European Journal of Pharmaceutics and Biopharmaceutics
Review ArticleLipid–polymer hybrid nanoparticles as a new generation therapeutic delivery platform: A review
Graphical abstract
Introduction
Nanotechnology represents a powerful tool in the field of medicine to combat a plethora of diseases, such as cancer and cardiovascular diseases. Thus, it is not surprising that nanoscale structures (<1000 nm) have been extensively used as delivery vehicles of various therapeutic substances, ranging from small molecule drugs, genes, and biopharmaceuticals (e.g., proteins, peptides) to diagnostic imaging agents [1]. These substances are typically encapsulated inside nanoparticle carriers, or conjugated onto the surface of the nanoparticle carriers, where their release from the carriers is controlled by the carrier matrix formulation, or triggered by external stimuli (e.g., pH, temperature) [2], [3]. The widespread use of nanoparticles as therapeutic carriers is largely attributed to their small size that enables targeted delivery to the site of action resulting in higher therapeutic efficacy [4]. In addition, sufficiently small immunoinert nanoparticles can effectively evade capture by the reticuloendothelial system (RES) resulting in high bioavailability of the therapeutics [5].
Polymers (e.g., polymeric nanoparticles, polymeric micelles, dendrimers) [6], [7], [8], lipids (e.g., liposomes, solid lipid nanoparticles) [9], [10], [11], and metals (e.g., gold, silica) [12], [13] have been commonly used as nanocarriers. The in vivo properties of these nanocarriers can be tailored by means of various modification techniques, where properties such as (i) circulating longevity and stability, (ii) targeting ability, (iii) stimuli responsibility, and (iv) diagnostic ability are desired [14]. For example, long circulating chemotherapeutic nanoparticles with active targeting moieties (e.g., folic acid, antibody, aptamer) can be delivered specifically to tumor cells owed to the enhanced permeability and retention (EPR) effect [15]. Among the nanocarriers, the most prominent are the polymeric nanoparticles and liposomes, attributed to their advantageous characteristics [16], [17], as outlined in the next two paragraphs.
Polymeric nanoparticles have been widely used as they exhibit high structural integrity, stability during storage, and controlled release capability. In addition, they are also easy to prepare and readily functionalized for active targeted delivery, all of which make them highly attractive as therapeutic delivery vehicles [18]. Polymeric nanoparticles can be prepared from both natural polymers (e.g., chitosan) and synthetic biodegradable and biocompatible polymers (e.g., poly-lactic-co-glycolic acid (PLGA)). On this note, polyethylene glycol (PEG) is typically conjugated to the polymer to enhance the immunocompatibility of the nanoparticles attributed to the consequential RES removal avoidance [19]. Owing to its hydrophilicity, PEG reduces non-specific interactions of the polymeric nanoparticles, which are typically hydrophobic, with the opsonin that effectively targets hydrophobic substances. As a result, PEGylated polymeric nanoparticles exhibit prolonged in vivo circulation time resulting in their high bioavailability [20], [21].
Compared to polymeric nanoparticles, liposomes have long been perceived as the more ideal drug delivery vehicles because of their superior biocompatibility as liposomes are basically analogues of biological membranes, which can be prepared from both natural and synthetic phospholipids [22]. Liposomes on their own, however, are easily cleared by the RES leading to their poor bioavailability [23]. Similar to the PEGylation of polymeric nanoparticles to enhance the bioavailability, lipid–PEG is often used in liposome formulations to prolong the in vivo circulation time [24], [25]. Nevertheless, liposomes suffer from drawbacks of lack of structural integrity resulting in content leakage and instability during storage [23].
To address the limitations of polymeric nanoparticles and liposomes, a new generation delivery vehicle of therapeutics termed lipid–polymer hybrid nanoparticles (LPNs) has been developed [26]. The LPNs, which combine the characteristics of both polymeric nanoparticles and liposomes, comprise three components as illustrated in Fig. 1. They are (1) a polymer core in which the therapeutic substances are encapsulated, (2) an inner lipid layer enveloping the polymer core, the main function of which is to confer biocompatibility to the polymer core, and (3) an outer lipid–PEG layer, which functions as a stealth coating that prolongs in vivo circulation time of the LPNs, as well as providing steric stabilization. In addition, the inner lipid layer also functions as a molecular fence that minimizes leakage of the encapsulated content during the LPNs preparation. Furthermore, the inner lipid layer slows down the polymer degradation rate of the LPNs product by limiting inward water diffusion, hence enabling sustained release kinetics of the content.
