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.
Porous silicon nanoparticles (pSiNPs) act as a sensitizer for the 2‐photon excitation of a pendant porphyrin using NIR laser light, for imaging and photodynamic therapy. Mannose‐functionalized pSiNPs ...can be vectorized to MCF‐7 human breast cancer cells through a mannose receptor‐mediated endocytosis mechanism to provide a 3‐fold enhancement of the 2‐photon PDT effect.
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•Off-target activity of EGFR tyrosine kinase inhibitor AZD9291.•Chemical proteomic analysis of AZD9291 analogs.•Reduction of off-target activity with retention of T790M-EGFR ...inhibition.
Non-small-cell lung cancer (NSCLC) is a major disease that accounts for 85% of all lung cancer cases which claimed around 1.8 billion lives worldwide in 2020. Tyrosine kinase inhibitors (TKIs) that target EGFR have been used for the treatment of NSCLC, but often develop drug resistance, and the covalent inhibitor AZD9291 has been developed to tackle the problem of drug resistance mediated by the T790M EGFR mutation; however, there is a side effect of hyperglycemia that may be due to off-target activity. This study examines analogs of AZD9291 by chemical proteomics, identifying analogs that maintain T790M-EGFR engagement while showing reduced cross-reactivity with off-targets.
The development of personalized and non‐invasive cancer therapies based on new targets combined with nanodevices is a major challenge in nanomedicine. In this work, the over‐expression of a membrane ...lectin, the cation‐independent mannose 6‐phosphate receptor (M6PR), was specifically demonstrated in prostate cancer cell lines and tissues. To efficiently target this lectin a mannose‐6‐phosphate analogue was synthesized in six steps and grafted onto the surface of functionalized mesoporous silica nanoparticles (MSNs). These MSNs were used for in vitro and ex vivo photodynamic therapy to treat prostate cancer cell lines and primary cell cultures prepared from patient biopsies. The results demonstrated the efficiency of M6PR targeting for prostate cancer theranostic.
On target: The over‐expression of a mannose‐6‐phosphate receptor was demonstrated in prostate tissues and cancer cell lines. This receptor was targeted with a mannose‐6‐phosphate analogue grafted onto the surface of mesoporous silica nanoparticles (MSNs). MSNs were efficient for cancer imaging and therapy, thus demonstrating the potential of M6PR targeting for prostate cancer theranostics.
Le récepteur du mannose 6-phosphate cation indépendant (RM6P-CI) permet l'endocytose puis le transfert de molécules porteuses du marqueur mannose 6-phosphate (M6P) vers les lysosomes. Le RM6P-CI, qui ...est surexprimé par les cellules de cancer de la prostate, est une cible de choix pour augmenter la délivrance de principes actifs dans ces cellules. Cependant le M6P est dégradé par les phosphatases présentes dans le sérum. Dans le but d'augmenter à la fois la stabilité et l'affinité pour le RM6P-CI, nous avons entrepris la synthèse d'analogues isostères du mannose 6-phosphate. Ces analogues sont fonctionnalisés en position anomère afin de permettre leur greffage sur des nanoparticules de silice mésoporeuse incorporant un photosensibilisateur. L'évaluation biologique a montré un gain d'affinité des nouveaux analogues synthétisés pour le RM6P-CI ainsi qu'une forte augmentation de l'efficacité des nanoparticules fonctionnalisées avec les analogues pour la thérapie photodynamique, in vitro, de cellules de cancer de la prostate.
The cation independant mannose 6-phosphate receptor (CI-M6PR) allows the endocytosis and the transport of mannose 6-phosphate (M6P) bearing molecules toward the lysosomes. The CI-M6PR, which is overexpressed by prostate cancer cells, is a target of interest to increase drug delivery in these cells. However, M6P is sensitive to degradation by phosphatases in the serum. To increase both the stability and the affinity for the CI-M6PR, we synthesized new M6P isosteric analogs. These analogs are functionnalized at the anomeric position to permit their grafting on mesoporous silica nanoparticles incorporating a photosensitizer. The biological evaluation demonstrated an affinity gain of the new analogs for the CI-M6PR as well as an increase of the efficacy of the nanoparticles functionnalized with these analogs for the in vitro photodynamic therapy of cancer prostate cells.
Mannosylglycerate (MG) and its derivatives have received much attention during the past decade, especially because they play an important role as thermal‐stabilizers of several enzymes. Here we ...report a new and original synthetic method of (2R)‐2‐(α‐D‐mannopyranosyl)glycerate, which was prepared according to a five‐step procedure starting from commercially available 3,4‐O‐isopropylidene‐D‐mannitol as the glycerate source.
The mannosylglycerate was synthesized from the 3,4‐O‐isopropylidene‐D‐Mannitol used as the source of the glycerate moiety.
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