Among various inflammatory factors/mediators, autocrine and paracrine prostaglandin 2 (PGE2), which are abundant in various tumors, promote the proliferation and chemoresistance of cancer cells. Thus, eliminating the cytoprotective effect of PGE2 may strengthen the antitumor effect of chemotherapy. Chemo/anti-inflammatory combination therapy requires the programmed activities of two different kinds of drugs that critically depend on their spatiotemporal manipulation inside the tumor. Here, a micellar polymeric nanosphere, encapsulating chemotherapeutic paclitaxel (PTX) in the core and conjugating anti-inflammatory celecoxib (CXB) to the shell through a peptide linker (PLGLAG), was developed. The PLGLAG linker was cleavable by the enzyme matrix metalloproteinase-2 (MMP-2) in the tumor tissue, causing CXB release and turning the negatively charged nanosphere into a positively charged one to facilitate PTX delivery into cancer cells. The released CXB not only acted on cyclooxygenase-2 (COX-2) to suppress the production of pro-inflammatory PGE2 in multiple cell types but also suppressed the expression of the anti-apoptotic Bcl-2 gene to sensitize cancer cells to chemotherapy, thus resulting in a synergistic anticancer effect of PTX and CXB. This study represents an example of using a surface charge-switchable nanosphere with on-demand drug release properties to act on multiple cell types for highly effective chemo/anti-inflammatory combination therapy of cancer.

The pH-sensitive copolymer enhanced the lysosome escape of polyplexes and modification of iRGD endowed the polyplexes with effective intratumoral delivery and high transfection efficiency.

An extracellular pH and intracellular reduction dual-sensitive polymeric nanomicelle was developed for tumor microenvironment triggered selective cellular uptake and controlled cytoplasm drug release.

Bone morphogenetic proteins (BMPs) are growth factors that have important functions in cell proliferation, migration and differentiation. To date, BMP pathway activation has been found in multiple human tumors and is associated with enhanced malignant tumor growth and metastasis. BMP activity is tightly regulated by a family of soluble extracellular secreted BMP modulators. Twisted gastrulation BMP signaling modulator 1 (TWSG1) is a direct BMP regulator that is required for the full signaling activity of BMPs. However, the functions and mechanisms of TWSG1 in papillary thyroid cancer (PTC) metastasis have not been reported. TWSG1 expression was detected in 44 PTC tissues with lymph node metastasis (LNM) and 56 PTC tissues without LNM using quantitative real-time polymerase chain reaction (qRT-PCR). Gain- and loss-of-function approaches were used to assess the biological function of TWSG1 in PTC cells. Matrigel assays demonstrated the effect of tumor cell-derived TWSG1 on endothelial cell function. Our results showed that TWSG1 expression was significantly enhanced in PTC with LNM compared to that in PTC without LNM. TWSG1 knockdown inhibited migration, invasion and proliferation of PTC cells. Additionally, TWSG1 suppression impaired the tumor cell-induced endothelial cell sprout formation. We found that TWSG1 signaling may be transduced by the BMP target transcription factor inhibitor of DNA binding 1 (Id1) and matrix metalloproteinases (MMPs) 2 and 9. In conclusion, TWSG1 was highly expressed in metastasized PTC; tumor growth, migration and invasion were dependent on TWSG1, and it may be a new diagnostic and therapeutic target for PTC.