Biomedical Applications of the AuNP-Liposome Nanocomposites: History
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AuNP-liposome nanocomposites have been evaluated for several biomedical applications including imaging, sensing, cancer therapy, and light-responsive drug delivery.

  • gold
  • nanoparticles
  • plasmonic
  • liposomes
  • lipid

1. Biomedical Applications of the AuNP-Liposome Nanocomposites

1.1. Imaging

The employment of gold in biomedical imaging is attributed to its ability to exhibit unique optical imaging properties and being excellent contrast for TEM-based and X-ray based imaging. For instance, Sanzhakov et al. have developed a AuNP-liposome nanocomposites for tumor imaging [33]. The accumulation of AuNP-liposome nanocomposite was tracked in mice using computed tomography (CT) scanner to evaluate the contribution of targeting moiety on the uptake into tumor in vivo and to confirm that PEGylation of AuNP-Phospholipid nanocomposite improves the accumulation of AuNP in the tumor site. In another study, AuNP-liposome nanocomposite (150–200 nm) have been prepared and illustrated a good CT contrast with better signals compared to commercially available AuNP (15 and 40 nm), and thus proposing a novel approach for cancer imaging [173]. Similarly, the signal from AuNP-liposome nanocomposite was strong and stable inside the tumor after injection, signifying the potential stability and tissue retention of the construct [174,175].

1.2. Sensing

AuNP have been widely applied in biosensing for biomedical purposes including DNA hybridization [176,177], DNA–protein interactions [178,179], and cell transfections [180,181] due to their optical properties, their simple preparation techniques, and the ease of surface modification. Currently available detection techniques for bacteria, primarily nucleic acid-based methods, could achieve low detection limits. In this regard, a simple and nanoscale assay based on AuNP-liposome nanocomposites was developed for bacterial detection purposes [182]. For example, a simple colorimetric assay based on AuNP-liposome nanocomposites was developed to detect bacterial toxins. For example, Listeriolysin (LLO) is a toxin produced by the bacterium Listeria monocytogenes and acts primarily on lipid membranes to induce pores. Liposomes loaded with cysteine were used as the natural recognition element in this assay, in which the presence of LLO induces the liberation of cysteine from liposomes, and consequently induce aggregation of the suspended AuNP resulting in a strong optical response (a colorimetric transformation from red to purple/blue). The intensity of the produced color correlates with the LLO concentration, and thus, proposing a simple and rapid quantitative nanoscale assay for further development of portable sensors. In a similar colorimetric assay-based attempt, amine-functionalized AuNP-liposome nanocomposite was fabricated as an attempt to detect thrombin molecule by triggering a color change from blue to red [183]. The employed AuNP-liposome nanocomposites possessed an improved sensitivity by almost 3 folds in the existence of AuNP compared with the condition without AuNP. As an attempt to enhance the plasmonic biosensing using AuNP-liposome nanocomposites, detection of the bacterial toxin has significantly improved reaching a limit of detection (LOD) of 0.1 ng/mL [184]. Moreover, the proposed nanocomposite illustrated strong properties for optical biosensing as well as demonstrating a long shelf life, and conserved efficiency for over four weeks. Additionally, a unique AuNP-liposome nanocomposites was proposed for electrochemical investigation of lipopolysaccharide in food samples in which it plays a role as a signal amplifier, a signal output component and a molecular recognizer [185].

1.3. Phototherapy and Laser-Triggered Drug Delivery

Perhaps, the strongest justification and greatest interest for preparing AuNP-liposome nanocomposites is the preparation of laser-triggered drug release systems and combining chemotherapy from loaded therapeutics with photothermal effect from the excited AuNP. First, AuNP are optically active and exhibit strong photothermal conversion efficiency in the NIR as discussed in previous sections. However, AuNP has poor intrinsic drug loading capability due to the absence of reservoir or matrix for loading. At the other end, liposomes are excellent carriers for vast range of therapeutics with proven biocompatibility and presence in clinics. The fabrication of AuNP-liposome nanocomposites should bring the best of both: (1) excellent drug loading into the liposomes and (2) light responsiveness which can trigger the release of loaded therapeutics. Excellent examples are reported in the literature using various types of liposomes and AuNP [123,124,186,187,188]. This approach was first reported in 2007 by Lauri and co-workers who encapsulated hydrophilic and hydrophobic AuNP into the lipid bilayer or the aqueous reservoir of liposomes, respectively [124]. At physiological temperature, the AuNP-liposome nanocomposites remained intact while upon irradiation, a rapid release of the encapsulated fluorescent marker was observed. It is important to note that in this novel and one of the first proof of concept evaluations, UV light was employed which is not preferred for biomedical applications as the tissue penetration at this wavelength is poor. In 2008, Zasadzinski and co-workers prepared an NIR-responsive AuNP-liposome nanocomposites using hollow gold nanoshells (HGN) [189]. Interestingly, the triggered release rate was dependent on the attachment route of HGN to liposomes (in-liposome, on- liposome or even freely and independently outside the liposomes), the laser power and the irradiation time. The mechanism of release upon laser irradiation was explained by the microbubble formation upon heating and the resulting lipid membrane disturbance and fragmentation of the liposomes. Following these two pioneering works, many research groups reported the use of light-responsive AuNP-liposome nanocomposites both in vitro and in vivo [37,121,122,132,190,191]. Indeed, combination of AuNP and liposome is not only a tool to induce a triggered drug release, but to achieve synergistic anticancer activity. For example, Gao and co-workers reported a synergistic antitumor effect in tumor-bearing mice from combing wedelolactone (loaded anticancer agents into the liposomes) and NIR-absorbing AuNP and reported up to 95.73% inhibition rate [192]. Away from light, AuNP-liposome nanocomposite can be fabricated to trigger their payload therapeutics in the presence of other stimuli. For example, bacterial toxins were utilized to deliver antimicrobial agents specifically to the sites of bacterial infections [34].

