Strategies of Overcoming the Physiological Barriers for Tumo

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Current Pharmaceutical Design, 2015, 21, 6236-6245

Strategies of Overcoming the Physiological Barriers for Tumor-Targeted Nano-Sized Drug Delivery Systems

Yufang Pi 1, Jinge Zhou1, Jing Wang1, Jian Zhong2, Lin Zhang3, Yiting Wang1, Lei Yu1,* and Zhiqiang Yan1,*

Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal university, Shanghai 200062, P.R. China; 2College of Food Science & Technology, Shanghai Ocean University, Shanghai 201306, Shanghai 200241, P.R. China; 3Department of Pharmacy, Shaoxing People’s Hospital, Shaox-ing Hospital of ZheJiang University, Shaoxing 312000, P.R. China

Abstract: Nano drug delivery systems (NDDSs) have been widely used in tumor-targeted therapy since they can effectively reduce the side effects of traditional antitumor drugs and improve the anti-tumor effect. We divided the in vivo process of tumor-targeted NDDSs into seven steps: blood circulation, tumor accumulation, tumor tissue penetration, target cells internalization, lysosome escape, drug release and drug response. In each step, NDDSs will encounter different types of barriers preventing their effective delivery or response. The researchers have been making efforts to find different strategies of overcoming the corresponding barriers for NDDSs. Hence, we here

reviewed the recent progress of NDDSs in breaking the physiological barriers for more effective in vivo anti-tumor effect, in order to shed a new perspective on the development of tumor-targeted NDDSs.

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Keywords: Nano drug delivery systems, tumor-targeted nanomedicines, pathophysiological basis, physiological barriers. INTRODUCTION

Cancer is one of the leading causes of death in the world. Cur-rently, the main treatments in clinic for cancer are surgery, chemo-therapy and radiation therapy. Although traditional chemotherapy can effectively control the growth of tumor, it could cause severe toxic effects on healthy tissues. Compared with traditional che-motherapeutic drugs, NDDSs have demonstrated great superiority due to their ability of improving the efficacy of chemotherapy and reducing the side effects [1-3].

The most common types of NDDSs include nanoparticles, liposomes, micelles, dendrimers, etc. [4]. According to the tumor targeting mechanism, the NDDSs can be divided into passive tar-geting and active targeting NDDSs. The passive targeting mecha-nism mainly involves the “Enhanced permeability and retention (EPR) effect” arisen from the abnormal, leaky and highly heteroge-neous microvasculature and the dysfunction of lymphatic drainage in tumor tissues [5]. The active targeting mechanism refers to the interaction of specific receptors overexpressed on target cells in tumor tissues and the targeting moieties conjugated to the surface of nanocarriers [6, 7]. Large amounts of reports on NDDSs have proved the effectiveness of the passive targeting and active target-ing mechanism on improving the therapeutic outcomes of NDDSs and reducing the side effect to normal tissues [8-12].

The NDDSs need to overcome a number of anatomical and physiological barriers before they can effectively arrive at target site and release drugs in tumor. We divide the systemic journey of tumor-targeted NDDSs into seven steps: blood circulation, tumor accumulation, tumor tissue penetration, target cell internalization, lysosome escape, drug release and drug response. In each step, there are different types of barriers which prevent the effective delivery or response of NDDSs. In order to improve the therapeutic outcomes, researchers have attempted many strategies on NDDSs design to overcome the physiological barriers in each step of the

*Address correspondence to these authors at the NO. 3663 Zhongshan Road, Shanghai 200062, P.R. China; E-mails: zqyan@sat.ecnu.edu.cn; yulei@nbic.ecnu.edu.cn

systemic journey. Hence, based on the analysis of physiological basis of tumor targeting, we here reviewed the different physiologi-cal barriers which may impede the systemic transport and response of tumor-targeted NDDSs, and the corresponding strategies of overcoming these barriers reported recently.

PATHOPHYSIOLOGICAL BASIS OF TUMOR TARGET-ING

Tumor grows and progresses in an intricate and complicated tumor microenvironment (TME). The TME contains a variety of components including vascular systems such as blood and lym-phatic vascular endothelial cells, dense extracellular matrix (includ-ing hyaluronic acid, smooth muscle actin, collagen fibers and pro-teolytic enzymes), hypoxia and oxidosis environment, a large num-ber of tumor cells and cancer stem cells (CSCs) [13]. As a unique microenvironment, it has the properties of leaky vasculatures, low pH, and high interstitial fluid pressure within the tumor, which have important influences on tumor proliferation, metastasis and deterio-ration [14]. The pathophysiological features of tumor tissue is the basis of designing the tumor-targeted NDDSs [15].

Tumor Cells

Different from normal cells, tumor cells allow themselves to grow out of control and become invasive. In order to meet the un-limited proliferation of tumor cells, a variety of receptors become over-expressed on the cell surface, such as transferrin receptors, folate receptors, low density lipoprotein receptors and tumor necro-sis factor receptor family [16]. Besides, there is also over-expressed P-glycoprotein (P-gp) on the surface of tumor cells. It can efflux antitumor drugs outside the cell, causing the decrease of intracellu-lar drug concentration and further the failure of chemotherapy, which is called tumor multidrug resistance (MDR) [17]. Almost all human tumor cell …… 此处隐藏：25014字，全部文档内容请下载后查看。喜欢就下载吧 ……