The design and synthesis of dextran-doxorubicin prodrug-based pH-sensitive drug delivery system for improving chemotherapy efficacy

Tumor cells show acidic conditions compared with normal cells,which further inspires scientist to build nanocarrier responsive to tumor microenvironment(TME)for enhancing tumor therapeutic efficacy.Here,we report a pH-sensitive and biocompatible polyprodrug based on dextran-doxorubicin(DOX)prodrug(DOXDT)for enhanced chemotherapy.Highdensity DOX component was covalently decorated on the nanocarrier and the drug molecules could be effectively released in the acidic tumor tissue/cells,improving chemotherapy efficacy.Specifically,a dextran-based copolymer was preliminarily prepared by one-step atom transfer radical polymerization(ATRP);then DOX was conjugated on the copolymer component via pH-responsive hydrazone bond.The structure of DOXDT can be well-controlled.The resulting DOXDT was able to further self-assemble into nanoscale micelles with a hydration diameter of about 32.4 nm,which presented excellent micellar stability.Compared to lipid-based drug delivery system,the DOXDT prodrug showed higher drug load capacity up to 23.6%.In addition,excellent stability and smaller size of the nanocarrier contributed to better tissue permeability and tumor suppressive effects in vivo.Hence,this amphipathic DOXDT prodrug is promising in the development of translational DOX formulations,which would be widely applied in cancer therapy.

miR-7/TGF-β2 axis sustains acidic tumor microenvironment-induced lung cancer metastasis

Acidosis,regardless of hypoxia involvement,is recognized as a chronic and harsh tumor microenvironment(TME)that educates malignant cells to thrive and metastasize.Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression,the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy.Here,chemical-induced and transgenic mouse models for colon,liver and lung cancer were established,respectively.miR-7 and TGF-β2 expressions were examined in clinical tissues(n=184).RNA-seq,miRNA-seq,proteomics,biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis.Our data show that lung cancer is sensitive to the increased acidification of TME,and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5 p.TGF-β2 is a direct target of miR-7-5 p.The reduced expression of miR-7-5 p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer.Indeed,overexpression of miR-7-5 p reduces the acidic p H-enhanced lung cancer metastasis.Furthermore,the human lung tumor samples also show a reduced miR-7-5 p expression but an elevated level of activated TGF-β2;the expressions of both miR-7-5 p and TGF-β2 are correlated with patients’survival.We are the first to identify the role of the miR-7/TGF-β2 axis in acidic p H-enhanced lung cancer metastasis.Our study not only delineates how acidification directly affects tumorigenesis,but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer(NSCLC)treatment.Our study opens an avenue to explore the p H-sensitive subcellular components as novel therapeutic targets for cancer treatment.