2. Biodistribution and Pharmacokinetics of AuNP-Liposome Nanocomposites

The fate of AuNP is significantly influenced by their physiochemical characteristics such as size, shape and surface chemistry [193]; thus, tuning these properties during fabrication could earn it the desired biodistribution and pharmacokinetics profile. The non-specific adsorption of plasma proteins (opsonization) to AuNP [194] and subsequent recognition and elimination by the reticuloendothelial system (RES) are among the main challenges in achieving the desired biodistribution profile [195]. The instant uptake from the plasma by the immune system when administered intravenously affects their residence time in blood circulation, and thus their therapeutic function. Hence, an effective strategy to preserve the nanoparticle characteristics and enhance its biodistribution and pharmacokinetics profile is desired. Zhang et al. reported the preparation of AuNP-liposome nanocomposites in ‘cluster bomb’ structures with unique load release pattern as an effective strategy to improve the pharmacokinetic properties of loaded paclitaxel (PTX) [196]. This system can be visualized as a hybrid system in which a part of PTX was covalently linked to AuNP (slow-release carrier) and another part was physically encapsulated into the liposome carrier (fast release carrier). The ratio of free to covalently attached PTX was simply tuned by mixing liposome encapsulating free PTX and PTX-conjugated AuNP. This nanocomposite exhibited a “burst” release of PTX from liposomes in the site of action and maintained a slower release rate from the PTX-conjugated AuNP. The described “multi-order” release of PTX enabled rapid Cmax values and steadily elevated AUC0−t values. This example demonstrates the added benefit of preparing a hybrid system of AuNP and liposome to tune the pattern and rate of drug release, and thus to control the collective pharmacokinetics of therapeutics.
The clearance of AuNP and generally inorganic nanoparticles is determined mainly by their size. Small size particles of less than 5.5 nm (a molecular weight of approximately less than 50 kD) stay in the circulation for a shorter duration due to the renal glomerular filtration process into urine [197]. Incorporating small AuNP into larger liposomes shift very significantly the hybrid system’s clearance (mainly hepatic) by ten folds. Hence, encapsulated AuNP are protected from clearance and stay in circulation for longer periods of time, which could reach up to 14 days [122,198]. Upon the degradation of AuNP-liposome nanocomposites, the resulting smaller AuNP particles could then be eliminated by renal routes (if they are less than 5.5 nm in diameter). Rengan et al. reported the preparation of biodegradable NIR-responsive AuNP-liposome nanocomposites by the “on-liposome” reduction method discussed in previous sections. Their synthesis resulted in the formation of “golden shell” that is composed from assembled ultrasmall AuNP (2–8 nm in diameter) that support collectively the photothermal effect in the NIR [122]. Remarkably, the described hybrid system liberated ultrasmall AuNP upon degradation, which was renally eliminated as confirmed in vivo by ICP-MS analysis of urine.
Another factor that has been shown to influence the clearance of AuNP-liposome nanocomposites systems was the surface charge. For example, cationic AuNP-liposome nanocomposites system, coated with positively-charged 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC), exhibited enhanced excretion of AuNP-liposome through the negatively charged glomerular basement membrane and gold was detected in urine. This charge repulsion mechanism in the kidney controls the filtration of molecules, in which those with a negative charge are repelled; while the positively charged molecules are filtered [122,199].
Generally, once AuNP are injected intravenously, they are captured by RES through macrophages and delivered to the liver, spleen, and lungs. Various approaches were employed to provide a stealth character to AuNP including modification of the nanoparticle’s surface with PEG, zwitterionic ligands, cell membranes and proteins [200,201,202]. Recently, liposomes were proposed as a carrier to alter the cellular uptake, biodistribution and pharmacokinetics of AuNP. For example, Nam et al. [203] and Zhang et al. [196] prepared pegylated AuNP-liposome nanocomposites in order to prolong their circulation. Although PEG-AuNP-liposome nanocomposites were able to escape the immune system, in vivo experiments demonstrated the majority of the injected dose accumulated in the liver and spleen, but in 1.5 folds lower concentrations than the conventional AuNP.
Overall, different formulations of AuNP-liposome nanocomposites revealed different kinetics than the conventional AuNP. AuNP-liposome nanocomposites synthesized with biodegradable lipid accumulate gradually in the liver and are subjected to biological degradation by lipid enzymes resulting in losing the spherical morphology and free AuNP redistributing back to plasma and excreted in urine [122]. On the other hand, AuNP-liposome nanocomposites coated with PEG have more stable physiochemical properties and pharmacokinetic profile with enhanced permeability and retention (EPR) effect in tumors [193,204], as the half-life was shown in vivo to reach up to 25 hours, staying in the body for up to 14 days [122].

This entry is adapted from the peer-reviewed paper 10.3390/jnt4030010

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