Review
Emerging 2D material-based nanocarrier for cancer therapy beyond graphene

https://doi.org/10.1016/j.ccr.2019.213041Get rights and content

Highlights

  • Highlight the emerging 2D material based nanocarriers for biomedical applications.

  • Summarized surface engineering strategy used in nanocarriers.

  • Overview the biomedical application of 2D material nanocarriers.

  • Give a guide to design stimuli-responsive controllable drug release strategy.

  • Proposed insightful prospects for the future development of 2D material based nanocarriers application.

Abstract

2D materials (e.g., graphene, graphene analogues), with unique physical and chemical properties, shows intriguing potential for the realization of versatile biomedical applications. Tremendous attention has been attracted on 2D material based nanocarriers, which play a crucial role in therapeutic drug, gene, and biomedical agent delivery for cancer theranostics. This review provides an up-to-date review on the development of nanocarriers based on 2D materials beyond graphene, including basic and emerging synthesis methods, the catalog of 2D material-based nanocarriers, biosafety, surface functional engineering, the realization of stimuli-responsive controllable release and biomedical applications. Among the properties and performance to be summarized, there is particular focus on nanocarriers loading capability, biosafety, and therapy efficiency and so on. Finally, by addressing major issues and challenges, some prospects for future directions in this area are provided.

Introduction

Cancer is currently principal cause of death, with more than 18 million new cases every year [1]. Because of the development of cancer treatment strategies, the mortality of cancer has been appreciably decreased compared to that in the past few decades. Photothermal therapy [2], [3], photodynamic therapy [3], [4], immunotherapy [5] and theranostic treatment [6], [7] are some emerging and efficient ways for antitumor treatment. In conventional, surgery, radiotherapy, and chemotherapy have been accepted as the main strategies for clinical cancer therapy [8], [9]. However, some limitations of chemotherapy, such as underutilization of drug, unavoidable severe side effects, still impede its high performance in eliminating cancer cells [10].

Inspired by the first liposome and polymer-protein conjugate nanocarriers that reached clinical trials in the mid-1980s and were approved onto market in the 1990s, researchers have focused great efforts on the search for and design of nanocarriers [10]. Nanocarriers that incorporate molecules to target cancer cells during therapeutic and diagnostic applications have been regarded as a “magic bullet” (Paul Ehrlich in 1908). This theranostic strategy can avoid the disadvantages of conventional chemotherapy, for instance, ineffective drug access to target tumors, poor bioavailability, unfavorable biodistribution, and multidrug resistance [11], [12], [13]. These enhancements can remarkably improve the performance of chemotherapy. Natural polymers, artificial polymers, and solid lipids are popular nanocarriers typically used for clinical applications due to their biocompatibility and biodegradability [14]. While limited drug load ability and uncontrollable drug release impede further development of conventional nanocarrier for cancer therapy application.

Ultrathin 2D (two dimensional) materials were defined as free-standing sheet-like crystals with size larger than 100 nm in plane, while only single or few atoms layer in thickness [15], [16]. 2D materials based nanocarrier biomedical application may match well with requirement for nanocarrier application attributed to its unique properties include high stability under complex physiological conditions, high carrier capacity, biosafety, and easy incorporation with cancer drug molecules or agents [10].

The reasons that the biomedical application of 2D materials has progressed so quickly is summarized as follows. First, 2D materials have a large “material library” that provides abundant choices to satisfy various requirements for nanocarriers during biomedical applications. Recently, valuable and interdisciplinary research reports about biomedical applications have been reviewed, and these reports are typically classified by 2D material system, including graphene [17], [18], [19], transition metal dichalcogenides (TMDs) [20], group-VA semiconductors [21], [22], [23], [24], transition metal carbides (MXenes) [25], [26], graphitic carbon nitride (g-C3N4) [27], and hexagonal boron nitride (h-BN) [28]. Second, the excellent physicochemical properties of 2D materials enable them to match well with practical biomedical applications. For instance, large surface areas are induced by their unique ultrathin planar structures, which facilitate high drug loading efficiency [29], [30], high biocompatibility and biodegradability. For instance, because phosphorus is an essential element in our body (1% of human body weight), Black phosphorous (BP) nanocarriers exhibit intrinsic biocompatibility for biomedical applications [31], [32], [33]. Third, laboratory procedures for synthesizing 2D materials with high quality and high yields are straightforward to perform. Recently, many 2D material preparation approaches have been developed to obtain materials with various morphologies and expected dimensions. Owing to its low cost, high yield, and easy operation properties, liquid phase exfoliation is a potential candidate method of 2D material synthesis for theranostics-related biomedical applications. The aforementioned feasibility of 2D materials based biomedical applications indicates that 2D materials can be developed as a new robust nanoplatform for disease diagnosis and treatment. Biomedical applications of different 2D materials have been reviewed sufficiently. Recognizing the leading roles played by graphene and graphene oxide, tremendous progress has been reported and well summarized regarding the use of graphene and graphene oxide as nanocarriers. Recently, emerging 2D materials beyond graphene-based nanocarriers have been widely explored with exciting achievements including biosensor [34], [35], [36], antitumor therapy and so on. Nevertheless, we have yet to see a review focused on the perspective of 2D material-based nanocarriers beyond graphene.

