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Lipid–polymer hybrid nanoparticle-mediated therapeutics delivery: advances and challenges
Drug Discovery Today Volume 00, Number 00 May 2017
Lipid–polymer hybrid nanoparticlemediated therapeutics delivery: advances and challenges Q1
Rajendran J.C. Bose1, Rramaswamy Ravikumar2, Vengadeshprabu Karuppagounder3, Devasier Bennet4, Sabarinathan Rangasamy5 and Rajarajan A. Thandavarayan6 1
School of Integrative Engineering, Chung-Ang University, Seoul, Republic of Korea Department of Advanced Materials and Engineering, Hanseo University, Seosan-si, Republic of Korea 3 Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan 4 Department of Mechanical Engineering, Texas Tech University, Lubbock, TX, USA 5 Department of Chemistry, Central University of Tamil Nadu, Thiruvarur, India 6 Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA 2
With rapid advances in nanomedicine, lipid–polymer hybrid nanoparticles (LPHNPs) have emerged as promising nanocarriers for several biomedical applications, including therapeutics delivery and biomedical imaging. Significant research has been dedicated to biomimetic or targeting functionalization, as well as controlled and image-guided drug-release capabilities. Despite this research, the clinical translation of LPHNP-mediated therapeutics delivery has progressed incrementally. In this review, we discuss the recent advances in and challenges to the development and application of LPHNPs, present examples to demonstrate the advantages of LPHNPs in therapeutics delivery and imaging applications, and discuss the translational obstacles to LPHNP technology.
Introduction LPHNP delivery systems have been widely investigated at the preclinical level and are gaining increasing attention in clinical trials because of their attractive properties for drug delivery [1–3]. These HNPs combine the advantages of polymeric and liposomal drug carriers and, thus, are promising agents in different therapeutic and diagnostic fields [4]. LPHNPs comprise core–shell HNPs consisting of three distinct components: a biodegradable polymeric core for the efficient loading of poorly water-soluble drugs; a lipid monolayer surrounding the core to enhance the stability and reduce the outward diffusion of the drug; and a lipid-polyethylene glycol (PEG) outer corona to protect against immune recognition and enhance the systemic circulation of LPHNPs in vivo [1,3,5,6]. The polymeric cores of LPHNPs usually comprise biodegradable polymers, such as polylactic-co-glycolic acid (PLGA), owing to
Corresponding authors: Bose, Rajendran J.C. ([email protected]), ([email protected]), Thandavarayan, R.A. ([email protected]) 1359-6446/ã 2017 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2017.05.015
their biocompatibility, degradability, and previous use in US Food and Drug Administration (FDA)-approved products [2,7,8]. Q2 Compared with other types of nanocarrier, LPHNPs have several unique advantages, including the range of lipids, biocompatible polymers, and polymer–lipid combinations from which they are prepared, as well as their superior ability to co-encapsulate different therapeutic and imaging agents [2–5]. In previous reviews, researchers have focused on the preparation, characterization, and drug and/or gene delivery applications of LPHNPs [1,3,5], as well as the lipid-based surface engineering of polymeric NPs and their potential advantages in drug and gene delivery [2]. Additionally, advances in cell membrane-functionalized NPs (CMFNPs) from various cell sources, their characterization, and their diverse biomedical applications have also been reported [2,9]. Since these reviews, technological advances have led to remarkable progress in LPHNP research, particularly in the large-scale production and development of NPs coated with cell membrane-derived lipids [10–13]. In this review, we discuss recent advances in and
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challenges to the development and application of LPHNPs, present examples to demonstrate the advantages of LPHNPs in therapeutics delivery and imaging applications, and discuss translational obstacles in LPHNP technology.
Advances in the preparation of LPHNPs
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LPHNPs have been the subject of several promising preclinical studies owing to their multifunctional properties [1,4,14]. The major concern surrounding LPHNPs was their preparation [15,16]. At the laboratory scale, LPHNPs can be fabricated through either a single- or a two-step preparation method [7,8,17–19]. In the two-step preparation method, the lipid shell and the polymeric core are prepared individually and then fused together. Various mixing techniques, such as direct hydration, sonication, or extrusion, have been used to fuse the polymeric cores with the lipid vesicles to form bilayer LPHNPs [2–4]. Electrostatic interactions between the anionic polymeric core and the cationic lipid vesicle drive the fusion process [7,8]. However, an alternative single-step approach is now preferred, because it is easier and more convenient to use. In this single-step method, the lipid, polymer, and incorporated drugs are mixed together, and LPHNPs form by selfassembly [19,20]. Another method, the modified nanoprecipitation method, involves the addition of an organic phase containing a dissolved polymer onto a heated aqueous phase containing a lipid and lipid-PEG, followed by mechanical vortexing to complete the self-assembly and evaporation to remove the excess organic solvent [2,14,21]. A modified single-step sonication-based protocol that streamlines the laboratory-scale synthesis process, allowing for a 20-fold reduction in the nanoparticle fabrication time, has also been reported [22]. For instance, Dehaini et al. reported an easy method for the preparation of targeted ultra-small LPHNPs (25 nm), and explored their effectiveness in targeting docetaxel delivery in a mouse tumor model [14]. Conventionally prepared HNPs exhibit many characteristics of a reliable therapeutic carrier, including excellent stability, ability to load multiple drugs, and flexibility in functionalization with targeting ligands [1,3]. Despite these advantages, the preparation step needs further exploration for scaling up the production of LPHNPs to clinically relevant quantities. The preparation process can have an important role in optimizing the physicochemical attributes of LPHNPs. Laboratory-scale production by pipetting or vortex mixing introduces process variability, which can affect the quality and in vivo performance of LPHNPs [2,14,16,20]. The difficulties in manufacturing LPHNPs in a controlled, reproducible, and scalable manner also delays their clinical translation [23]. Recent microfluidic-platform-based rapidmixing protocols offer a unique advantage in generating uniformly sized LPHNPs [13]. The early design of hydrodynamic flow focusing resulted in low productivity [24]. However, successive designs that introduced high-speed convective and microvortex mixing were found to be successful and increased the productivity to 3 g/h with greater reproducibility and homogeneity [22]. In addition, the vortex and turbulence that occur in high-speed mixing allow a shorter mixing time and yield NPs of smaller sizes. In recent study, a microfluidic platform, exploiting superfast time intervals between sequential nanoprecipitation processes, was developed for high-throughput production of HNPs. This multiplexed microfluidic design enables a high-throughput production 2
Drug Discovery Today Volume 00, Number 00 May 2017
rate of approximately 700 g/day of HNPs on a single device and enhances the payload of drug, ensuring controlled drug release from the HNPs. A versatile coaxial turbulent jet mixer can increase the throughput production of NPs to 3 kg/day, while maintaining the advantages of homogeneity, reproducibility, and tunability [23]. Another study demonstrated that the incorporation and operation of multiple flow-focusing channels in the same device improved the throughput and scalability of the procedure [23]. Recent advances in particle replication in nonwetting templates (PRINT) technology have given researchers unprecedented control over the physicochemical properties of NPs and allowed large-scale fabrication [25]. When scaling up the formulation, there should be a trade-off between the production yield and the desired particle characteristics. This needs to be considered when tailoring largescale production to meet the requirements of specific applications. Despite the high prevalence of the microchannel method in LPHNP fabrication, there are certain limitations that prevent it from being suitable for all applications. A systematic screening study is required to determine the relations between the selected independent variables and the responses obtained from the LPHNP fabrication experiments. A list of recent advances in LPHNP preparation is given in Table 1.
