drug. In addition, the AmDM/DOX nanoparticles abolished significantly the toxicity related to the free drug. Collectively, our studies demonstrate that the drug delivery system based on nanomicelles formed with the self-assembling amphiphilic dendrimer constitutes a promising and effective drug carrier in cancer therapy.
Significance Nanotechnology-based drug delivery is expected to bring new hope for cancer treatment by enhancing anticancer drug efficacy, overcoming drug resistance, and reducing drug toxicity. In this respect, we developed an innovative drug delivery system based on a self-assembling amphiphilic dendrimer, which can generate supramolecular nanomicelles with large void space in their core to encapsulate anticancer drugs with high loading capacity. The resulting drug-encapsulated nanomicelles can effectively enhance drug potency and combat drug resistance by promoting cellular uptake and decreasing efflux of the anticancer drug. Moreover, this drug delivery system can significantly reduce the systemic toxicity of the free drug. The present study illustrates a successful example of how advances in dendrimer nanotechnology can be advantageously implemented to foster therapeutic perspectives.
The ligand shell (LS) determines a number of nanoparticles' properties. Nanoparticles' cores can be accurately characterized; yet the structure of the LS, when composed of mixture of molecules, can ...be described only qualitatively (e.g., patchy, Janus, and random). Here we show that quantitative description of the LS' morphology of monodisperse nanoparticles can be obtained using small-angle neutron scattering (SANS), measured at multiple contrasts, achieved by either ligand or solvent deuteration. Three-dimensional models of the nanoparticles' core and LS are generated using an ab initio reconstruction method. Characteristic length scales extracted from the models are compared with simulations. We also characterize the evolution of the LS upon thermal annealing, and investigate the LS morphology of mixed-ligand copper and silver nanoparticles as well as gold nanoparticles coated with ternary mixtures. Our results suggest that SANS combined with multiphase modeling is a versatile approach for the characterization of nanoparticles' LS.
Design and preparation of functional nanomaterials with specific properties requires precise control over their microscopic structure. A prototypical example is the self-assembly of diblock ...copolymers, which generate highly ordered structures controlled by three parameters: the chemical incompatibility between blocks, block size ratio and chain length. Recent advances in polymer synthesis have allowed for the preparation of gradient copolymers with controlled sequence chemistry, thus providing additional parameters to tailor their assembly. These are polydisperse monomer sequence, block size distribution and gradient strength. Here, we employ dissipative particle dynamics to describe the self-assembly of gradient copolymer melts with strong, intermediate, and weak gradient strength and compare their phase behavior to that of corresponding diblock copolymers. Gradient melts behave similarly when copolymers with a strong gradient are considered. Decreasing the gradient strength leads to the widening of the gyroid phase window, at the expense of cylindrical domains, and a remarkable extension of the lamellar phase. Finally, we show that weak gradient strength enhances chain packing in gyroid structures much more than in lamellar and cylindrical morphologies. Importantly, this work also provides a link between gradient copolymers morphology and parameters such as chemical incompatibility, chain length and monomer sequence as support for the rational design of these nanomaterials.
Self‐assembly is a fundamental concept and a powerful approach in molecular science. However, creating functional materials with the desired properties through self‐assembly remains challenging. In ...this work, through a combination of experimental and computational approaches, the self‐assembly of small amphiphilic dendrons into nanosized supramolecular dendrimer micelles with a degree of structural definition similar to traditional covalent high‐generation dendrimers is reported. It is demonstrated that, with the optimal balance of hydrophobicity and hydrophilicity, one of the self‐assembled nanomicellar systems, totally devoid of toxic side effects, is able to deliver small interfering RNA and achieve effective gene silencing both in cells – including the highly refractory human hematopoietic CD34+ stem cells – and in vivo, thus paving the way for future biomedical implementation. This work presents a case study of the concept of generating functional supramolecular dendrimers via self‐assembly. The ability of carefully designed and gauged building blocks to assemble into supramolecular structures opens new perspectives on the design of self‐assembling nanosystems for complex and functional applications.
Supramolecular dendrimers created from small amphiphilic dendrons are able to mimic covalently constructed high‐generation dendrimers for siRNA delivery. An optimal balance between the hydrophobic alkyl chain length and the hydrophilic dendritic portion is crucial for self‐assembly of these amphiphilic dendrons into micellar nanostructures, and critically impacts the effectiveness of siRNA delivery and functional gene silencing.
The acquisition of mutations within the BCR-ABL1 kinase domain is frequently associated with tyrosine kinase inhibitor (TKI) failure in chronic myeloid leukemia. Sensitive sequencing techniques have ...revealed a high prevalence of compound BCR-ABL1 mutations (polymutants) in patients failing TKI therapy. To investigate the molecular consequences of such complex mutant proteins with regards to TKI resistance, we determined by cloning techniques the presence of polymutants in a cohort of chronic-phase patients receiving imatinib followed by dasatinib therapy. The analysis revealed a high frequency of polymutant BCR-ABL1 alleles even after failure of frontline imatinib, and also the progressive exhaustion of the pool of unmutated BCR-ABL1 alleles over the course of sequential TKI therapy. Molecular dynamics analyses of the most frequent polymutants in complex with TKIs revealed the basis of TKI resistance. Modeling of BCR-ABL1 in complex with the potent pan-BCR-ABL1 TKI ponatinib highlighted potentially effective therapeutic strategies for patients carrying these recalcitrant and complex BCR-ABL1 mutant proteins while unveiling unique mechanisms of escape to ponatinib therapy.
