Zap 'em! Multifunctionalized mesoporous silica nanoparticles induce significant reduction of tumor size upon two‐photon excitation in the near‐infrared region while being nontoxic under daylight ...illumination. These nanoparticles were further tested for in vivo two‐photon photodynamic therapy (TPE‐PDT). A 70 % regression of tumor size after a single treatment was observed in athymic mice bearing tumor xenografts.
Targeted degradation of pathological proteins is a promising approach to enhance the effectiveness of therapeutic monoclonal antibodies (mAbs) in cancer therapy. In this study, we demonstrate that ...this objective can be efficiently achieved by the grafting of mannose 6-phosphate analogues called AMFAs22AMFA: Analogues of the Mannose 6-phosphate Functionalized at Anomeric Position onto the therapeutic antibodies trastuzumab and cetuximab, both directed against membrane antigens. The grafting of AMFAs confers to these antibodies the novel property of being internalized via the mannose 6-phosphate receptor (M6PR) pathway. AMFA conjugation to these mAbs significantly increases their cellular uptake and leads to enhanced degradation of the target antigens in cancer cells. This results in a drastic inhibition of cancer cell proliferation compared to unconjugated mAbs, as demonstrated in various cancer cell lines, and an increased therapeutic efficacy in mouse and zebrafish xenografted models. These findings highlight the potential of this technology to improve therapeutic outcomes in cancer treatment.
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•Analogues of mannose 6-phosphate M6Pn (AMFA) are grafted onto therapeutic antibodies.•Grafting few analogues enables higher uptake in cancer cells of antibodies via M6PR.•Drastic membrane antigen degradation is achieved with AMFA-antibodies in vitro.•AMFA-engineering allows better in vitro and in vivo efficacy in different models.
Biodegradable bridged silsesquioxane (BS) nanomaterials for two-photon-excited (TPE) imaging and therapy of breast cancer cells were described. A versatile synthesis was developed to design ...monodisperse tetra-alkoxysilylated diamino-diphenylbutadiene or Zn-porphyrin-based nanospheres of 30 to 50 nm.
Inducing the degradation of pathological soluble antigens could be the key to greatly enhancing the efficacy of therapeutic monoclonal antibodies (mAbs), extensively used in the treatment of ...autoimmune and inflammatory disorders or cancer. Lysosomal targeting has gained increasing interest in recent years due to its pharmaceutical applications far beyond the treatment of lysosomal diseases, as a way to address proteins to the lysosome for eventual degradation. Mannose 6-phosphonate derivatives (M6Pn), called AMFA, are unique glycovectors that can significantly enhance the cellular internalization of the proteins conjugated to AMFA
the cation-independent mannose 6-phosphate receptor (M6PR) pathway. AMFA engineering of mAbs results in the generation of a bifunctional antibody that is designed to bind both the antigen and the M6PR. The improvement of the therapeutic potential by AMFA engineering was investigated using two antibodies directed against soluble antigens: infliximab (IFX), directed against tumor necrosis factor α (TNF-α), and bevacizumab (BVZ), directed against the vascular endothelial growth factor (VEGF). AMFA conjugations to the antibodies were performed either on the oligosaccharidic chains of the antibodies or on the lysine residues. Both conjugations were controlled and reproducible and provided a novel affinity for the M6PR without altering the affinity for the antigen. The grafting of AMFA to mAb increased their cellular uptake through an M6PR-dependent mechanism. The antigens were also 2.6 to 5.7 times more internalized by mAb-AMFA and rapidly degraded in the cells. Additional cell culture studies also proved the significantly higher efficacy of IFX-AMFA and BVZ-AMFA compared to their unconjugated counterparts in inhibiting TNF-α and VEGF activities. Finally, studies in a zebrafish embryo model of angiogenesis and in xenografted chick embryos showed that BVZ-AMFA was more effective than BVZ in reducing angiogenesis. These results demonstrate that AMFA grafting induces the degradation of soluble antigens and a significant increase in the therapeutic efficacy. Engineering with mannose 6-phosphate analogues has the potential to develop a new class of antibodies for autoimmune and inflammatory diseases.