Advances in therapeutics delivery by LPHNPs LPHNPs represent a promising drug delivery platform owing to the positive attributes of both liposomes and polymeric NPs, their superior biomimicking ability, and their customized targeting features [1–3]. The encapsulation of therapeutics into LPHNPs can improve their stability and prevent their rapid leakage, thus prolonging their therapeutic effect and minimizing their toxicity [4,20]. The appropriate selection of lipids and biodegradable polymers allows for the design of HNPs with desired biological features for extended circulation and site-specific localization [4,5,17,19]. Additionally, tailoring lipids on the surface of the polymeric core can improve the biocompatibility and control the drug-release kinetics. Recently, a strategy was demonstrated to improve the antiproliferative efficacy, while minimizing the toxicity of sirolimus through different lipid-based surface-engineering techniques [20]. Furthermore, drug-loaded LPHNPs can be tailored by adjusting their physicochemical properties to control or trigger drug release [26]. In the following section, we highlight the latest advances in LPHNP-mediated therapeutics delivery.
Recent advances in LPHNPs designed for effective anticancer therapy Developed LPHNPs provide an alternative approach in anticancer therapy that can overcome the limitations of conventional cancer therapeutics [4]. LPHNPs represent a valuable therapeutics delivery system that protects drugs in the bloodstream, increases their biodistribution, and limits their adverse effects by achieving target specificity [2,4,12]. Additionally, their ability to encapsulate diverse therapeutics and release them in a controlled or sequential manner ensures the delivery of combinatorial cancer therapy [12,26]. Co-delivery of anticancer drugs and genes is a promising approach to achieve synergistic anticancer effects [27]. The rational design of LPHNPs with targeting moieties such as folic acid (FA), aptamers, and antibodies could further assist in the active
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TABLE 1
Q7 Title
Recent advances in the LPHNP production process Quick synthesis of LPHNPs using a single-step sonication method Large-scale synthesis of LPHNPs (10 g/h) using a multi-inlet vortex reactor (MIVR) Mass production of LPHNPs through controlled microvortices Ultrahigh-throughput synthesis of NPs using a coaxial turbulent jet mixer PRINT technology to generate highly uniform HNPs
Microfluidic electroporation-facilitated synthesis Ultra-small LPHNP synthesis via nanoprecipitation methods Advanced strategies in LPHNP-mediated therapeutics delivery Differentially charged hollow core–shell LPHNPs with distinct functional features Hybrid NPs for systemic delivery of functional mRNA to lungs LPHNPs with pH-triggered PEG shedding
MF-activated LPHNPs for stimuli-responsive drug release
Co-delivery of DOX and SOR via iRGD-conjugated LPHNPs Multiple layer-by-layer LPHNPs for co- delivery of 5-fluorouracil, irinotecan, oxaliplatin and folinic acid (FOLFIRINOX) for treatment of pancreatic cancer Erythrocyte-platelet hybrid membrane coated NPs
Advantages
Refs
Improves the production rate almost 20-fold while not compromising physicochemical properties Improves production rates to >10 g/h
[21]
Controls the flow rates [i.e., Reynolds number (30–150)], thereby enhancing LPHNP productivity to approximately 3 g/h Enhances LPHNP production up to 3 kg/day
[5] [6] [23]
Has numerous advantage associated with scalability, allowing the fabrication of monodispersed NPs with precise and independent control over physiochemical parameters (particle size, shape, and composition) Demonstrates the feasibility of the production of erythrocyte membrane-coated MNPs Enables the production of ultra-small, sub–25 nm LPHNPs
[25]
A novel scalable strategy that enhances the loading efficiency and controls the release of biomolecules Enables systemic delivery of functional mRNA Novel LPHNPs designed with a PEG coating that is shed in response to a low pH trigger; enables the NPs to be stable in the circulation and at neutral pH, but to destabilize and fuse with lipid membranes in acidic tumour microenvironments A stimuli-responsive NP (SRNP) strategy that enhances the therapeutic efficacy of drugs and minimizes adverse effects via the controllable release of the drug at the target site This co-drug delivery system has shown great promise in hepatocellular carcinoma therapy Innovative strategy that enhances the therapeutic effects of drugs, while minimizing adverse effects compared with the FOLFIRINOX regimen alone Dual cell membrane functionalization pf NPs results in their multifunctional capabilities
[37]
targeting and co-delivery of more than one therapeutic agent either simultaneously or in a sequential manner [3,4]. For example, Huang et al. synthesized aptamer-coated LPHNPs via a simple nanoprecipitation process with self-assembly for the co-delivery of paclitaxel (PTX) and doxorubicin (DOX) to cancer cells with high specificity and efficiency [28]. Arg-Gly-Asp RGD-decorated LPHNPs are used for the co-delivery of DOX and sorafenib (SOR) based on the ability of cells to internalize RGD-containing macromolecules. This method significantly enhanced their antitumor efficiency in a mouse xenograft model of hepatocellular carcinoma (HCC) [27]. In another study, Yang et al. developed cyclic RGD-modified LPHNPs for the targeted delivery of 10-hydroxycamptothecin to human breast cancer cells [29]. Furthermore, Wang et al. developed targeted tumor-penetrating NPs for the simultaneous delivery of a photosensitizer indocyanine green (ICG) and hypoxia-activated prodrug tirapazamine (TPZ), establishing a delivery platform for PDT and hypoxia-activated chemotherapy. In a recent study, Zhang et al. developed core-shell LPHNPs for the combined genetic and chemical therapy of childhood head and neck cancers [30]. The size of NPs can significantly influence their in vivo behavior. For example, Dehaini et al. synthesized ultra-small LPHNPs, <25 nm in size, and investigated their in vivo fate. They were found to demonstrate effective localization to deep tumor regions and to enhance the
[54] [14]
[39] [31]
[33]
[27] [6]
[53]
chemotherapeutic efficacy of DOX [14]. Recently, smart LPHNPs that respond to external or internal stimuli have been developed to enhance the therapeutic efficacy and site specificity [12]. This novel strategy is especially attractive in cancer chemotherapy because it improves the therapeutic efficacy and minimizes the adverse effects of drugs. For example, Clawson et al. designed a novel LPHNP with pH-triggered PEG shedding. This is especially useful in anticancer drug delivery because it exploits the slightly acidic extracellular space of tumors (pH 6.5) [31]. Upon arrival at the tumor site, a correctly adjusted pH-sensitive particle would shed its PEG coating and consequently fuse with the cell membrane and be internalized [31,32]. For further advances in drug delivery, magnetic field (MF)mediated thermo-responsive triggering is another mechanism that has been used to release anticancer drugs loaded within LPHNPs. For example, Kong et al. developed MF-activated LPHNPs containing Fe3O4 as stimuli-responsive drug release systems. These LPHNPs release the drugs by the following mechanism: upon remote radio frequency (RF) MF actuation, localized heating by Fe3O4 inside the LPHNPs loosens the polymer matrices and accelerates the release of the drug, for example, camptothecin (CPT) [33]. Advances in genetic nanomedicine have resulted in a significant increase in the number of nucleic acid-based drugs and have the potential to be novel treatment strategies. However, because of