Gold nanoparticles (AuNPs) covered with mixtures of immiscible ligands present potentially anisotropic surfaces that can modulate their interactions at complex nano–bio interfaces. Mixed, ...self‐assembled, monolayer (SAM)‐protected AuNPs, prepared with incompatible hydrocarbon and fluorocarbon amphiphilic ligands, are used here to probe the molecular basis of surface phase separation and disclose the role of fluorinated ligands on the interaction with lipid model membranes and cells, by integrating in silico and experimental approaches. These results indicate that the presence of fluorinated amphiphilic ligands enhances the membrane binding ability and cellular uptake of gold nanoparticles with respect to those coated only with hydrogenated amphiphilic ligands. For mixed monolayers, computational results suggest that ligand phase separation occurs on the gold surface, and the resulting anisotropy affects the number of contacts and adhesion energies with a membrane bilayer. This reflects in a diverse membrane interaction for NPs with different surface morphologies, as determined by surface plasmon resonance, as well as differential effects on cells, as observed by flow cytometry and confocal microscopy. Overall, limited changes in monolayer features can significantly affect NP surface interfacial properties, which, in turn, affect the interaction of SAM‐AuNPs with cellular membranes and subsequent effects on cells.
The structure that matters. Patterning of gold nanoparticles due to self‐assembling monolayers of amphiphilic immiscible ligands determines their behavior at the nano–bio interface.
Successful achievement of RNA interference in therapeutic applications requires safe and efficient vectors for siRNA delivery. In the present study, we demonstrate that a triethanolamine (TEA)-core ...PAMAM dendrimer of generation 5 (G 5 ) is able to deliver sticky siRNAs bearing complementary A n /T n 3′-overhangs effectively to a prostate cancer model in vitro and in vivo and produce potent gene silencing of the heat shock protein 27, leading to a notable anticancer effect. The complementary A n /T n (n = 5 or 7) overhangs characteristic of these sticky siRNA molecules help the siRNA molecules self-assemble into “gene-like” longer double-stranded RNAs thus endowing a low generation dendrimer such as G 5 with greater delivery capacity. In addition, the A n /T n (n = 5 or 7) overhangs act as protruding molecular arms that allow the siRNA molecule to enwrap the dendrimer and promote a better interaction and stronger binding, ultimately contributing toward the improved delivery activity of G 5 . Consequently, the low generation dendrimer G 5 in combination with sticky siRNA therapeutics may constitute a promising gene silencing-based approach for combating castration-resistant prostate tumors or other cancers and diseases, for which no effective treatment currently exists.
Nanogels are chemically crosslinked polymeric nanoparticles endowed with high encapsulation ability, tunable size, ease of preparation, and responsiveness to external stimuli. The presence of ...specific functional groups on their surfaces provides an opportunity to tune their surface properties and direct their behavior. In this work, we used mesoscale modeling to describe conformational and mechanical properties of nanogel surfaces formed by crosslinked polyethylene glycol and polyethyleneimine, and grafted by charged alkylamine brushes of different lengths. Simulations show that both number of chains per area and chain length can be used to tune the properties of the coating. Properly selecting these two parameters allows switching from a hydrated, responsive coating to a dried, highly charged layer. The results also suggest that the scaling behavior of alkylamine brushes, e.g., the transition from a mushroom to semi-dilute brush, is only weakly coupled with the shielding ability of the coating and much more with its compressibility.
This paper focuses on a thermodynamic model built to predict the reduction of organic drug melting temperature and enthalpy with nanocrystal size decrease. Indeed, this valuable information enables ...us to evaluate the increase of drug solubility, an aspect of paramount importance for poorly water-soluble organic drugs since a solubility increase is reflected in a bioavailability enhancement. In particular, the model considers the effect of nanocrystals shape (spherical, cylindrical, and parallelepiped-shaped) and morphology (from platelet to needle nanocrystals) on the melting temperature and enthalpy reduction with crystal size decrease. Nimesulide, a typical nonsteroidal and poorly water-soluble drug with anti-inflammatory action, has been chosen as a model drug to test model reliability. Model outcomes suggest that the reduction of melting temperature and enthalpy mainly depends on the ratio between crystals surface area and volume, i.e., on the ratio between the number of surface and bulk molecules constituting the nanocrystal network. The obtained prediction of solubility enhancement and the successful comparison with the outcomes obtained from a molecular dynamics approach, in terms of melting temperature and enthalpy decrease, have confirmed the reliability of the proposed model.
With the aim of developing dendrimer nanovectors with a precisely controlled architecture and flexible structure for DNA transfection, we designed PAMAM dendrimers bearing a triethanolamine (TEA) ...core, with branching units pointing away from the center to create void spaces, reduce steric congestion, and increase water accessibility for the benefit of DNA delivery. These dendrimers are shown to form stable nanoparticles with DNA, promote cell uptake mainly via macropinocytosis, and act as effective nanovectors for DNA transfection in vitro on epithelial and fibroblast cells and, most importantly, in vivo in the mouse thymus, an exceedingly challenging organ for immune gene therapy. Collectively, these results validate our rational design approach of structurally flexible dendrimers with a chemically defined structure as effective nanovectors for gene delivery, and demonstrate the potential of these dendrimers in intrathymus gene delivery for future applications in immune gene therapy.
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