The aim of the present work is the development of highly efficient targeting molecules to specifically address mesoporous silica nanoparticles (MSNs) designed for the photodynamic therapy (PDT) of ...prostate cancer. We chose the strategy to develop a novel compound that allows the improvement of the targeting of the cation-independent mannose 6-phosphate receptor, which is overexpressed in prostate cancer. This original sugar, a dimannoside-carboxylate (M6C-Man) grafted on the surface of MSN for PDT applications, leads to a higher endocytosis and thus increases the efficacy of MSNs.
Non-toxic porous silicon nanoparticles carry porphyrin covalently attached to their surface inside breast cancer cells for a more efficient photodynamic effect.
Different intracellular delivery systems of bioactive compounds have been developed, including cell‐penetrating peptides. Although usually nontoxic and biocompatible, these vectors share some of the ...general drawbacks of peptides, notably low bioavailability and susceptibility to protease degradation, that limit their use. Herein, the conversion of short peptide sequences into poly‐α‐amino‐γ‐lactam foldamers that adopt a ribbon‐like structure is investigated. This template is used to distribute critical cationic and/or hydrophobic groups on both sides of the backbone, leading to potent short, cell‐permeable foldamers with a low positive‐charge content. The lead compound showed dramatically improved protease resistance and was able to efficiently deliver a biologically relevant cargo inside cells. This study provided a simple strategy to convert short peptide sequences into efficient protease‐resistant cell‐penetrating foldamers.
Crossing membranes: Conversion of random coil α‐peptides into short cell‐penetrating foldamers, with controlled periodic distribution of cationic and tryptophan moieties, through a straightforward chemical approach, yields potent cell‐penetrating compounds that are resistant to protease degradation, possess a low content of cationic residues, and are able to deliver bioactive cargo inside the cytoplasm.
The biological fate of nanoparticles (NPs) for biomedical applications is highly dependent of their size and charge, their aggregation state and their surface chemistry. The chemical composition of ...the NPs surface influences their stability in biological fluids, their interaction with proteins, and their attraction to the cell membranes. In this work, core-shell magnetic mesoporous silica nanoparticles (Fe₃O₄@MSN), that are considered as potential theranostic candidates, are coated with polyethylene glycol (PEG) or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid bilayer. Their biological fate is studied in comparison to the native NPs. The physicochemical properties of these three types of NPs and their suspension behavior in different media are investigated. The attraction to a membrane model is also evaluated using a supported lipid bilayer. The surface composition of NPs strongly influences their dispersion in biological fluids mimics, protein binding and their interaction with cell membrane. While none of these types of NPs is found to be toxic on mice four days after intravenous injection of a dose of 40 mg kg
of NPs, their surface coating nature influences the in vivo biodistribution. Importantly, NP coated with DMPC exhibit a strong accumulation in liver and a very low accumulation in lung in comparison with nude or PEG ones.
Careful analysis of any new nanomedicine device or disposal should be undertaken to comprehensively characterize the new product before application, so that any unintended side effect is minimized. ...Because of the increasing number of nanotechnology-based drugs, we can anticipate that regulatory authorities might adapt the approval process for nanomedicine products due to safety concerns, e.g., request a more rigorous testing of the potential toxicity of nanoparticles (NPs). Currently, the use of mesoporous silica nanoparticles (MSN) as drug delivery systems is challenged by a lack of data on the toxicological profile of coated or non-coated MSN. In this context, we have carried out an extensive study documenting the influence of different functionalized MSN on the cellular internalization and in vivo behaviour. In this article, a synthesis of these works is reviewed and the perspectives are drawn. The use of magnetic MSN (Fe
O
@MSN) allows an efficient separation of coated NPs from cell cultures with a simple magnet, leading to results regarding corona formation without experimental bias. Our interest is focused on the mechanism of interaction with model membranes, the adsorption of proteins in biological fluids, the quantification of uptake, and the effect of such NPs on the transcriptomic profile of hepatic cells that are known to be readily concerned by NPs' uptake in vivo, especially in the case of an intravenous injection.
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