Albumin-based nanoparticles as potential controlled release drug delivery systems

Journal of Controlled Release 157 (2012) 168–182

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Journal of Controlled Release j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j c o n r e l

Review

Albumin-based nanoparticles as potential controlled release drug delivery systems Ahmed O. Elzoghby ⁎, Wael M. Samy, Nazik A. Elgindy Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, El-Khartoum Square, Azarita, Alexandria 21521, Egypt

a r t i c l e

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Article history: Received 21 April 2011 Accepted 20 July 2011 Available online 1 August 2011 Keywords: Albumin Nanoparticles Nanocomplexes Surface modification

a b s t r a c t Albumin, a versatile protein carrier for drug delivery, has been shown to be nontoxic, non-immunogenic, biocompatible and biodegradable. Therefore, it is ideal material to fabricate nanoparticles for drug delivery. Albumin nanoparticles have gained considerable attention owing to their high binding capacity of various drugs and being well tolerated without any serious side-effects. The current review embodies an in-depth discussion of albumin nanoparticles with respect to types, formulation aspects, major outcomes of in vitro and in vivo investigations as well as site-specific drug targeting using various ligands modifying the surface of albumin nanoparticles with special insights to the field of oncology. Specialized nanotechnological techniques like desolvation, emulsification, thermal gelation and recently nano-spray drying, nab-technology and self-assembly that have been investigated for fabrication of albumin nanoparticles, are also discussed. Nanocomplexes of albumin with other components in the area of drug delivery are also included in this review. © 2011 Elsevier B.V. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . Types of albumin . . . . . . . . . . . . . . . . . . 2.1. Ovalbumin (OVA) . . . . . . . . . . . . . . . 2.2. Bovine serum albumin (BSA) . . . . . . . . . 2.3. Human serum albumin (HSA) . . . . . . . . . Albumin nanoparticles . . . . . . . . . . . . . . . . 3.1. Preparation techniques . . . . . . . . . . . . 3.1.1. Desolvation (coacervation) . . . . . . 3.1.2. Emulsification . . . . . . . . . . . . 3.1.3. Thermal gelation . . . . . . . . . . . 3.1.4. Nano spray drying . . . . . . . . . . 3.1.5. Nanoparticle albumin-bound technology 3.1.6. Self-assembly . . . . . . . . . . . . 3.2. Drug loading . . . . . . . . . . . . . . . . . 3.3. In vitro studies . . . . . . . . . . . . . . . . 3.4. In vivo studies . . . . . . . . . . . . . . . . 3.5. Accumulation of HSA nanoparticles in tumors . Albumin nanocomplexes . . . . . . . . . . . . . . . Surface-modified albumin nanoparticles . . . . . . . . 5.1. Surfactants . . . . . . . . . . . . . . . . . . 5.2. Cationic polymers . . . . . . . . . . . . . . . 5.3. Thermosensitive polymers . . . . . . . . . . . 5.4. Polyethylene glycol (PEG) . . . . . . . . . . . 5.5. Folate . . . . . . . . . . . . . . . . . . . . 5.6. Peptides . . . . . . . . . . . . . . . . . . . 5.7. Apolipoprotein . . . . . . . . . . . . . . . . 5.8. Transferrin . . . . . . . . . . . . . . . . . . 5.9. Monoclonal antibodies . . . . . . . . . . . .

⁎ Corresponding author. Tel.: + 20 3 3825 212; fax: + 20 3 4873 273. E-mail address: [email protected] (A.O. Elzoghby). 0168-3659/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2011.07.031

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6. Drawbacks and challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction