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their high molecular weight, negative charge, enzyme-mediated degradation, and rapid elimination of naked plasmids and short interfering (siRNA), their delivery is challenging [1–4]. Fortunately, the use of nanocarriers for the effective delivery of therapeutics to their specific target locations has allowed researchers to overcome this issue. LPHNPs, in particular, have been used as nanocarriers for the target-specific delivery of oligonucleotides (OGN) and siRNA, alone or in combination with other therapeutics [34]. Tailoring the surface of LPHNPs with cationic lipids or polymers has been generally used for gene or siRNA delivery. In particular, cationic lipid (DOTAP)-layered LPHNPs have numerous advantages, including their ability to integrate large DNA and their high transfection efficiency. The influence of lipid composition on the performance of LPHNPs has been studied thoroughly [7,8,35]. For example, a recent study reported the effects of DOTAP concentration on the physicochemical and biological properties of LPHNPs used in gene delivery [7]. Similarly, other researchers have demonstrated the effect of higher concentrations of cholesterol in LPHNPs on the properties of the latter [35]. Currently, therapeutics can be encapsulated within the core or lipid shell or, alternatively, can be conjugated on the surface of LPHNPs [2,4]. However, this physical encapsulation enables loading efficiencies of approximately 10 20%, implying that at least 80% of the injected LPHNP mass will provide no therapeutic contribution. Therefore, various strategies have recently been used to improve the loading efficiency of therapeutics. For example, Hasan et al. used a PRINT process to synthesize lipid-coated PLGA/siRNA particles, which demonstrated higher siRNA encapsulation efficiency and therapeutic effects in prostate cancer [36]. Shi et al. developed a differentially charged hollow core of a lipid layer surrounded by a PLGA polymer layer and then a neutral lipid layer that interlaced between the PLGA and the outermost PEG layer to form a lipid–polymer–lipid hybrid nanostructure. These hollow core-shell NPs showed higher siRNA encapsulation efficiency compared with PLGA and PLGA-PEG NPs. [37]. Zhao et al. developed LPHNPs to co-deliver hypoxia-inducible factor (HIF)-1a siRNA (si-HIF1a) and gemcitabine for pancreatic cancer treatment in subcutaneous and orthotopic tumor models [38]. Their results showed that LPHNP-Gem-siHIF1a not only exhibited synergistic antitumor effects, but also inhibited tumor metastasis in the orthotopic tumor model [38]. Colombo et al. studied the dynamics of nucleic acid delivery from LPHNPs using different biophysical characterization methods, and suggested that the core–shell structure of LPHNPs influences the delivery dynamics and release kinetics [34]. The mechanism appears to be mediated via the release of transfection-competent siRNA–DOTAP lipoplexes from the LPHNPs [34]. In a recent study, Kaczmarek et al. demonstrated that LPHNPs can be used for the systemic delivery of mRNA to the lungs of mice [39]. Recent developments in molecular imaging and nanotechnology have enabled the use of LPHNPs for biomedical imaging as a novel imaging technique [40]. This was achieved by the encapsulation of therapeutic agents and imaging probes in the core, and targeting functionalization by tailored surface engineering, thus rendering LPHNPs a valuable tool in preclinical theranostics. Multimodality imaging with two or more imaging modalities allows the integration of the advantages of individual modalities, while overcoming their limitations [41]. By incorporating multiple 4
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contrast agents or molecular probes in an LPHNP platform, we can achieve synergism in molecular imaging. Several LPHNPs have been developed to improve contrast in multimodality with simultaneous drug delivery. For example, LPHNPs with tunable bioimaging features have been developed by the integration of metallic gold nanocrystals and quantum dots for computed tomography (CT) and magnetic resonance imaging (MRI). Liao et al. developed a multifunctional LPHNP platform with DOX and gadolinium-DTPA for simultaneous MRI and therapeutics targeting [42]. Qiu et al. developed multimodal NPs by incorporating quantum dots, superparamagnetic iron oxide, and gold NPs for neutrophil imaging and tracking [43]. In a recent study, Gd chelates and PTX-incorporated multifunctional LPHNPs were prepared for image-guided drug delivery [44]. Currently used contrast agents for MRI have major limitations, such as lack of specificity, poor circulation time, and insufficient relaxivity [45]. To overcome these challenges, Aryal et al. synthesized magnetic LPHNPs (MHNPs) encapsulating ultra-small superparamagnetic iron oxide particles (USPIOs) and decorated with Gd3+ ions for MRI [45]. Kim et al. developed theranostic LPHNPs using gold nanocrystals and a fluorescent dye, and investigated their permeability across the inflamed endothelium in an experimental model of atherosclerotic plaques [46]. Similarly, Mieszawska et al. fabricated multifunctional theranostic LPHNPs comprising gold NPs, DOX, and SOR [47]. Recently, Wang et al. developed reduction-responsive SPIO/DOX-loaded pegylated polymeric lipid vesicles (SPIO/DOX-PPLVs) for MRIguided drug delivery [48].
Recent advances in the LPHNP-mediated delivery of antimicrobial agents Bacterial biofilms are matrix-enclosed populations of bacteria that have high antibiotic resistance and are able to evade the immune system; they can cause recalcitrant infections, which cannot be cured with conventional antibiotics [49]. LPHNP-mediated antibiotic delivery systems are being explored to combat such bacterial biofilms because of their superior physicochemical stability, excellent biofilm affinity, and sputum-penetrating capability. These HNPs are able to improve the controlled delivery of antibiotics to bacterial cells, thereby enhancing their antibacterial activity. Moreno et al. designed pH-responsive, surface charge-switching PLGAPLH-PEG NPs for targeting and the potential treatment of polymicrobial infections associated with acidity [50]. Similarly, Cheow et al. investigated the antibiotic encapsulation efficiency, stability, and drug-release kinetics of LPHNPs. In another study, the same research group investigated the effect of lipids on the antibiofilm efficacy of LPHNPs encapsulating levofloxacin against Pseudomonas aeruginosa. Similarly, Seedat et al. explored the effect of helper lipids and different excipients on the antibacterial activity of vancomycin-loaded LPHNPs against both Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) [51]. In addition, Sonawane et al. developed a new lipid–dendrimer hybrid NP (LDHN) system for the efficient delivery of vancomycin to MRSA-infected sites [52]. Additionally, researchers investigated the possibilities of triggered antibiotic release from LPHNPs in response to encountering rhamnolipids, which are ubiquitously present in biofilm colonies of P. aeruginosa [26]. Altogether, LPHNPs have been used for diverse therapeutics delivery applications. The list is extensive
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DNA delivery
Cationic lipid/polymer functionalization
Cell membrane functionalization
siRNA delivery
mRNA delivery Extended circulation Immunotherapy
Nanoantibiotics Inhibition of immune cell recognition/phagocytic uptake
Anionic/Zwiterionic/Neutral lipid functionalization
Cancer immunotherapy Targeting macrophages (Eat-me NPs)
PEG-lipid functionalization
Enhance biocompatibility
Core–shell: structural advantage
Improve therapeutic efficacy
Long circulation Co-delivery of therapeutics Congugation with targeting moiety Improve drug encapsulation efficiency Active targeting
Advanced theranostics
Triggered or stimuli-responsive drug release Passive targeting
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FIGURE 1
Q6 Title. Legend.
and, therefore, we have provided only the most recent applicaQ3 tions of LPHNPs in therapeutics delivery (Fig. 1).
Advances in the development of cell membranederived LPHNPs The cell membrane coating of NPs has recently been studied as an alternative to PEG coating because of its biocompatibility, source cell-mimicking properties, and adaptability to a range of therapeutic and imaging applications [9]. This class of novel LPHNPs has been fabricated with lipids derived from a variety of cells, such as red blood cells (RBCs), platelets, white blood cells, cancer cells, and bacteria; thus, they exhibit the characteristic properties of the source cell [2,9,53]. Among these cells, RBCs have been used as the primary source for cell-mimetic LPHNPs, owing to their self-signaling proteins responsible for immune-evading properties, which lead to extended circulation time [9,54]. Furthermore, recent advances in cell membrane functionalization have been used for the disease-specific targeting of NPs. For example, platelets have inherent affinity towards injured vascular subendothelium and circulating pathogens. Therefore, transferring the platelet membrane to polymeric NPs provides them with natural platelet-like functions [55]. Interestingly, Dehaini et al. demonstrated a novel proof-of-concept study for custom-tailored biomimetic NPs with varying hybrid functionalities [53]. They developed dual-cell
membrane-coated NPs from the fusion of RBCs and platelets. This RBC-platelet HNP platform exhibited a long circulation time and opened the door for the development of biocompatible, customtailored biomimetic NPs with varying hybrid functionalities [53]. Additionally, advances in the synthesis of CMFNPs have been attempted. For example, Rao et al. used a microfluidic electroporation method to synthesize RBC membrane-capped magnetic NPs (RBC-MNPs) to improve cancer diagnosis and therapy [54]. A selective list of LPHNPs mediated therapeutics delivery is given in Table 1.
