Transferrin Receptor Targeting Nanomedicine Delivering Wild Type P53 Gene Sensitizes Pancreatic Cancer to Gemcitabine Therapy

Abstract

To overcome gene therapy barriers such as low transfection efficiency and nonspecific delivery, liposomal nanoparticles targeted by a single-chain antibody fragment to the transferrin receptor (TfRscFv) delivering wild-type (wt) human p53 (SGT-53) were developed for tumor-specific targeting, We hypothesize that SGT-53 in combination with gemcitabine will demonstrate enhanced therapeutic benefit in an in vivo metastatic pancreatic cancer model. Intrasplenic injection of 1 × 10 6 Panc02 murine pancreatic cancer cells was used to generate in vivo hepatic metastatic tumors. Nanoparticle localization was assessed by tail vein injection of TfRscFv with fluorescently labeled oligonucleotides (6-carboxyfluorescein phosphoramidite (6FAM) ODN) imaged by Xenogen IVIS 200 scan. SGT-53 (equivalent to 30 μg of p53 intravenously) and gemcitabine (20 mg/kg Intraperitoneally) alone and in combination were administered biweekly and compared with untreated mice. Survival was determined by blinded daily assessment of morbidity. Human wt p53 expression and transferrin levels in the tumors were assessed by western blot analysis. Tumor burden was quantified by liver weight, Xenogen imaging demonstrated tumor-specific uptake of TfRscFv-6FAM ODN. Exogenous human wt p53 protein was detected in the SGT-53-treated tumors compared with control. Compared with untreated mice with metastatic tumors demonstrating median survival of 20 days, SGT-53, gemcitabine and the combination demonstrated improved median survival of 29, 30 and 37 days, respectively. The combination treatment prolonged median survival when compared with single drug treatment and decreased tumor burden. The tumor targeting liposomal-based SGT-53 nanoparticle is capable of sensitizing pancreatic cancer to conventional chemotherapy in pancreatic cancer models. This approach has

Magnetic resonance-guided regional gene delivery strategy using a tumor stroma-permeable nanocarrier for pancreatic cancer

“…26 On the other hand, in PDAC, pancreatic tumor cells have not been shown to express specific biomarkers; to date, there are very few examples of nanoparticles with therapeutic efficacy in experimental pancreatic models that have been functionalized with specific ligands, including nanoparticles decorated with epidermal growth factor, 27 arginine-glycine-aspartic acid peptides, 28 or an antibody against the transferrin receptor. 29,30 In this study, dendrimers were modified by Gd to construct T 1 relaxationsensitive nanoprobes for MRI. Although minimally invasive, the imaging-guided percutaneous intratumoral gene delivery strategy efficiently targeted tumor tissue with an enhanced loaded gene transfection efficiency ( Figure 6).…”

Nanodrug Delivery Systems: A Promising Technology for Detection, Diagnosis, and Treatment of Cancer

“…Camp et al (86) reported that anti-transferrin receptor (TfRscFv) targeted liposomes were able to specifically deliver wildtype human p53 tumor suppressor genes (SGT-53) in a metastatic pancreatic mouse model. In combination with gemcitabine, survival rates of mice with metastatic tumors were significantly improved.…”

“…In combination with gemcitabine, survival rates of mice with metastatic tumors were significantly improved. Importantly, such preclinical studies have propelled the induction of multiple phases I and II clinical trials investigating targeted-liposome-p53 complexes (86,87). In one such trial, the SGT-53 was targeted using the anti-transferrin receptor to deliver p53 and restore tumor suppressor function in patients with advanced solid tumors.…”

Peptide-functionalized nanoparticles for selective targeting of pancreatic tumor

“…To date, there are very few examples of drug-loaded nanoparticles functionalized with specific ligands showing a therapeutic efficacy in experimental pancreatic cancer models. For instance, nanocarriers were decorated with the epidermal growth factor receptor (EGFR) [16], the arginine-glycineaspartic acid (RGD) peptide [17] or an antibody towards the transferrin receptor [18]. However, apart from the fact that these nanodevices exhibited poor drug loading [17,18] they were functionalized with homing devices not specific for pancreatic cancer since typically expressed also on several other types of healthy and/or cancer cells.…”

“…For instance, nanocarriers were decorated with the epidermal growth factor receptor (EGFR) [16], the arginine-glycineaspartic acid (RGD) peptide [17] or an antibody towards the transferrin receptor [18]. However, apart from the fact that these nanodevices exhibited poor drug loading [17,18] they were functionalized with homing devices not specific for pancreatic cancer since typically expressed also on several other types of healthy and/or cancer cells. This explains the inability of these materials to reach the pancreatic cancer tissue, even at a low concentration [19].Therefore, the discovery of more specific ligands for pancreatic tumor targeting is urgently needed and represents an important challenge.…”