Tumor-penetrating iRGD facilitates penetration of poly(floxuridine-ketal)-based nanomedicine for enhanced pancreatic cancer therapy

》》文章原文链接：Tumor-penetrating iRGD facilitates penetration of poly(floxuridine-ketal)-based nanomedicine for enhanced pancreatic cancer therapy

》》Journal：J Control Release .

》》相关产品：iRGD peptide (SJ-BP0302)

》》产品引用描述：

》》Abstract：

Efficient intratumoral penetration is essential for nanomedicine to eradicate pancreatic tumors. Although nanomedicine can enter the perivascular space of pancreatic tumors, their access to distal tumor cells, aloof from the vessels, remains a formidable challenge. Here, we synthesized an acid-activatable macromolecular prodrug of floxuridine (FUDR)-poly(FUDR-ketal), engineered a micellar nanomedicine of FUDR, and intravenously co-administered the nanomedicine with the tumor-penetrating peptide iRGD for enhanced treatment of pancreatic tumor. A FUDR-derived mono-isopropenyl ether was synthesized and underwent self-addition polymerization to afford the hydrophobic poly(FUDR-ketal), which was subsequently co-assembled with amphiphilic DSPE-mPEG into the micellar nanomedicine with size of 12 nm and drug content of 56.8 wt% using nanoprecipitation technique. The acetone-based ketal-linked poly(FUDR-ketal) was triggered by acid to release FUDR to inhibit cell proliferation. In an orthotopic pancreatic tumor model derived from KPC (Kras^LSL-G12D/+; Trp53^LSL-R172H/+; Pdx1-Cre) cells that overexpress neuropilin-1 (NRP-1) receptor, iRGD improved penetration of FUDR nanomedicine into tumor parenchyma and potentiated the therapeutic efficacy. Our nanoplatform, along with iRGD, thus appears to be promising for efficient penetration and activation of acid-responsive nanomedicines for enhanced pancreatic cancer therapy.

》》部分实验数据展示：

Fig.6：Co-administration of iRGD boosts the antitumor efficacy of PolyF@E micelles. (a) Treatment schedule of FUDR formulations in the orthotopic KPC-derived mouse model. (b) Photographs and (c) weight of tumors at the end of therapy. (d) The 8-OHdG levels in tumors excised at the end of the treatments. (e) Detection of released Cytochrome C and activated Caspase 3 in tumors of various groups by CLSM and (f) their quantitative mean fluorescence intensity analysis. Green: Cytochrome C; red: Cleaved-Caspase 3; blue: nuclei.