Challenges to clinical translations LPHNPs are potential platforms for the delivery of several therapeutic agents [1,2,56]. Their small size, biodegradable nature, and multitargeting ability are characteristics that are urgently needed in several clinical areas, such as drug delivery, imaging, tissue engineering, and gene therapy [1,2,56]. However, the design of optimal formulations with all the characteristics desirable for specific applications is a challenge that could hinder clinical translation [56]. The successful and complete clinical execution of LPHNPs requires addressing major technical challenges, such as improving the loading efficacy of therapeutics, ensuring controlled drug release, evading immune cells, and maximizing the NP accumulation at target sites [4]. Another challenge that could emerge is the large-scale production of these LPHNPs [4,15].
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Natural targeting
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Clinical translation
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Cell membrane functionalizedLPHNPs
Hollow-core LPHNPs
Translational barriers
Lipogel
Preclinical investigation Core–shell LPHNPs
PEG-shedding LPHNPs
Robust characterization
Nanoengineering concepts
Laboratory-scale process
Safety and efficacy
Advanced microfluidics
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FIGURE 2
Title. Legend.
Currently, most LPHNPs are prepared on a small scale in a laboratory setting, and it is difficult to produce LPHNPs with identical properties on a large scale in an industrial setting [15,16,22,24]. In addition, from a financial point of view, multiple fabrication steps are not preferred because they usually increase manufacturing costs [57]. Another important aspect of LPHNPs is their potential adverse effects on the biological system. Furthermore, adoption of emerging technologies could create a marketing barrier to HNP systems, because the end-users might hesitate to try this new technology [57]. Competition with evolving technologies and novel ideas also poses a challenge that should not be ignored [4,40,57]. Finally, there are additional economic and quality considerations when producing LPHNPs on an industrial scale. The development of scalable methods with highly predictable in vivo characteristics will enable faster clinical translation. Therefore, additional studies focusing on the in vivo efficacy, biodistribution, clearance, and toxicity of LPHNPs are required [4,40,57]. Fig. 2 provides a schematic representation of LPHNPs, from their strategic design to clinical translation.
Concluding remarks and future directions In conclusion, LPHNPs are considered to be revolutionary nanomedicines in the field of biomedical sciences. They show signifi6
cant therapeutic potential, selective targeting, robust biological response, and ensured safety. In addition, most of the LPHNPs demonstrate long circulation times, which allow them to accumulate at the desired sites. Increasing attention has been paid to the use of LPHNPs to enhance the efficacy of diverse therapeutics. With growing interest in combinatorial cancer therapy, research in this area is also likely to expand. Furthermore, the multifunctional LPHNP platform with simultaneous imaging and drug delivery characteristics could have important applications in cancer chemotherapy and diagnosis. Additionally, motivated by the promises of gene therapy, there is much interest in developing LPHNP-mediated nonviral gene delivery vectors for different therapeutic applications. Biomimetic functionalization with cell membrane-derived lipids is another emerging approach that could provide multifunctionalities and dramatically expand the applications of HNPs. Furthermore, recent advances in cell membrane functionalization on the surfaces of NPs could improve the targeting capabilities of CMFNPs beyond their natural function. Several other interesting scale-up studies could also be explored further. For example, recent developments in microfluidics and PRINT technology could increase the production scale of LPHNPs in larger quantities with defined material characteristics. Despite these advances in the development and application of LPHNPs,
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lated cargoes. With more clinical studies foreseen to take place over the next few years, we believe that more encouraging data indicating the versatility of LPHNPs as a therapeutics delivery platform will be reported.
Acknowledgments We thank Hansoo Park and Soo Hong lee for their valuable guidelines and support. R.J.C.B. is supported by the Chung-Ang University Young Scientist Scholarship (CAYSS) program.
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26 Cheow, W.S. and Hadinoto, K. (2012) Lipid–polymer hybrid nanoparticles with rhamnolipid-triggered release capabilities as anti-biofilm drug delivery vehicles. Particuology 10, 327–333 27 Zhang, J. et al. (2016) iRGD decorated lipid–polymer hybrid nanoparticles for targeted co-delivery of doxorubicin and sorafenib to enhance anti-hepatocellular carcinoma efficacy. Nanomed. Nanotechnol. Biol. Med. 12, 1303–1311 28 Huang, F. et al. (2014) Self-assembled hybrid nanoparticles for targeted co-delivery of two drugs into cancer cells. Chem. Commun. 50, 3103–3105 29 Yang, Z. et al. (2013) Targeted delivery of 10-hydroxycamptothecin to human breast cancers by cyclic RGD-modified lipid–polymer hybrid nanoparticles. Biomed. Mater. 8, 025012 30 Zhang, T. et al. (2017) Core–shell lipid polymer nanoparticles for combined chemo and gene therapy of childhood head and neck cancers. Oncol. Rep. 37, 1653 31 Clawson, C. et al. (2011) Synthesis and characterization of lipid–polymer hybrid nanoparticles with pH-triggered poly (ethylene glycol) shedding. Langmuir 27, 10556–10561 32 Xu, H. et al. (2015) Self-assembled monomethoxy (polyethylene glycol)-bP (D,LLactic-co-Glycolic acid)-bP (L-Glutamic acid) hybrid-core nanoparticles for intracellular pH-triggered release of doxorubicin. J. Biomed. Nanotechnol. 11, 1354– 1369 33 Kong, S.D. et al. (2013) Magnetic field activated lipid–polymer hybrid nanoparticles for stimuli-responsive drug release. Acta Biomater. 9, 5447–5452 34 Colombo, S. et al. (2015) Mechanistic profiling of the siRNA delivery dynamics of lipid–polymer hybrid nanoparticles. J. Controlled Release 201, 22–31 35 Hu, Y. et al. (2015) Engineering the lipid layer of lipid–PLGA hybrid nanoparticles for enhanced in vitro cellular uptake and improved stability. Acta Biomater. 28, 149– 159 36 Hasan, W. et al. (2011) Delivery of multiple siRNAs using lipid-coated PLGA nanoparticles for treatment of prostate cancer. Nano Lett. 12, 287–292 37 Shi, J. et al. (2011) Differentially charged hollow core/shell lipid–polymer–lipid hybrid nanoparticles for small interfering RNA delivery. Angew. Chem. 123, 7165– 7169 38 Zhao, X. et al. (2015) Co-delivery of HIF1a siRNA and gemcitabine via biocompatible lipid–polymer hybrid nanoparticles for effective treatment of pancreatic cancer. Biomaterials 46, 13–25 39 Kaczmarek, J.C. et al. (2016) Polymer–lipid nanoparticles for systemic delivery of mRNA to the lungs. Angew. Chem. 128, 14012–14016 40 Luk, B.T. et al. (2012) Lipid-and polymer-based nanostructures for cancer theranostics. Theranostics 2, 1117–1126 41 Newton, I.G. et al. (2012) Optical imaging of progenitor cell homing to patientderived tumors. Contrast Media Mol. Imaging 7, 525–536 42 Liao, Z. et al. (2011) Multifunctional nanoparticles composed of a poly (D,L-lactidecoglycolide) core and a paramagnetic liposome shell for simultaneous magnetic resonance imaging and targeted therapeutics. Adv. Funct. Mater. 21, 1179–1186 43 Qiu, Y. et al. (2013) Design of hybrid multimodal poly (lactic-co-glycolic acid) polymer nanoparticles for neutrophil labeling, imaging and tracking. Nanoscale 5, 12624–12632 44 Tng, D.J.H. et al. (2015) Synthesis and characterization of multifunctional hybrid– polymeric nanoparticles for drug delivery and multimodal imaging of cancer. Int. J. Nanomed. 10, 5771 45 Aryal, S. et al. (2013) Engineered magnetic hybrid nanoparticles with enhanced relaxivity for tumor imaging. Biomaterials 34, 7725–7732 46 Kim, Y. et al. (2014) Probing nanoparticle translocation across the permeable endothelium in experimental atherosclerosis. Proc. Natl. Acad. Sci. U. S. A. 111, 1078–1083 47 Mieszawska, A.J. et al. (2013) Synthesis of polymer–lipid nanoparticles for imageguided delivery of dual modality therapy. Bioconjug. Chem. 24, 1429–1434
