MAPK‐Targeted Drug Delivered by a pH‐Sensitive MSNP Nanocarrier Synergizes with PD‐1 Blockade in Melanoma without T‐Cell Suppression

Abstract

The combination of BRAF/MEK‐targeted therapy with immune checkpoint blockade is regarded as a promising regimen for patients with metastatic melanoma due to their complementary advantages. However, MEK‐inhibitor‐induced T‐cell toxicity impedes effective cooperation. In this experiment, a pH‐responsive on‐demand controlled release mesoporous silica nanoparticles (MSNPs) system is designed. Fluorescein‐isothiocyanate‐loaded MSNP can be specifically delivered into tumor cells rather than T‐cells. MEK‐inhibitor‐loaded MSNP avoids proliferative and functional inhibitions of T‐cells, while preserving growth suppression of tumor cells in vitro. In an in vivo model, MSNP encapsulation reverses the MEK‐inhibitor‐induced suppression of activated CD8+ T‐cells, and enhances the secretion of INF‐γ and IL‐2. The combination of BRAF inhibitor plus MSNP‐loaded MEK inhibitor and anti‐PD‐1 antibody synergistically inhibits tumor growth via promoting robust immune‐related antitumor response. This work provides a novel and generalized framework for combining T‐cell‐impaired targeted therapy and immune checkpoint blockade by using a nanoparticle‐based delivery system.

The Evolution of Acquired Resistance to BRAFV600E kinase inhibitor Is Sustained by IGF1-Driven Tumor Vascular Remodeling

“…To this end, we recapitulated the clinical therapeutic process with a mouse model. SMM102, a Vemurafenib sensitive mouse cell line (Liu et al, 2019), was subcutaneously inoculated on both flanks of C57BL/6 mice (Figure 2a; Supplementary Figure S5a and b). In Vem-treated group, mice were treated with either Vemurafenib or 5% DMSO 5 times a week once the tumor volumes reached 150-300 mm 3 .…”

Integrin-Src-YAP1 signaling mediates the melanoma acquired resistance to MAPK and PI3K/mTOR dual targeted therapy

“…Based on our in vitro data, we then wanted to investigate the effect of treatment with dual drugs in mice model. To this end, we inoculated C57 with SMM102 [28], a BRAFi sensitive mouse melanoma cell line ( Supplementary Fig. 1b).…”

“…To prepare the tumor samples for IHC staining, the tumor pieces were fixed with 10% formalin followed by paraffin embedding. Tumor sections of 4 μm thickness were mounted on glass slides for IHC staining as described previously [28]. For p-S6, p-4E-BP1, 4E-BP1, p-ERK, integrin α3, integrin α11, integrin β1, p-Src, Src, p-YAP1, YAP1 immunohistochemistry staining, the slides were deparaffinized, incubated in 3% hydrogen peroxide, antigen retrieval was performed in EDTA (pH = 9.0) or citrate (pH = 6.0) for 3 min in pressure cooker.…”

“…In vivo mouse studies SMM102 cell line derived from transgenic Braf V600E /wt, Cdkn2−/−, Pten−/− mouse as described [28]. Female C57BL/6 mice were obtained from Beijing HFK Bioscience Co.,Ltd.…”

An Artificial Intelligent Signal Amplification System for in vivo Detection of miRNA

“…Third, and most critically, the cytoplasmic concentration of the active components released and transported by the AISA system must be sufficient to guarantee an effective detection reaction, and these components should be able to distinguish the target miRNA and its analogs effectively so that we can obtain an image with a high signal/noise (SNR) ratio. In the previous studies, many researchers have innovatively prepared vectors to deliver small interfering RNA, miRNA, and immunotherapeutic antibody for molecular therapy (Zhong et al, 2015; Wang et al, 2018; Yaghini et al, 2018; Liu et al, 2019; Wu et al, 2019; Xu et al, 2019). These carriers can transport the substances into cells, but their transport efficiency varies, which will affect subsequent calculation of the relationship between fluorescence intensity and RNA concentration.…”