Refinement of Covalent EGFR Inhibitor AZD9291 to Eliminate Off-target Activity.

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 analogues of AZD9291 by chemical proteomics, identifying analogues that maintain T790M-EGFR engagement while showing reduced cross-reactivity with off-targets.

Efficient Photodynamic Therapy of Prostate Cancer Cells through an Improved Targeting of the Cation-Independent Mannose 6-Phosphate Receptor.

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.

Mannose-6-phosphate receptor: a target for theranostics of prostate cancer.

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.

Ruthenium(ii) complex-photosensitized multifunctionalized porous silicon nanoparticles for two-photon near-infrared light responsive imaging and photodynamic cancer therapy.

Multifunctionalized porous silicon nanoparticles (pSiNPs), containing the novel Ru(ii) complex-photosensitizer, the polyethylene glycol moiety, and mannose molecules as cancer targeting ligands, are constructed and showcased for application in near infrared (NIR) light-responsive photodynamic therapy (PDT) and imaging of cancer. Exposure to NIR light leads to two-photon excitation of the Ru(ii)-complex which allows efficient simultaneous cancer-imaging and targeted PDT therapy with the functionalized biodegradable pSiNP nanocarriers.

Mesoporous silicon nanoparticles for targeted two-photon theranostics of prostate cancer.

A novel non-toxic porous silicon nanoparticle grafted with a mannose-6-phosphate analogue and applicable in 2-photon imaging and photodynamic therapy was specifically designed for targeting prostate cancer cells.

Two-photon excitation of porphyrin-functionalized porous silicon nanoparticles for photodynamic therapy.

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.