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this field of research is in its infancy and there are several challenges that need to be overcome to meet clinical expectations. Fortunately, this situation is likely to change in the near future. We expect that LPHNPs will eventually replace current liposome and polymeric NP therapeutics delivery systems. The past decade has witnessed interesting developments in the field of lipid– polymer hybrid nanotechnology; there has been an exponential increase in the number of studies performed using these hybrid systems, with a dazzling array of surface coatings and encapsu-
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48 Wang, S. et al. (2016) Multifunctional reduction-responsive SPIO&DOX-loaded PEGylated polymeric lipid vesicles for magnetic resonance imaging-guided drug delivery. Nanotechnology 27, 165101 49 Flemming, H.-C. et al. (2016) Biofilms: an emergent form of bacterial life. Nat. Rev. Microbiol. 14, 563–575 50 Radovic-Moreno, A.F. et al. (2012) Surface charge-switching polymeric nanoparticles for bacterial cell wall-targeted delivery of antibiotics. ACS Nano 6, 4279–4287 51 Seedat, N. et al. (2016) Co-encapsulation of multi-lipids and polymers enhances the performance of vancomycin in lipid–polymer hybrid nanoparticles: in vitro and in silico studies. Mater. Sci. Eng. C 61, 616–630 52 Sonawane, S.J. et al. (2016) Ultra-small lipid-dendrimer hybrid nanoparticles as a promising strategy for antibiotic delivery: in vitro and in silico studies. Int. J. Pharm. 504, 1–10
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53 Dehaini, D. et al. (2017) Erythrocyte–platelet hybrid membrane coating for Q5 enhanced nanoparticle functionalization. Adv. Mater. 54 Rao, L. et al. (2017) Microfluidic electroporation-facilitated synthesis of erythrocyte membrane-coated magnetic nanoparticles for enhanced imaging-guided cancer therapy. ACS Nano 55 Hu, C.-M.J. et al. (2015) Nanoparticle biointerfacing by platelet membrane cloaking. Nature 526, 118–121 56 Raemdonck, K. et al. (2014) Merging the best of both worlds: hybrid lipid-enveloped matrix nanocomposites in drug delivery. Chem. Soc. Rev. 43, 444–472 57 Bregoli, L. et al. (2016) Nanomedicine applied to translational oncology: a future perspective on cancer treatment. Nanomed. Nanotechnol. Biol. Med. 12, 81–103
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Lipid–polymer hybrid nanoparticlemediated therapeutics delivery: advances and challenges Q1
Rajendran J.C. Bose1, Rramaswamy Ravikumar2, Vengadeshprabu Karuppagounder3, Devasier Bennet4, Sabarinathan Rangasamy5 and Rajarajan A. Thandavarayan6 1
School of Integrative Engineering, Chung-Ang University, Seoul, Republic of Korea Department of Advanced Materials and Engineering, Hanseo University, Seosan-si, Republic of Korea 3 Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan 4 Department of Mechanical Engineering, Texas Tech University, Lubbock, TX, USA 5 Department of Chemistry, Central University of Tamil Nadu, Thiruvarur, India 6 Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA 2
With rapid advances in nanomedicine, lipid–polymer hybrid nanoparticles (LPHNPs) have emerged as promising nanocarriers for several biomedical applications, including therapeutics delivery and biomedical imaging. Significant research has been dedicated to biomimetic or targeting functionalization, as well as controlled and image-guided drug-release capabilities. Despite this research, the clinical translation of LPHNP-mediated therapeutics delivery has progressed incrementally. In this review, we discuss the recent advances in and challenges to the development and application of LPHNPs, present examples to demonstrate the advantages of LPHNPs in therapeutics delivery and imaging applications, and discuss the translational obstacles to LPHNP technology.
Introduction LPHNP delivery systems have been widely investigated at the preclinical level and are gaining increasing attention in clinical trials because of their attractive properties for drug delivery [1–3]. These HNPs combine the advantages of polymeric and liposomal drug carriers and, thus, are promising agents in different therapeutic and diagnostic fields [4]. LPHNPs comprise core–shell HNPs consisting of three distinct components: a biodegradable polymeric core for the efficient loading of poorly water-soluble drugs; a lipid monolayer surrounding the core to enhance the stability and reduce the outward diffusion of the drug; and a lipid-polyethylene glycol (PEG) outer corona to protect against immune recognition and enhance the systemic circulation of LPHNPs in vivo [1,3,5,6]. The polymeric cores of LPHNPs usually comprise biodegradable polymers, such as polylactic-co-glycolic acid (PLGA), owing to
Corresponding authors: Bose, Rajendran J.C. ([email protected]), ([email protected]), Thandavarayan, R.A. ([email protected]) 1359-6446/ã 2017 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2017.05.015
their biocompatibility, degradability, and previous use in US Food and Drug Administration (FDA)-approved products [2,7,8]. Q2 Compared with other types of nanocarrier, LPHNPs have several unique advantages, including the range of lipids, biocompatible polymers, and polymer–lipid combinations from which they are prepared, as well as their superior ability to co-encapsulate different therapeutic and imaging agents [2–5]. In previous reviews, researchers have focused on the preparation, characterization, and drug and/or gene delivery applications of LPHNPs [1,3,5], as well as the lipid-based surface engineering of polymeric NPs and their potential advantages in drug and gene delivery [2]. Additionally, advances in cell membrane-functionalized NPs (CMFNPs) from various cell sources, their characterization, and their diverse biomedical applications have also been reported [2,9]. Since these reviews, technological advances have led to remarkable progress in LPHNP research, particularly in the large-scale production and development of NPs coated with cell membrane-derived lipids [10–13]. In this review, we discuss recent advances in and
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challenges to the development and application of LPHNPs, present examples to demonstrate the advantages of LPHNPs in therapeutics delivery and imaging applications, and discuss translational obstacles in LPHNP technology.
