Review
Recent advances in polymeric core–shell nanocarriers for targeted delivery of chemotherapeutic drugs

https://doi.org/10.1016/j.ijpharm.2021.121094Get rights and content

Abstract

The treatment effect of chemotherapeutics is often impeded by nonspecific biodistribution and limited biocompatibility. Polymeric core–shell nanocarriers (PCS NCs) composed of a polymer core and at least one shell have been widely applied for cancer therapy and have shown great potential in selectively delivering chemotherapeutic drugs to tumor sites. These PCS NCs can effectively ameliorate the delivery efficiency and therapeutic index of anticarcinogens by prolonging drug residence in the bloodstream, enhancing tumor tissue drug penetration, facilitating cellular drug uptake, controlling the spatiotemporal release of payloads, or codelivering two or more bioactive agents. This review summarizes recently published literature on using PCS NCs to transport chemotherapeutic drugs with poor aqueous solubility and discusses their design principles, structural features, functional properties, and potential limitations.

Introduction

The World Health Organization has estimated that cancer, which is the second leading cause of death in humans worldwide, will cause 13.1 million deaths by 2030, motivating the world’s attention on human health with a focus on cancer therapy (Ferlay et al., 2010, Global Burden of Disease Cancer et al., 2017). In past decades, several cancer treatment strategies, such as chemotherapy, radiotherapy, surgery, and immunotherapy, have been implemented clinically since they can remove tumors or eliminate local or systemic cancer cells via various mechanisms (Kim et al., 2004a, Qin et al., 2018). Among these strategies, chemotherapy is the cornerstone treatment for cancer because it is capable of restraining the growth and proliferation of tumor cells in a short period of time, and thus far, it has been sufficiently studied in clinical applications (Hossen et al., 2019, Wilson et al., 2019). Nevertheless, as chemotherapeutic agents lack specific targeting capabilities and biocompatibility, the accumulation of these drugs in tumors is poor; for instance, platinum anticancer drug accumulation per gram of tumor tissue in vivo was only 0.001–0.05% of the injected dose (Dowell et al., 2000), resulting in serious side effects and tumor multidrug resistance and therefore dramatically weakening the chemotherapeutic efficacy. There is a strong incentive to explore novel approaches to precisely deliver chemotherapeutic agents to action sites (cancerous cells) other than normal tissues or cells and thus enhance the recovery rate and patient compliance with chemotherapy.

Nanocarriers (NCs) have emerged in recent years as intelligent drug delivery systems at a tiny scale (10–1000 nm) (Herrero and Medarde, 2015). Many biocompatible materials have been applied as NCs, including hyaluronic acid (HA), chitosan (CS), polylactic acid (PLA), and poly(ethylene glycol) (PEG), since they exhibit numerous advantages, such as good physical stability, biodegradability, low toxicity, excellent passive and active targeting capability, and high drug loading capacity (Deng et al., 2017, Tao et al., 2021, Xie et al., 2019). Some traditional chemotherapeutics have been encapsulated into, bound to, or attached to NCs via hydrophobic interactions, chemical coupling, or electrostatic attraction to form liposomes, polymeric micelles, nanogels, or dendrimers and to consequently facilitate the precise arrival of these drugs at niduses and promote antitumor effects (Cao et al., 2020, Deng et al., 2015). For example, triphenylphosphine-Pluronic F127-HA nanoparticles were constructed to load paclitaxel (PTX), which could quickly anchor to the mitochondrial after being specifically internalized by A549 cells, and a high tumor inhibition rate (∼80%) in lung cancer models was achieved after intravenous injection into mice (Wang et al., 2020b). Overall, NCs have substantial potential in the targeted delivery of chemotherapeutic drugs and are worthy of further exploration to improve the therapeutic effect of chemotherapeutics on malignant tumors.

