Spurred by recent progress in materials chemistry and drug delivery, stimuli-responsive devices that deliver a drug in spatial-, temporal- and dosage-controlled fashions have become possible. Implementation of such devices requires the use of biocompatible materials that are susceptible to a specific physical incitement or that, in response to a specific stimulus, undergo a protonation, a hydrolytic cleavage or a (supra)molecular conformational change. In this Review, we discuss recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temperature, magnetic field, ultrasound intensity, light or electric pulses) or endogenous (changes in pH, enzyme concentration or redox gradients).
Design and functionalization strategies for multifunctional nanocarriers (e.g., nanoparticles, micelles, polymersomes) based on biodegradable/biocompatible polymers intended to be employed for active targeting and drug delivery are reviewed. This review will focus on the nature of the polymers involved in the preparation of targeted nanocarriers, the synthesis methods to achieve the desired macromolecular architecture, the selected coupling strategy, the choice of the homing molecules (vitamins, hormones, peptides, proteins, etc.), as well as the various strategies to display them at the surface of nanocarriers. The resulting morphologies and the main colloidal features will be given as well as an overview of the biological activities, with a special focus on the main in vivo achievements.
The application of nanotechnology in the biomedical field, known as nanomedicine, has gained much interest in the recent past, as versatile strategy for selective drug delivery and diagnostic purposes. The already encouraging results obtained with monofunctional nanomedicines have directed the efforts of the scientists towards the creation of "nanotheranostics" (i.e. theranostic nanomedicines) which integrate imaging and therapeutic functions in a single platform. Nanotheranostics hold great promises because they combine the simultaneous non-invasive diagnosis and treatment of diseases with the exciting possibility to monitor in real time drug release and distribution, thus predicting and validating the effectiveness of the therapy. Due to these features nanotheranostics are extremely attractive for optimizing treatment outcomes in cancer and other severe diseases. The following step is the attempt to use nanotheranostics for performing a real personalized medicine which will tailor optimized treatment to each patient, taking into account the individual variability. Clinical application of nanotheranostics would enable earlier detection and treatment of diseases and earlier assessment of the response, thus allowing screening for patients which would potentially respond to therapy and have higher possibilities of a favorable outcome. This concept makes nanotheranostics extremely appealing to elaborate personalized therapeutic protocols for achieving the maximal benefit along with a high safety profile. Among the several systems developed up to now, this review focuses on the nanotheranostics which, due to the promising results, show the highest potential of translation to clinical applications and may transform into concrete practice the concept of personalized nanomedicine.
Pancreatic tumor microenvironment is characterized by abundant fibrosis and aberrant vasculature. Aiming to reproduce in vitro these features, cancer cells have been already co-cultured with fibroblasts or endothelial cells separately but the integration of both these essential components of the pancreatic tumor microenvironment in a unique system, although urgently needed, was still missing. In this study, we successfully integrated cellular and acellular microenvironment components (i.e., fibroblasts, endothelial cells, fibronectin) in a hetero-type scaffold-free multicellular tumor spheroid. This new 3D triple co-culture model closely mimicked the resistance to treatments observed in vivo, resulting in a reduction of cancer cell sensitivity to the anticancer treatment.
Application of 3D multicellular tumor spheroids to the investigation of polymer nanomedicines.
A versatile and efficient functionalization strategy for polymeric nanoparticles (NPs) has been reported and successfully applied to PEGylated, biodegradable poly(alkyl cyanoacrylate) (PACA) nanocarriers. The relevance of this platform was demonstrated in both the fields of cancer and Alzheimer's disease (AD). Prepared by copper-catalyzed azide-alkyne cycloaddition (CuAAC) and subsequent self-assembly in aqueous solution of amphiphilic copolymers, the resulting functionalized polymeric NPs exhibited requisite characteristics for drug delivery purposes: (i) a biodegradable core made of poly(alkyl cyanoacrylate), (ii) a hydrophilic poly(ethylene glycol) (PEG) outer shell leading to colloidal stabilization, (iii) fluorescent properties provided by the covalent linkage of a rhodamine B-based dye to the polymer backbone, and (iv) surface functionalization with biologically active ligands that enabled specific targeting. The construction method is very versatile and was illustrated by the coupling of a small library of ligands (e.g., biotin, curcumin derivatives, and antibody), resulting in high affinity toward (i) murine lung carcinoma (M109) and human breast cancer (MCF7) cell lines, even in a coculture environment with healthy cells and (ii) the β-amyloid peptide 1-42 (Aβ(1-42)), believed to be the most representative and toxic species in AD, both under its monomeric and fibrillar forms. In the case of AD, the ligand-functionalized NPs exhibited higher affinity toward Aβ(1-42) species comparatively to other kinds of colloidal systems and led to significant aggregation inhibition and toxicity rescue of Aβ(1-42) at low molar ratios.
International audienceThe nitroxide-mediated copolymerization of poly(ethylene glycol) methyl ether methacrylate (MePEGMA) with a small amount of acrylonitrile using an SG1-based alkoxyamine initiator was shown to be a very simple and efficient technique to synthesize graft copolymers with poly(ethylene glycol) side chains. The copolymerizations were carried out in ethanol/water solutions as environmentally friendly media. Following our observation that the rate increased with the proportion of water, a polymerization temperature as low as 71 °C could be used for a water content of 75%, which conferred great flexibility to the process. The so-formed copolymers were living, with high crossover efficiency toward block copolymers. Importantly, following a cytotoxicity study over three different cell lines that represent important mammalian cell types, these polymers were shown to be noncytotoxic even at very high doses without any other purification step than a simple precipitation. These comb-shaped PEG-based polymers may represent an ideal platform for the synthesis of PEGylating moieties for proteins and nanoparticles intended to be used in the biomedical field
Once introduced in the organism, the interaction of nanoparticles with various biomolecules strongly impacts their fate. Here we show that nanoparticles made of the squalene derivative of gemcitabine (SQGem) interact with lipoproteins (LPs), indirectly enabling the targeting of cancer cells with high LP receptors expression. In vitro and in vivo experiments reveal preeminent affinity of the squalene-gemcitabine bioconjugates towards LP particles with the highest cholesterol content and in silico simulations further display their incorporation into the hydrophobic core of LPs. To the best of our knowledge, the use of squalene to induce drug insertion into LPs for indirect cancer cell targeting is a novel concept in drug delivery. Interestingly, not only SQGem but also other squalene derivatives interact similarly with lipoproteins while such interaction is not observed with liposomes. The conjugation to squalene represents a versatile platform that would enable efficient drug delivery by simply exploiting endogenous lipoproteins.
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