Advances in the preparation of LPHNPs
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LPHNPs have been the subject of several promising preclinical studies owing to their multifunctional properties [1,4,14]. The major concern surrounding LPHNPs was their preparation [15,16]. At the laboratory scale, LPHNPs can be fabricated through either a single- or a two-step preparation method [7,8,17–19]. In the two-step preparation method, the lipid shell and the polymeric core are prepared individually and then fused together. Various mixing techniques, such as direct hydration, sonication, or extrusion, have been used to fuse the polymeric cores with the lipid vesicles to form bilayer LPHNPs [2–4]. Electrostatic interactions between the anionic polymeric core and the cationic lipid vesicle drive the fusion process [7,8]. However, an alternative single-step approach is now preferred, because it is easier and more convenient to use. In this single-step method, the lipid, polymer, and incorporated drugs are mixed together, and LPHNPs form by selfassembly [19,20]. Another method, the modified nanoprecipitation method, involves the addition of an organic phase containing a dissolved polymer onto a heated aqueous phase containing a lipid and lipid-PEG, followed by mechanical vortexing to complete the self-assembly and evaporation to remove the excess organic solvent [2,14,21]. A modified single-step sonication-based protocol that streamlines the laboratory-scale synthesis process, allowing for a 20-fold reduction in the nanoparticle fabrication time, has also been reported [22]. For instance, Dehaini et al. reported an easy method for the preparation of targeted ultra-small LPHNPs (25 nm), and explored their effectiveness in targeting docetaxel delivery in a mouse tumor model [14]. Conventionally prepared HNPs exhibit many characteristics of a reliable therapeutic carrier, including excellent stability, ability to load multiple drugs, and flexibility in functionalization with targeting ligands [1,3]. Despite these advantages, the preparation step needs further exploration for scaling up the production of LPHNPs to clinically relevant quantities. The preparation process can have an important role in optimizing the physicochemical attributes of LPHNPs. Laboratory-scale production by pipetting or vortex mixing introduces process variability, which can affect the quality and in vivo performance of LPHNPs [2,14,16,20]. The difficulties in manufacturing LPHNPs in a controlled, reproducible, and scalable manner also delays their clinical translation [23]. Recent microfluidic-platform-based rapidmixing protocols offer a unique advantage in generating uniformly sized LPHNPs [13]. The early design of hydrodynamic flow focusing resulted in low productivity [24]. However, successive designs that introduced high-speed convective and microvortex mixing were found to be successful and increased the productivity to 3 g/h with greater reproducibility and homogeneity [22]. In addition, the vortex and turbulence that occur in high-speed mixing allow a shorter mixing time and yield NPs of smaller sizes. In recent study, a microfluidic platform, exploiting superfast time intervals between sequential nanoprecipitation processes, was developed for high-throughput production of HNPs. This multiplexed microfluidic design enables a high-throughput production 2
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rate of approximately 700 g/day of HNPs on a single device and enhances the payload of drug, ensuring controlled drug release from the HNPs. A versatile coaxial turbulent jet mixer can increase the throughput production of NPs to 3 kg/day, while maintaining the advantages of homogeneity, reproducibility, and tunability [23]. Another study demonstrated that the incorporation and operation of multiple flow-focusing channels in the same device improved the throughput and scalability of the procedure [23]. Recent advances in particle replication in nonwetting templates (PRINT) technology have given researchers unprecedented control over the physicochemical properties of NPs and allowed large-scale fabrication [25]. When scaling up the formulation, there should be a trade-off between the production yield and the desired particle characteristics. This needs to be considered when tailoring largescale production to meet the requirements of specific applications. Despite the high prevalence of the microchannel method in LPHNP fabrication, there are certain limitations that prevent it from being suitable for all applications. A systematic screening study is required to determine the relations between the selected independent variables and the responses obtained from the LPHNP fabrication experiments. A list of recent advances in LPHNP preparation is given in Table 1.
Advances in therapeutics delivery by LPHNPs LPHNPs represent a promising drug delivery platform owing to the positive attributes of both liposomes and polymeric NPs, their superior biomimicking ability, and their customized targeting features [1–3]. The encapsulation of therapeutics into LPHNPs can improve their stability and prevent their rapid leakage, thus prolonging their therapeutic effect and minimizing their toxicity [4,20]. The appropriate selection of lipids and biodegradable polymers allows for the design of HNPs with desired biological features for extended circulation and site-specific localization [4,5,17,19]. Additionally, tailoring lipids on the surface of the polymeric core can improve the biocompatibility and control the drug-release kinetics. Recently, a strategy was demonstrated to improve the antiproliferative efficacy, while minimizing the toxicity of sirolimus through different lipid-based surface-engineering techniques [20]. Furthermore, drug-loaded LPHNPs can be tailored by adjusting their physicochemical properties to control or trigger drug release [26]. In the following section, we highlight the latest advances in LPHNP-mediated therapeutics delivery.
Recent advances in LPHNPs designed for effective anticancer therapy Developed LPHNPs provide an alternative approach in anticancer therapy that can overcome the limitations of conventional cancer therapeutics [4]. LPHNPs represent a valuable therapeutics delivery system that protects drugs in the bloodstream, increases their biodistribution, and limits their adverse effects by achieving target specificity [2,4,12]. Additionally, their ability to encapsulate diverse therapeutics and release them in a controlled or sequential manner ensures the delivery of combinatorial cancer therapy [12,26]. Co-delivery of anticancer drugs and genes is a promising approach to achieve synergistic anticancer effects [27]. The rational design of LPHNPs with targeting moieties such as folic acid (FA), aptamers, and antibodies could further assist in the active
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TABLE 1
Q7 Title
Recent advances in the LPHNP production process Quick synthesis of LPHNPs using a single-step sonication method Large-scale synthesis of LPHNPs (10 g/h) using a multi-inlet vortex reactor (MIVR) Mass production of LPHNPs through controlled microvortices Ultrahigh-throughput synthesis of NPs using a coaxial turbulent jet mixer PRINT technology to generate highly uniform HNPs
Microfluidic electroporation-facilitated synthesis Ultra-small LPHNP synthesis via nanoprecipitation methods Advanced strategies in LPHNP-mediated therapeutics delivery Differentially charged hollow core–shell LPHNPs with distinct functional features Hybrid NPs for systemic delivery of functional mRNA to lungs LPHNPs with pH-triggered PEG shedding
MF-activated LPHNPs for stimuli-responsive drug release
Co-delivery of DOX and SOR via iRGD-conjugated LPHNPs Multiple layer-by-layer LPHNPs for co- delivery of 5-fluorouracil, irinotecan, oxaliplatin and folinic acid (FOLFIRINOX) for treatment of pancreatic cancer Erythrocyte-platelet hybrid membrane coated NPs
Advantages
Refs
Improves the production rate almost 20-fold while not compromising physicochemical properties Improves production rates to >10 g/h
[21]
Controls the flow rates [i.e., Reynolds number (30–150)], thereby enhancing LPHNP productivity to approximately 3 g/h Enhances LPHNP production up to 3 kg/day
[5] [6] [23]
Has numerous advantage associated with scalability, allowing the fabrication of monodispersed NPs with precise and independent control over physiochemical parameters (particle size, shape, and composition) Demonstrates the feasibility of the production of erythrocyte membrane-coated MNPs Enables the production of ultra-small, sub–25 nm LPHNPs
[25]
