Anticancer effects of gemcitabine are enhanced by co-administered iRGD peptide in murine pancreatic cancer models that overexpressed neuropilin-1

Abstract

Background:Impaired drug transport is an important factor that reduces the efficacy of anticancer agents against pancreatic cancer. Here, we report a novel combination chemotherapy using gemcitabine (GEM) and internalised-RGD (iRGD) peptide, which enhances tumour-specific drug penetration by binding neuropilin-1 (NRP1) receptor.Methods:A total of five pancreatic cancer murine models (two cell line-based xenografts (CXs) and three tumour grafts (TGs)) were treated with either GEM (100 mg kg−1, q3d × 4) alone or GEM plus iRGD peptide (8 μmol kg−1). Evaluation of NRP1 expression in xenografts and 48 clinical cancer specimens was performed by immunohistochemistry (IHC).Results:We identified a subset of pancreatic cancer models that showed NRP1 overexpression sensitive to iRGD co-administration. Treatment with GEM plus iRGD peptide resulted in a significant tumour reduction compared with GEM monotherapy in CXs, but not remarkable in TGs. Potential targets of iRGD were characterised as cases showing NRP1 overexpression (IHC-2+/3+), and these accounted for 45.8% of the clinical specimens.Conclusions:Internalised RGD peptide enhances the effects of co-administered drugs in pancreatic cancer models, its efficacy is however only appreciable in those employing cell lines. Therefore, the clinical application needs to be given careful consideration.

A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin–Drug Conjugate (LDC)

“…injection without notable adverse events. However, it should also be noted that the EPR effect showing the predominant accumulation of LDC in PDX tumors in mouse models may not be reproduced in clinical PDAC, because human PDACs are known to be hypoperfused and poorly vascularized compared with xenotransplanted tumors (24,25). Compared with the affinity of antibodies for peptide antigens (Kd ¼ 0.1-10 nmol/L), the affinity of lectins for their target glycans is typically weaker (Kd ¼ 100-1,000 nmol/L).…”

Improving Drug Penetrability with iRGD Leverages the Therapeutic Response to Sorafenib and Doxorubicin in Hepatocellular Carcinoma

“…As HCCs arise in the predominant number of cases in livers with advanced fibrosis or Cancer Researchcirrhosis (2), iRGD might be particularly useful to increase tumor drug delivery in this tumor entity. The efficacy of iRGD to increase the penetrability of tumors for therapeutic substances is likely to show tumor-to-tumor variation, which could be, for instance, due to differential expression of a v b 3/5 integrins and NRP1 (14). Thus, a clinically feasible method to determine whether a particular tumor can be permeabilized by iRGD would be highly beneficial for a potential translation of iRGD into patients.…”

“…iRGD can also increase the concentrations of diverse systemically administered substances specifically in tumors, when coadministered rather than being directly coupled to the cargo in some tumor models (5,14,15). This bystander effect of iRGD would be much more convenient and versatile, as it would allow combined application with the currently used antitumor drugs but is less well-investigated than its transport-enhancing effect upon coupling to the cargo and thus needs validation and examination in other tumor entities.…”

“…This bystander effect of iRGD would be much more convenient and versatile, as it would allow combined application with the currently used antitumor drugs but is less well-investigated than its transport-enhancing effect upon coupling to the cargo and thus needs validation and examination in other tumor entities. Moreover, the effect of iRGD on tumor penetrability is likely to vary among different tumors, for instance, due to differential expression of a v b 3/5 integrins and NRP1 (14). Thus, for an efficient use of iRGD, a clinically applicable method to determine whether a particular tumor reacts to iRGD would be highly beneficial.…”

Tumor-penetrating peptide enhances transcytosis of silicasome-based chemotherapy for pancreatic cancer

“…The transcytosis pathway is not only distinct from other endocytic uptake mechanisms (e.g., caveolae, clathrin-coated pits, and macropinocytosis), but it also allows entry of small drug molecules, monoclonal antibodies (e.g., trastuzumab), and nanoparticles (e.g., Abraxane and doxorubicin liposomes) during iRGD coadministration (19,21). Importantly, this effect is not dependent on direct conjugation of the peptide to the drug or carrier, as demonstrated by gemcitabine uptake in some (but not all) experimental PDAC models (22). However, no detailed investigation of the PDAC transcytosis pathway has been undertaken, and it is unknown whether it could be beneficial from the perspective of iRGD peptide coadministration to further enhance the nanocarrier OS effects (7,8).…”