Targeted therapy of spontaneous murine pancreatic tumors by polymeric micelles prolongs survival and prevents peritoneal metastasis

Abstract

Nanoscaled drug-loaded carriers are of particular interest for efficient tumor therapy as numerous studies have shown improved targeting and efficacy. Nevertheless, most of these studies have been performed against allograft and xenograft tumor models, which have altered microenvironment features affecting the accumulation and penetration of nanocarriers. Conversely, the evaluation of nanocarriers on genetically engineered mice, which can gradually develop clinically relevant tumors, permits the validation of their design under normal processes of immunity, angiogenesis, and inflammation. Therefore, considering the poor prognosis of pancreatic cancer, we used the elastase 1-promoted luciferase and Simian virus 40 T and t antigens transgenic mice, which develop spontaneous bioluminescent pancreatic carcinoma, and showed that long circulating micellar nanocarriers, incorporating the parent complex of oxaliplatin, inhibited the tumor growth as a result of their efficient accumulation and penetration in the tumors. The reduction of the photon flux from the endogenous tumor by the micelles correlated with the decrease of serum carbohydrate-associated antigen 19-9 marker. Micelles also reduced the incidence of metastasis and ascites, extending the survival of the transgenic mice.chemotherapy | drug delivery | (1,2-diaminocyclohexane)platinum (II)

Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors

“…For example, gemcitabine (2′-2′-difluorodeoxycytidine) is used as a frontline therapeutic drug for pancreatic tumor. However, gemcitabine when combined with other therapeutic mediators, such as platinum analogs, 126 antimetabolites 127 or topoisomerase inhibitors, 93 did not improve the therapeutic outcome or survival rate. FOLFIRINOX replaced gemcitabine-based therapy owing to its better average overall survival of 11.1 months in comparison to 6.8 months of the former.…”

“…125 Nowadays, Doxil is used for the treatment of a wide range of solid tumors and platinum-resistant ovarian cancer. 128 Chemotherapeutic drug oxaliplatin-loaded nanoparticulate micelles were prepared by Cabral et al, 126 with slow release of encapsulated drug once they were in contact with the tumor microenvironment, resulting in enhanced antitumor effect. Similarly, encapsulated nanocarriers of gemcitabine were used as the first-line treatment for the locally advanced or metastatic pancreatic tumor.…”

Phenylboronic Acids-based Diagnostic and Therapeutic Applications

“…38 and 42. active targeting strategy may offer promising options. 51 Our recent study has described a polymer micelle installed with PBA as a ligand to SA (Fig. 3).…”

Functionalized milk-protein-coated magnetic nanoparticles for MRI-monitored targeted therapy of pancreatic cancer

“…33,34 Given the hydrodynamic size of ~30 nm, ATF-CNIO-CDDP can take advantage of the prolonged blood circulation half life time (t 1/2~4 .2 hours), allowing sufficient time to reach the targeted tumor, thus enhancing tumor accumulation via the enhanced permeability and retention (EPR) effect. The lower antitumor effect of free CDDP in the orthotopic pancreatic cancer model here can be explained by the fact that free CDDP has a much shorter blood circulation time and faster clearance, thus it fails to maintain a sufficient plasma level and gradient that can drive the drug to the tumor.…”