A novel scalable strategy that enhances the loading efficiency and controls the release of biomolecules Enables systemic delivery of functional mRNA Novel LPHNPs designed with a PEG coating that is shed in response to a low pH trigger; enables the NPs to be stable in the circulation and at neutral pH, but to destabilize and fuse with lipid membranes in acidic tumour microenvironments A stimuli-responsive NP (SRNP) strategy that enhances the therapeutic efficacy of drugs and minimizes adverse effects via the controllable release of the drug at the target site This co-drug delivery system has shown great promise in hepatocellular carcinoma therapy Innovative strategy that enhances the therapeutic effects of drugs, while minimizing adverse effects compared with the FOLFIRINOX regimen alone Dual cell membrane functionalization pf NPs results in their multifunctional capabilities
[37]
targeting and co-delivery of more than one therapeutic agent either simultaneously or in a sequential manner [3,4]. For example, Huang et al. synthesized aptamer-coated LPHNPs via a simple nanoprecipitation process with self-assembly for the co-delivery of paclitaxel (PTX) and doxorubicin (DOX) to cancer cells with high specificity and efficiency [28]. Arg-Gly-Asp RGD-decorated LPHNPs are used for the co-delivery of DOX and sorafenib (SOR) based on the ability of cells to internalize RGD-containing macromolecules. This method significantly enhanced their antitumor efficiency in a mouse xenograft model of hepatocellular carcinoma (HCC) [27]. In another study, Yang et al. developed cyclic RGD-modified LPHNPs for the targeted delivery of 10-hydroxycamptothecin to human breast cancer cells [29]. Furthermore, Wang et al. developed targeted tumor-penetrating NPs for the simultaneous delivery of a photosensitizer indocyanine green (ICG) and hypoxia-activated prodrug tirapazamine (TPZ), establishing a delivery platform for PDT and hypoxia-activated chemotherapy. In a recent study, Zhang et al. developed core-shell LPHNPs for the combined genetic and chemical therapy of childhood head and neck cancers [30]. The size of NPs can significantly influence their in vivo behavior. For example, Dehaini et al. synthesized ultra-small LPHNPs, <25 nm in size, and investigated their in vivo fate. They were found to demonstrate effective localization to deep tumor regions and to enhance the
[54] [14]
[39] [31]
[33]
[27] [6]
[53]
chemotherapeutic efficacy of DOX [14]. Recently, smart LPHNPs that respond to external or internal stimuli have been developed to enhance the therapeutic efficacy and site specificity [12]. This novel strategy is especially attractive in cancer chemotherapy because it improves the therapeutic efficacy and minimizes the adverse effects of drugs. For example, Clawson et al. designed a novel LPHNP with pH-triggered PEG shedding. This is especially useful in anticancer drug delivery because it exploits the slightly acidic extracellular space of tumors (pH 6.5) [31]. Upon arrival at the tumor site, a correctly adjusted pH-sensitive particle would shed its PEG coating and consequently fuse with the cell membrane and be internalized [31,32]. For further advances in drug delivery, magnetic field (MF)mediated thermo-responsive triggering is another mechanism that has been used to release anticancer drugs loaded within LPHNPs. For example, Kong et al. developed MF-activated LPHNPs containing Fe3O4 as stimuli-responsive drug release systems. These LPHNPs release the drugs by the following mechanism: upon remote radio frequency (RF) MF actuation, localized heating by Fe3O4 inside the LPHNPs loosens the polymer matrices and accelerates the release of the drug, for example, camptothecin (CPT) [33]. Advances in genetic nanomedicine have resulted in a significant increase in the number of nucleic acid-based drugs and have the potential to be novel treatment strategies. However, because of
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their high molecular weight, negative charge, enzyme-mediated degradation, and rapid elimination of naked plasmids and short interfering (siRNA), their delivery is challenging [1–4]. Fortunately, the use of nanocarriers for the effective delivery of therapeutics to their specific target locations has allowed researchers to overcome this issue. LPHNPs, in particular, have been used as nanocarriers for the target-specific delivery of oligonucleotides (OGN) and siRNA, alone or in combination with other therapeutics [34]. Tailoring the surface of LPHNPs with cationic lipids or polymers has been generally used for gene or siRNA delivery. In particular, cationic lipid (DOTAP)-layered LPHNPs have numerous advantages, including their ability to integrate large DNA and their high transfection efficiency. The influence of lipid composition on the performance of LPHNPs has been studied thoroughly [7,8,35]. For example, a recent study reported the effects of DOTAP concentration on the physicochemical and biological properties of LPHNPs used in gene delivery [7]. Similarly, other researchers have demonstrated the effect of higher concentrations of cholesterol in LPHNPs on the properties of the latter [35]. Currently, therapeutics can be encapsulated within the core or lipid shell or, alternatively, can be conjugated on the surface of LPHNPs [2,4]. However, this physical encapsulation enables loading efficiencies of approximately 10 20%, implying that at least 80% of the injected LPHNP mass will provide no therapeutic contribution. Therefore, various strategies have recently been used to improve the loading efficiency of therapeutics. For example, Hasan et al. used a PRINT process to synthesize lipid-coated PLGA/siRNA particles, which demonstrated higher siRNA encapsulation efficiency and therapeutic effects in prostate cancer [36]. Shi et al. developed a differentially charged hollow core of a lipid layer surrounded by a PLGA polymer layer and then a neutral lipid layer that interlaced between the PLGA and the outermost PEG layer to form a lipid–polymer–lipid hybrid nanostructure. These hollow core-shell NPs showed higher siRNA encapsulation efficiency compared with PLGA and PLGA-PEG NPs. [37]. Zhao et al. developed LPHNPs to co-deliver hypoxia-inducible factor (HIF)-1a siRNA (si-HIF1a) and gemcitabine for pancreatic cancer treatment in subcutaneous and orthotopic tumor models [38]. Their results showed that LPHNP-Gem-siHIF1a not only exhibited synergistic antitumor effects, but also inhibited tumor metastasis in the orthotopic tumor model [38]. Colombo et al. studied the dynamics of nucleic acid delivery from LPHNPs using different biophysical characterization methods, and suggested that the core–shell structure of LPHNPs influences the delivery dynamics and release kinetics [34]. The mechanism appears to be mediated via the release of transfection-competent siRNA–DOTAP lipoplexes from the LPHNPs [34]. In a recent study, Kaczmarek et al. demonstrated that LPHNPs can be used for the systemic delivery of mRNA to the lungs of mice [39]. Recent developments in molecular imaging and nanotechnology have enabled the use of LPHNPs for biomedical imaging as a novel imaging technique [40]. This was achieved by the encapsulation of therapeutic agents and imaging probes in the core, and targeting functionalization by tailored surface engineering, thus rendering LPHNPs a valuable tool in preclinical theranostics. Multimodality imaging with two or more imaging modalities allows the integration of the advantages of individual modalities, while overcoming their limitations [41]. By incorporating multiple 4
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contrast agents or molecular probes in an LPHNP platform, we can achieve synergism in molecular imaging. Several LPHNPs have been developed to improve contrast in multimodality with simultaneous drug delivery. For example, LPHNPs with tunable bioimaging features have been developed by the integration of metallic gold nanocrystals and quantum dots for computed tomography (CT) and magnetic resonance imaging (MRI). Liao et al. developed a multifunctional LPHNP platform with DOX and gadolinium-DTPA for simultaneous MRI and therapeutics targeting [42]. Qiu et al. developed multimodal NPs by incorporating quantum dots, superparamagnetic iron oxide, and gold NPs for neutrophil imaging and tracking [43]. In a recent study, Gd chelates and PTX-incorporated multifunctional LPHNPs were prepared for image-guided drug delivery [44]. Currently used contrast agents for MRI have major limitations, such as lack of specificity, poor circulation time, and insufficient relaxivity [45]. To overcome these challenges, Aryal et al. synthesized magnetic LPHNPs (MHNPs) encapsulating ultra-small superparamagnetic iron oxide particles (USPIOs) and decorated with Gd3+ ions for MRI [45]. Kim et al. developed theranostic LPHNPs using gold nanocrystals and a fluorescent dye, and investigated their permeability across the inflamed endothelium in an experimental model of atherosclerotic plaques [46]. Similarly, Mieszawska et al. fabricated multifunctional theranostic LPHNPs comprising gold NPs, DOX, and SOR [47]. Recently, Wang et al. developed reduction-responsive SPIO/DOX-loaded pegylated polymeric lipid vesicles (SPIO/DOX-PPLVs) for MRIguided drug delivery [48].