As a result of its core–shell structure, the LPNs exhibit (1) high structural integrity, stability during storage, and controlled release capability attributed to the polymer core, and (2) high biocompatibility and bioavailability owed to the lipid and lipid–PEG layers [27]. With such favorable characteristics, LPNs have rapidly evolved into a robust drug delivery platform. On this note, modifying the end group of the PEG chains of the lipid–PEG using methoxyl groups has been shown to lower the complement activation level of the immune system toward LPNs, resulting in lower immunogenicity [28], thus further establishing the LPNs’ potential as an effective drug delivery platform.
In an earlier review by Zhang and Zhang [29], existing LPNs preparation strategies along with physical characteristics and drug delivery applications of LPNs were discussed. Another review by Mandal et al. [30] focused on the conventional preparation methods and characteristics of the LPNs, as well as introducing the non-drug delivery applications of LPNs. Since then, further innovations have led to tremendous progress in this field, contributing significant studies not covered in the aforementioned reviews. Prominent among these has been the innovation in the LPNs preparation methods, for example, by soft lithography particle molding [31] and by continuous nanoprecipitation in a microchannel for large-scale productions [32]. Apart from drug delivery, the spectrum of applications of LPNs has also now expanded to include deliveries of genetic materials [33], vaccines [34], and diagnostic imaging agents [35].
Furthermore, recently an increasing number of studies have reported successful in vivo deliveries of drug-loaded LPNs [36], [37]. One recent study by Hu et al. [38] went further by demonstrating in vivo that by replacing the lipid–PEG with red blood cells (RBC) membrane-derived vesicles, extracted from the same diseased mice, the immunogenicity of the LPNs was lowered and its biocompatibility was enhanced. Specifically, the LPNs enveloped by the RBC membrane-derived vesicles exhibited superior retention after 24 h (≈29%) compared to the LPNs enveloped by lipid–PEG layers (≈11%). This result signified the potential use of the patient’s own RBC for personalized medicine involving LPNs.
In this review, we aim to provide an updated overview of the LPNs development to include recent innovations in its preparation strategies and applications. First, we present the conventional and state-of-the-art methods that have been employed to prepare LPNs, where they can be broadly classified into two basic categories of one-step and two-step methods. For each method, we identify formulation parameters that govern the LPNs’ physical characteristics (e.g., size, colloidal stability, encapsulation efficiency). Second, we discuss drug delivery applications of LPNs, with an emphasis on the recent innovations for anticancer therapy, via combinatorial drug and active targeted delivery. New LPNs applications as delivery vehicles of genetic materials (e.g., deoxyribonucleic acid (DNA), small interfering DNA (siRNA)) and diagnostic imaging agents are also presented. Lastly, we conclude by highlighting future research needs and challenges in the LPNs development.
Section snippets
Conventional two-step method
The two-step method was the most common method employed in the early phase of LPNs development. In the conventional two-step method, preformed polymeric nanoparticles are mixed with preformed lipid vesicles, where the lipid vesicles are adsorbed on the polymeric nanoparticles by electrostatic interactions. A list of LPNs studies, which employ the conventional two-step method, with or without encapsulated substances, is provided in Table 1. The materials used and the physical characteristics of
Drug delivery
The different preparation methods available for LPNs have enabled encapsulation of a wide range of drugs, regardless of their aqueous solubility, ionicity, hydrophilicity, and lipophilicity as demonstrated in Cheow et al. [59]. The drug delivery applications of LPNs nonetheless have been dominated by deliveries of anticancer drugs. This tendency is mainly due to the presence of multi-drug resistant cancer cells as the foremost challenging issue in chemotherapy, thereby improved innovative
Preparation of LPNs
At its current state of development, LPNs preparation has been successfully demonstrated, where good controls over the desired LPNs’ physical characteristics are evident. A majority of the LPNs reported in the literature were prepared by the one-step method, in particular by nanoprecipitation. The one-step method has been increasingly preferred over the two-step method because the one-step method is simpler and faster in terms of the actual preparation, despite the fact that it is conceptually
Acknowledgement
The authors would like to acknowledge the funding from Ministry of Education of Singapore AcRF Grant No. RG 76/10.
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