As a characteristic category of NCs, polymeric core–shell nanocarriers (PCS NCs) composed of a polymer core and at least one shell have played a crucial role in cancer therapy. These PCS NCs exhibit many advantages, such as long blood circulation time, high drug load capacity, effectiveness in preventing drug leakage, and good dispersity and solubility. In addition, they can not only passively accumulate at the vasculature in tumors via the enhanced permeability and retention (EPR) effects but also further promote targeting ability by decorating the shells with ligands that can interact with overexpressed receptors on malignant cells (Chatterjee et al., 2014). More importantly, their unique structure enables PCS NCs to integrate multiple functional characteristics (e.g., charge conversion and size reduction) in a single delivery system, which aids in NCs bypassing multiple physiological barriers and achieving on-demand drug delivery (Kumar et al., 2020, Panday et al., 2018, Pugliese et al., 2018). Currently, some representative PCS NCs have been designed and synthesized, such as HA-based enzyme-sensitive polymeric micelles (Shi et al., 2020), pH-sensitive nanoparticles with alternating layers of HA and poly(β-amino ester) (PBAE) on liposomes (Men et al., 2020), and dimethyl maleic anhydride- and poly(methacrylic acid-co-N,N-bis(acryloyl) cysteamine)-modified dual pH/reduction-sensitive nanoparticles (Miao et al., 2018), which have a favorable anticancer effect both in vivo and in vitro. Apparently, PCS NCs offer a preferable platform for developing smart nanosystems with optimal physicochemical properties to improve the antitumor efficacy of chemotherapeutics and simultaneously diminish the side effects of chemotherapeutics.

It is noteworthy that the PCS NCs reported in recent years have mainly focused on the following three types: single-layer core–shell nanocarriers, double-layer core–shell nanocarriers, and multilayer core–shell nanocarriers, as schematically illustrated in Fig. 1. To sufficiently exploit the potential of these PCS NCs in targeted tumor chemotherapy, we summarized the recent progress in PCS NCs applied to the site-specific delivery of chemotherapeutic drugs and discussed the design principles, structural features, functional properties, and potential limitations of each PCS NCs as well as the current challenges and prospects in transporting hydrophobic chemotherapeutic drugs. The current review will provide some inspiration for designing smart nanodrug delivery systems to resolve the issue of the limited treatment efficiency of chemotherapeutic drugs.

Section snippets

Single-layer core–shell nanocarriers

Single-layer core–shell nanocarriers containing a hydrophobic core and a hydrophilic shell, also termed polymer micelles, are formed by self-assembly of amphiphilic polymers in an aqueous solution. The inner hydrophobic core of the micelles can package drugs with poor aqueous solubility via hydrophobic interactions, hydrogen bonding, or π − π stacking, while their outer hydrophilic shell can hinder adsorption of opsonin proteins, evade recognition and phagocytosis of the mononuclear phagocyte

Double-layer core–shell nanocarriers

Double-layer core–shell nanocarriers refer to a class of multicomponent nanocarriers that consist of a functional outer shell surrounding core–shell structured polymeric nanoparticles (PNs) with a hollow or solid core for the storage of drugs. In general, these double-layer core–shell nanocarriers are constructed in such a way that drug molecules are encapsulated into PNs at first, followed by attachment of the outer layer material to PNs via different assembly strategies. Double-layer

Multilayer core–shell nanocarriers

Multilayer core–shell nanocarriers refer to a type of self-assembled, spherical, supramolecular nanoparticle prepared by alternately depositing oppositely charged polyelectrolytes onto various colloids in aqueous medium without organic solvents and surfactant, which could be divided into polymeric vesicles and hollow lipid vesicles according to compositions and structures of their inner colloids (Liu and Picart, 2016, Wu et al., 2020). As the efficient anticancer drug carriers, multilayer

Conclusions and perspectives

This review summarizes some valuable studies for the targeted delivery of chemotherapeutics to specific tumor sites using PCS NCs composed of a polymer core as well as at least one shell and highlights their design strategies, structural characteristics, functional properties, and possible limitations. To date, many PCS NCs, including single-layer core–shell nanocarriers (e.g., single copolymer micelles, polymeric prodrug micelles, and mixed micelles), double-layer core–shell nanocarriers (e.g.

CRediT authorship contribution statement

Xiuru Yang: Visualization, Writing – review & editing. Yan Xie: Conceptualization, Writing – review & editing, Supervision.

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 the National Natural Science Foundation of China (81873198), the Program of Shanghai Academic/Technology Research Leader (19XD1423700, China), and the Shanghai Natural Science Foundation (19ZR1444200, China).

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