Here, we aim to provide recent advances in emerging 2D material based nanocarriers beyond graphene (Fig. 1). First, we introduced the arsenal of 2D material-based nanocarriers, including the synthesis and classification of relevant 2D materials. Specifically, we summarized the typical synthesis methods of 2D materials and highlighted suitable methods for fabricating nanocarriers. Next, surface engineering of emerging 2D materials, including surface functionalization for stability in a physiological environment and surface functionalization for a specific target, was discussed. After that, the great potential applications of 2D materials in drug delivery systems (DDS), gene delivery systems, imaging delivery systems, and multifunctional theranostic agent delivery systems, followed by examining the realization of stimuli-responsive controllable release and biosafety, are summarized. Finally, according to the current progress, we highlight the challenges and outlook in 2D materials and provide some personal insight into future trends in this research field.

Section snippets

The arsenal of 2D nanocarrier materials

Nanocarriers are identified as nanomaterials that are hundreds of nanometers in size and possess the ability to load drugs or other biomedical agents. Nanocarriers are small and stable enough to free flow in blood vessels, and can be easily enter into the cell via phagocytosis and to be finally expelled from the cell. These properties are important for the proper design of an expected nanocarrier system. For a prospective nanocarrier, high stability in the blood stream, high loading capability,

Surface engineering of 2D nanocarriers

Surface engineering or modification is a major issue when 2D materials are used in biomedical nanocarrier applications. On the one hand, the bare 2D material always shows some charges on its surface that readily induce aggregation in a physiological environment. On the other hand, from a biological perspective, when the bare 2D material is injected into the bloodstream, plasma proteins and glycoproteins will rapidly coat it, and it will activate defense system of the body, the mononuclear

Therapeutic drug delivery

Graphene has been widely reported as a drug carrier for loading various kinds of drug molecules [19]. 2D materials beyond graphene or graphene analogues share many unique physiochemical properties, such as high surface area and abundant anchor points. Therefore, a high loading capacity of 2D materials beyond graphene was expected.

Yin and coauthor [41] synthesized monolayer MoS2 with tunable size by a modified exfoliation method (Fig. 7a). This simple strategy demonstrated a high-throughput with

Stimuli-responsive controllable release

Substantial nanomedicine research strategies have been proposed to increase drug delivery efficiency by engineering multifunctional nanocarriers [178]. The treatment efficacy of a nanomedicine is intensely decided by the administration method and drug release efficiency. The growing desire for precision and personalized cancer therapy leads to the urgent need for precise drug release. The pH values, enzyme concentrations, and redox species significantly differ between tumor sites and normal

Biocompatibility of 2D material nanocarrier

It is vital to study biocompatibility and toxicity using cells and animal models so that we can gain insight into the health hazard that 2D nanocarriers may pose, if any. To meet the requirements of biomedical applications, the biocompatibility of 2D material nanocarriers should be evaluated in vitro and vivo. Three common strategies to investigate the biocompatibility of 2D materials include toxicity, biodistribution and biodegradability.

In recent decades, the biocompatibility studies of

Conclusion and prospects

Due to the unique intrinsic structural/compositional/morphological characteristics, 2D materials have provided unprecedented opportunities to advance the development of nanomaterial-based drug delivery systems for biomedical applications. This review highlights the recent advances in drug delivery systems based on emerging 2D materials beyond graphene and summarizes the recent progress in fabrication, modification strategies, stimuli-responsive drug release and biomedical applications and

Acknowledgements

This research was supported in partially by the National Natural Science Fund, China (Grant No. 61875138, 61435010, 11904239 and 6181101252), and Science and Technology Innovation Commission of Shenzhen, China (KQTD2015032416270385, JCYJ20150625103619275, JCYJ20170818141407343, JCYJ20170818141519879, JCYJ20170818141429525 and JCYJ20170811093453105). China Postdoctoral Science Foundation, China (Grants 2017M620383; 2018M633118; 2018M633127). This work was also supported in part by a CRI project,

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