Recent advances in the LPHNP-mediated delivery of antimicrobial agents Bacterial biofilms are matrix-enclosed populations of bacteria that have high antibiotic resistance and are able to evade the immune system; they can cause recalcitrant infections, which cannot be cured with conventional antibiotics [49]. LPHNP-mediated antibiotic delivery systems are being explored to combat such bacterial biofilms because of their superior physicochemical stability, excellent biofilm affinity, and sputum-penetrating capability. These HNPs are able to improve the controlled delivery of antibiotics to bacterial cells, thereby enhancing their antibacterial activity. Moreno et al. designed pH-responsive, surface charge-switching PLGAPLH-PEG NPs for targeting and the potential treatment of polymicrobial infections associated with acidity [50]. Similarly, Cheow et al. investigated the antibiotic encapsulation efficiency, stability, and drug-release kinetics of LPHNPs. In another study, the same research group investigated the effect of lipids on the antibiofilm efficacy of LPHNPs encapsulating levofloxacin against Pseudomonas aeruginosa. Similarly, Seedat et al. explored the effect of helper lipids and different excipients on the antibacterial activity of vancomycin-loaded LPHNPs against both Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) [51]. In addition, Sonawane et al. developed a new lipid–dendrimer hybrid NP (LDHN) system for the efficient delivery of vancomycin to MRSA-infected sites [52]. Additionally, researchers investigated the possibilities of triggered antibiotic release from LPHNPs in response to encountering rhamnolipids, which are ubiquitously present in biofilm colonies of P. aeruginosa [26]. Altogether, LPHNPs have been used for diverse therapeutics delivery applications. The list is extensive
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DNA delivery
Cationic lipid/polymer functionalization
Cell membrane functionalization
siRNA delivery
mRNA delivery Extended circulation Immunotherapy
Nanoantibiotics Inhibition of immune cell recognition/phagocytic uptake
Anionic/Zwiterionic/Neutral lipid functionalization
Cancer immunotherapy Targeting macrophages (Eat-me NPs)
PEG-lipid functionalization
Enhance biocompatibility
Core–shell: structural advantage
Improve therapeutic efficacy
Long circulation Co-delivery of therapeutics Congugation with targeting moiety Improve drug encapsulation efficiency Active targeting
Advanced theranostics
Triggered or stimuli-responsive drug release Passive targeting
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FIGURE 1
Q6 Title. Legend.
and, therefore, we have provided only the most recent applicaQ3 tions of LPHNPs in therapeutics delivery (Fig. 1).
Advances in the development of cell membranederived LPHNPs The cell membrane coating of NPs has recently been studied as an alternative to PEG coating because of its biocompatibility, source cell-mimicking properties, and adaptability to a range of therapeutic and imaging applications [9]. This class of novel LPHNPs has been fabricated with lipids derived from a variety of cells, such as red blood cells (RBCs), platelets, white blood cells, cancer cells, and bacteria; thus, they exhibit the characteristic properties of the source cell [2,9,53]. Among these cells, RBCs have been used as the primary source for cell-mimetic LPHNPs, owing to their self-signaling proteins responsible for immune-evading properties, which lead to extended circulation time [9,54]. Furthermore, recent advances in cell membrane functionalization have been used for the disease-specific targeting of NPs. For example, platelets have inherent affinity towards injured vascular subendothelium and circulating pathogens. Therefore, transferring the platelet membrane to polymeric NPs provides them with natural platelet-like functions [55]. Interestingly, Dehaini et al. demonstrated a novel proof-of-concept study for custom-tailored biomimetic NPs with varying hybrid functionalities [53]. They developed dual-cell
membrane-coated NPs from the fusion of RBCs and platelets. This RBC-platelet HNP platform exhibited a long circulation time and opened the door for the development of biocompatible, customtailored biomimetic NPs with varying hybrid functionalities [53]. Additionally, advances in the synthesis of CMFNPs have been attempted. For example, Rao et al. used a microfluidic electroporation method to synthesize RBC membrane-capped magnetic NPs (RBC-MNPs) to improve cancer diagnosis and therapy [54]. A selective list of LPHNPs mediated therapeutics delivery is given in Table 1.
Challenges to clinical translations LPHNPs are potential platforms for the delivery of several therapeutic agents [1,2,56]. Their small size, biodegradable nature, and multitargeting ability are characteristics that are urgently needed in several clinical areas, such as drug delivery, imaging, tissue engineering, and gene therapy [1,2,56]. However, the design of optimal formulations with all the characteristics desirable for specific applications is a challenge that could hinder clinical translation [56]. The successful and complete clinical execution of LPHNPs requires addressing major technical challenges, such as improving the loading efficacy of therapeutics, ensuring controlled drug release, evading immune cells, and maximizing the NP accumulation at target sites [4]. Another challenge that could emerge is the large-scale production of these LPHNPs [4,15].
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Natural targeting
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Clinical translation
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Cell membrane functionalizedLPHNPs
Hollow-core LPHNPs
Translational barriers
Lipogel
Preclinical investigation Core–shell LPHNPs
PEG-shedding LPHNPs
Robust characterization
Nanoengineering concepts
Laboratory-scale process
Safety and efficacy
Advanced microfluidics
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FIGURE 2
Title. Legend.
Currently, most LPHNPs are prepared on a small scale in a laboratory setting, and it is difficult to produce LPHNPs with identical properties on a large scale in an industrial setting [15,16,22,24]. In addition, from a financial point of view, multiple fabrication steps are not preferred because they usually increase manufacturing costs [57]. Another important aspect of LPHNPs is their potential adverse effects on the biological system. Furthermore, adoption of emerging technologies could create a marketing barrier to HNP systems, because the end-users might hesitate to try this new technology [57]. Competition with evolving technologies and novel ideas also poses a challenge that should not be ignored [4,40,57]. Finally, there are additional economic and quality considerations when producing LPHNPs on an industrial scale. The development of scalable methods with highly predictable in vivo characteristics will enable faster clinical translation. Therefore, additional studies focusing on the in vivo efficacy, biodistribution, clearance, and toxicity of LPHNPs are required [4,40,57]. Fig. 2 provides a schematic representation of LPHNPs, from their strategic design to clinical translation.
Concluding remarks and future directions In conclusion, LPHNPs are considered to be revolutionary nanomedicines in the field of biomedical sciences. They show signifi6
cant therapeutic potential, selective targeting, robust biological response, and ensured safety. In addition, most of the LPHNPs demonstrate long circulation times, which allow them to accumulate at the desired sites. Increasing attention has been paid to the use of LPHNPs to enhance the efficacy of diverse therapeutics. With growing interest in combinatorial cancer therapy, research in this area is also likely to expand. Furthermore, the multifunctional LPHNP platform with simultaneous imaging and drug delivery characteristics could have important applications in cancer chemotherapy and diagnosis. Additionally, motivated by the promises of gene therapy, there is much interest in developing LPHNP-mediated nonviral gene delivery vectors for different therapeutic applications. Biomimetic functionalization with cell membrane-derived lipids is another emerging approach that could provide multifunctionalities and dramatically expand the applications of HNPs. Furthermore, recent advances in cell membrane functionalization on the surfaces of NPs could improve the targeting capabilities of CMFNPs beyond their natural function. Several other interesting scale-up studies could also be explored further. For example, recent developments in microfluidics and PRINT technology could increase the production scale of LPHNPs in larger quantities with defined material characteristics. Despite these advances in the development and application of LPHNPs,
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lated cargoes. With more clinical studies foreseen to take place over the next few years, we believe that more encouraging data indicating the versatility of LPHNPs as a therapeutics delivery platform will be reported.
Acknowledgments We thank Hansoo Park and Soo Hong lee for their valuable guidelines and support. R.J.C.B. is supported by the Chung-Ang University Young Scientist Scholarship (CAYSS) program.
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this field of research is in its infancy and there are several challenges that need to be overcome to meet clinical expectations. Fortunately, this situation is likely to change in the near future. We expect that LPHNPs will eventually replace current liposome and polymeric NP therapeutics delivery systems. The past decade has witnessed interesting developments in the field of lipid– polymer hybrid nanotechnology; there has been an exponential increase in the number of studies performed using these hybrid systems, with a dazzling array of surface coatings and encapsu-
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