Abstract 2833: Enhanced therapeutic efficacy of a combination of gemcitabine and albumin-bound paclitaxel in multistage nanovectors in pancreatic ductal adenocarcinoma: Evaluation of transport phenomena

Abstract

The purpose of this study was to evaluate the effect of encapsulation of albumin-bound paclitaxel (ABX) in multistage nanovector (MSV) administered in combination with gemcitabine (Gem) in pancreatic ductal adenocarcinoma (PDA) therapy. PDA is one of the most aggressive malignancies with a 5-year survival rate of less than 3%. The inefficiency in treatment of primary pancreatic cancer can be related to the biophysical barriers in the tumor microenvironment which prevent delivery of therapeutics to the lesion. The best chemotherapy currently available for PDA is the combination therapy with Gem + ABX, which was reported to extend the overall survival as compared to patients receiving Gem alone by <2 months. ABX utilizes endogenous albumin pathways of endothelial transcytosis (gp60) and intratumoral binding of SPARC to transport the drug into the tumor's interstitium. Our previous studies in several tumor models report that MSV can overcome biophysical barriers and carry therapeutic cargo to the tumor microenvironment increasing therapeutic efficacy of the drug. In this study, we used ABX loaded into the MSV in combination with Gem to improve the therapeutic efficacy of the ABX + Gem combination in PDA. We further evaluated transport mechanisms which can be responsible for the observed efficacy. Mice bearing orthotopic PDA tumors (L3.6pl) were treated once a week for up to four months with ABX, Gem, ABX + Gem, MSV/ABX, MSV or MSV/ABX + Gem and PBS control. Subsets of mice were sacrificed after the first and third treatment. Levels of the drugs in tumor/plasma were evaluated by LC/MS-MS. Tumors were immunostained for evaluation of apoptosis (TUNEL), proliferation (Ki67) and the tumor stromal components (F4/80, CD204, CD31, SPARC). Survival of remaining animals was monitored (n = 10/group). The results indicate that treatment with MSV/ABX + Gem was highly efficient prolonging the survival of 50% of the animals until sacrificed at the endpoint of the study at four months as compared to median survival of ABX + Gem mice of 70.5 days. MSV/ABX + Gem increased tumor levels of paclitaxel in comparison to treatment with Gem + ABX. Furthermore, the use of the MSV system as a delivery vehicle resulted in increased macrophage infiltration and SPARC expression in the tumor, while reducing cancer cell proliferation and increasing apoptosis. In conclusion, MSV/ABX + Gem outperforms the current standard-of-care (ABX + Gem) in a mouse model of PDA. The possible mechanism is related to increased transport of ABX encapsulated in MSV/ABX mediated by macrophages or SPARC. Citation Format: Carlotta Borsoi, Kenji Yokoi, Fransisca Leonard, Mauro Ferrari, Biana Godin Vilentchouk. Enhanced therapeutic efficacy of a combination of gemcitabine and albumin-bound paclitaxel in multistage nanovectors in pancreatic ductal adenocarcinoma: Evaluation of transport phenomena. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2833. doi:10.1158/1538-7445.AM2015-2833

Modeling of Nanotherapy Response as a Function of the Tumor Microenvironment: Focus on Liver Metastasis

“…The composition of the stroma in preclinical models of orthotopic primary pancreatic based on L3.6pL cells were analyzed in Yokoi et al (2013) . Profound differences in the cellular elements of pancreatic stroma as a result of different treatments were observed ( Figure 3 , Borsoi et al, 2015 ). Mice were treated with a combination of gemcitabine and nAb-PTX encapsulated or nAb-PTX packed into an engineered MSV ( Tasciotti et al, 2011 ; Yokoi et al, 2013 ; Borsoi et al, 2015 , 2017 ).…”

“…Profound differences in the cellular elements of pancreatic stroma as a result of different treatments were observed ( Figure 3 , Borsoi et al, 2015 ). Mice were treated with a combination of gemcitabine and nAb-PTX encapsulated or nAb-PTX packed into an engineered MSV ( Tasciotti et al, 2011 ; Yokoi et al, 2013 ; Borsoi et al, 2015 , 2017 ). These data demonstrate that cellular elements in the TME of poorly perfused tumors dramatically change during disease progression and in response to therapy.…”

“…M2 macrophages (CD204, red) and M1 + M2 macrophages (F4/80, green) were visualized using confocal microscopy. (A) Untreated mice; (B) mice treated 2×; (C) mice treated 12×; (D) M1 macrophages quantification; (E) M1 + M2 macrophages quantification [data from Borsoi et al (2015) ].…”