Use of nano engineered approaches to overcome the stromal barrier in pancreatic cancer

Abstract

While chemotherapy is the only approved non-surgical option for the majority of pancreatic cancer patients, it rarely results in a cure. The failure to respond to chemotherapy is due to the presence of an abundant dysplastic stroma that interferes in drug delivery and as a result of drug resistance. It is appropriate, therefore, to consider the stromal contribution to the resistance to chemotherapy and sidestepping this barrier with nanocarriers that improve survival outcome. In this paper, we provide a short overview of the role of the stroma in chemotherapy resistance, including the use of nanocarriers to negate this barrier. We provide a perspective and guidance towards the implementation of nanotherapeutic approaches to improve therapeutic delivery and efficacy of PDAC management.

Introduction

Pancreatic cancer (PDAC) is the 4th leading cause of cancer death, with ~43,090 deaths in the US in 2017 [1]. In terms of mortality trends, Cancer Facts & Figures 2018 demonstrates that the 5-year survival rate has remained unchanged from 2006 to 2015 [2]. In the US, around 56,000 new cases of PDAC will be diagnosed in 2018 [2]. Collectively, for all stages of disease, the 5-year relative survival rate is only 8%. This number includes patients with metastatic (~52% patients) and local disease (~10% patients), with a 5-year survival rate of 3% and 32%, respectively. Due to the late diagnosis and early metastasis, for the majority patients with advanced disease, chemotherapy is considered as the only approved treatment, with the standard of care involving the use of nucleoside analog gemcitabine (GEM) or a more potent but highly toxic 4-drug regimen, FOLFIRINOX (i.e. oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin). Moreover, chemotherapy is also used to treat the patients who are suitable for surgery (<20%), as neoadjuvant with a hope to lower recurrence. Unfortunately, these chemo applications seldom lead to a disease cure.

Chemotherapy failure can be partly explained by the presence of a dense desmoplastic stroma serving as a physical and biological barrier for drug delivery in PDAC and an unfavorable pharmacokinetics (PK) profile [3]. It is reasonable to consider, therefore, overcoming of the stromal interference in drug delivery and chemo-resistance to improve efficacy and patient survival [3]. A popular approach to overcoming the stromal resistance is to take advantage of the ability of nanocarriers to deliver therapeutic agents to the tumor site by mechanisms that differ from the uptake and retention of classic non-encapsulated molecular drug. A recent meta-analysis on PDAC clinical trials demonstrated that nanoparticles are promising approach to increase efficacy while reducing toxicity of multiple cancer drugs in PDAC patients [4]. Another exciting development is the use of smart design of the nanocarriers to enable them to negotiate the stroma barrier and improve drug delivery [5]. In fact, understanding the stromal contribution to the tumor access by an enhanced permeability and retention effect (EPR) in solid tumors is of particular relevance to the study of PDAC [[6], [7], [8], [9]]. The concept of “enhanced permeability” as an across-the-board explanation for nanocarrier access to solid tumor sites is over-simplified and needs to be re-interpreted [[10], [11], [12], [13], [14], [15]]. While enlarged tumor vascular fenestrations, irregular branching and abnormal angiogenesis have been reported in different cancer scenarios (many of them are xenograft models in mice) [6], the dysplastic stroma in PDAC indicate that additional consideration needs to be given to the poorly perfused, collapsed and obstructed blood vessels in this cancer as a result of tight adherence of stromal fibroblasts or pericytes to the vascular wall. In this communication, we provide a short overview to address the inhibitory effect of the stroma on PDAC treatment, including the consideration for the use of nanocarriers to potentially engineer and past this obstacle. We also provide a perspective and guidance towards the implementation of nanotherapeutic approaches in PDAC and other stroma-rich solid tumor types.