Review
Stimuli-responsive charge-reversal nano drug delivery system: The promising targeted carriers for tumor therapy

https://doi.org/10.1016/j.ijpharm.2019.118841Get rights and content

Abstract

The stimuli-responsive charge-reversal nano drug delivery system (CRNDDS) for the treatment of tumors has attracted much attention as an effective drug delivery system. The charge-reversal nanocarriers are either uncharged or negatively charged under normal physiological environment; however, they acquire positive charged in tumor tissue microenvironment. The process of charge reversal from negative-to-positive results in not only quick drug release in acidic environment but also enhance the cellular uptake of drug through electrostatic absorptive endocytosis resulting in improvement of cancer therapeutic outcome. In this review, we discuss the recent advances in the study of charge-reversal nanocarriers that could control the distribution of drugs in response to specific stimuli, such as pH, reduced glutathione (GSH) concentration, enzyme concentration, light and thermal stimulation. The applications of CRNDDS in the tumor treatment was also analyzed and summarized.

Introduction

At present, cancer is still one of the leading causes of death in humans around the world (Orzechowska et al., 2017). Besides surgery, radiation therapy, immunotherapy, and chemotherapy are the main treatment approaches for cancer treatment (Whittaker et al., 2010). In fact, many chemotherapy drugs can significantly improve the prognosis and quality of life of cancer patients (Zha et al., 2014). However, the poor selectivity and toxic side effects of chemotherapy drugs are still the major problem encountered in cancer chemotherapy. These chemotherapy drugs often damage healthy cells while killing tumor cells and resulting in toxicity to patients, which causes serious complications (Baker et al., 2009). For example, the chemotherapy drug, doxorubicin (DOX), is commonly used for the treatment of breast cancer and lymphoma (Sun et al., 2017). However, similar to other chemotherapy drug, DOX causes significant toxicity such as myelosuppression, gastrointestinal reactions and cardiotoxicity (Tahover et al., 2015), which greatly limits the clinical application of DOX. In addition, multidrug-resistance through complex mechanisms pose as another challenge in cancer treatment (Caitriona et al., 2013, Kanamala et al., 2016). Nanomedicines are reported to reduce the toxic effects and overcome the development of multidrug-resistance (Markman et al., 2013).

In the past few decades, nano-drug delivery systems (NDDS) have shown significant benefits in cancer diagnostics & treatment and have established themselves as promising drug delivery tools for chemotherapy (He et al., 2017a). The NDDS generally use either natural or synthetic high molecular polymers to encapsulate drugs in nanoparticle or adsorb drugs on the surface of the nanoparticle. NDDS have the advantages of increased aqueous solubility, improved stability, and extending the duration of action of the drug. A number of different forms of NDDS have been developed as new cancer therapeutics which including liposomes (Sen et al., 2013), nanoparticles (Gao et al., 2010), micelles (Keskin et al., 2017), etc.

Tumor tissues and cells have unique structural and physicochemical properties compared to normal tissues and cells (Chen et al., 2017a, Lu et al., 2017). Tumor tissues are weakly acidic, over-express certain enzymes such as esterase, contain high intracellular concentration of reduced glutathione (GSH) and high levels of hydrogen peroxide (H2O2) in mitochondria (Khawar et al., 2015). The different forms of NDDS are being developed based on these characteristics of tumor cells. In recent years, the stimuli-responsive NDDS are being designed and studied to prove and produce intended experimental outcomes. Despite the capabilities of water-soluble polymers like poly(ethylene glycol) (PEG) that could prolong the drug’s blood circulation time and enhance its accumulation in tumor tissues through improved permeability and retention effect (EPR), they failed to produce optimal cellular uptake of drugs at the tumor sites (Hiroto et al., 2013). The cellular uptake of drugs was improved by the introduction of the drug on the surface of the nanocarrier with specific binding ability to the receptors on the tumor cell (Cai et al., 2015, Cai et al., 2016, He et al., 2017b, Zhu et al., 2016). However, the heterogenous nature of tumors still poses problems for tumor penetration and retention (Jain and Triantafyllos, 2010). Therefore, the key challenges in the preparation of high-efficient NDDS involve steps in improving the stability of drugs during systemic circulation, increasing their penetration in tumor tissues, and accumulation of required drug concentration in tumor cells.

Studies have shown that (Hu et al., 2016, Wang et al., 2019), the surface properties of nanocarriers have a great impact on the drug delivery process. Nanocarriers with positive charges on the surface are more likely to be taken up into negatively charged tumor cells by electrostatic attraction-mediated targeting (Deng et al., 2014). However, the positive charge on the surface of the nanocarriers might also be responsible for nonspecific binding with negatively charged proteins in the blood resulting in rapid clearance from the blood circulation (Huang et al., 2012). In order to maximize the therapeutic effect, the drug delivery system must first be stable in the circulatory system and enable the drug to accumulate in tumor cells. The charge-reversing nano-drug delivery system (CRNDDS) combines positive and negative surface charges in the drug delivery process (Scheme 1). The advantage in this is expected to balance the contradiction between cellular uptake and blood circulation of nanoparticles. CRNDDS are either negatively charged or uncharged in the blood, do not bind to proteins in the blood, avoid phagocytosis by mononuclear phagocytic system, and can achieve longer circulation times in blood. The negative-to-positive charge reversal is possible by specific stimulation conditions at the tumor site, including pH, redox reactions, reactive oxygen-, enzyme-, light- and thermo-responsiveness. The overall performance of CRNDDS is superior, and the affinity with the cells is enhanced, thereby selectively increasing the uptake of tumor cells (Chen et al., 2016, Hiroshi et al., 2013, Hu et al., 2016). Thus, these novel vectors had already created a great interest for the development of delivery systems for anticancer drugs. In this review article, the different methods to develop CRNDDS were discussed.

Section snippets

Stimuli-responsive charge-reversal delivery system

According to the literature, the charge reversal of CRNDDS mainly relies on certain stimuli in response to the external environment to change certain chemical groups of CRNDDS, such as bond cleavage, protonation, structural changes and so on. There were many stimulating factors that have been reported so far, namely pH, oxidative reduction, enzymes, light, and heat, and so on. Basing on the different stimulating factors on charge reversal, CRNDDS could be classified into pH-, reduction-, active

Chemotherapeutics delivery

Hydrophilic copolymers such as PEG and HPMA have been widely studied as drug carriers for tumor therapy. The copolymer drug conjugate is capable of passive accumulation at the tumor site due to the EPR effect. However, the highly hydrophilic, neutrally charged, dense polymer layer prevents the efficient uptake of this polymeric system by the cancer cells. Thus, the CRNDDS provides a promising way for chemotherapeutic drug delivery to complete rapid cellular uptake with carried drug at the tumor

Conclusions

CRNDDS can achieve “negative-positive” charge reversal in response to tumor site stimulation, so it is widely used in the research of tumor therapy and shows great potential. CRNDDS achieve efficient delivery by sensitivity to specific stimuli such as pH, GSH concentration, and enzyme levels. By introducing methods such as functional bonds or groups that stimulate responsive charge reversal, the carriers could be obtained for longer cycle times and charge reversal under the stimulation of the

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was supported by Shandong Provincial Natural Science Foundation, China (No. ZR2017MH086) and National Natural Science Foundation, China (No. 81803474).

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