2. Types of albumin

Nanoparticulate delivery systems are extensively investigated as a drug delivery strategy in the pharmaceutical research. In general, nanocarriers may protect a drug from degradation, enhance drug absorption by facilitating diffusion through epithelium, modify pharmacokinetic and drug tissue distribution profile and/or improve intracellular penetration and distribution. Furthermore, by modulating the surface properties, composition and milieu, the desired release pattern of the drug and its biodistribution can be achieved [1–3]. Additionally, one of the major advantages associated with the nanoparticulate systems is their ability to withstand physiological stress or improved biological stability and possibility of oral delivery which makes them more attractive as a drug delivery strategy than liposomes [4–6]. Different types of nano-sized carriers, such as polymeric nanoparticles, solid lipid nanoparticles, ceramic nanoparticles, magnetic nanoparticles, polymeric micelles, polymer-drug conjugates, nanotubes, nanowires, nanocages and dendrimers, etc., are being developed for various drug-delivery applications [7]. Polymeric nanoparticles can be fabricated from polysaccharides [8,9], proteins [10,11] and synthetic polymers [12,13]. Nanoparticles made from natural hydrophilic polymers have been proved efficient in terms of better drug-loading capacity, biocompatibility and possibly less opsonization by reticuloendothelial system (RES) through an aqueous steric barrier [8]. Systems based on proteins including gelatin, collagen, casein, albumin and whey protein have been studied for delivering drugs, nutrients, bioactive peptides and probiotic organisms [14,15]. Proteins represent good raw materials since they have the advantages of synthetic polymers together with the advantages of absorbability and low toxicity of the degradation end products [16,17]. Among the available potential colloidal drug carrier systems, protein-based nanoparticles are particularly interesting as they hold certain advantages such as greater stability during storage and in vivo, being non-toxic and non-antigenic and their ease to scale up during manufacture over other drug delivery systems [18–21]. Albumin is an attractive macromolecular carrier that has been shown to be biodegradable, nontoxic, metabolized in vivo to produce innocuous degradation products, non-immunogenic, easy to purify and soluble in water allowing ease of delivery by injection and thus an ideal candidate for nanoparticle preparation [22,23]. Albumin-based nanoparticle carrier systems represent an attractive strategy, since a significant amount of drug can be incorporated into the particle matrix because of the different drug binding sites present in the albumin molecule [24]. Due to the defined albumin primary structure and high content of charged amino acids (e.g. lysine), albumin-based nanoparticles could allow the electrostatic adsorption of positively (e.g. ganciclovir) or negatively charged (e.g. oligonucleotide) molecules without the requirement of other compounds [25,26]. In addition, albumin nanoparticles can be easily prepared under soft conditions by coacervation, controlled desolvation or emulsion formation. They show a smaller size (50 to 300 nm) compared to microparticles and, in general, better controlled release properties than liposomes which may improve patient acceptance and compliance. Commercially, albumins are obtained with significant quantities from egg white (ovalbumin), bovine serum (bovine serum albumin, BSA), and human serum (human serum albumin, HSA) and also available from soybeans, milk, and grains [27]. This review gives an account of the nanoparticulate drug delivery systems that make use of albumin as a drug carrier.

2.1. Ovalbumin (OVA)

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Ovalbumin is a highly functional food protein that is frequently used in food matrix design. Chemically, it is a monomeric phosphoglycoprotein that consists of 385 amino acid residues, with each molecule having one internal disulfide bond and four free sulphydryl groups. It has a molecular weight of 47,000 Da and isoelectric point (pI) of 4.8 [28]. OVA was chosen as a carrier for drug delivery owing to its availability and low cost, compared with other proteins. Moreover, OVA exhibits several interesting functionalities such as its ability to form gel networks and stabilization of emulsions and foams. Due to its pH- and temperature-sensitive properties, it has a high potential for use as a carrier for controlled drug release [29].

2.2. Bovine serum albumin (BSA) Bovine serum albumin, having a molecular weight of 69,323 Da and an isoelectric point (pI) of 4.7 in water (at 25 °C), is widely used for drug delivery because of its medical importance, abundance, low cost, ease of purification, unusual ligand-binding properties and its wide acceptance in the pharmaceutical industry [30,31].

2.3. Human serum albumin (HSA) Bovine serum albumin could be substituted by human serum albumin in order to avoid a possible immunologic response in vivo. HSA is the most abundant plasma protein (35–50 g/L human serum) with an average half-life of 19 days. HSA is a very soluble globular monomeric protein consisting of 585 amino acid residues with a relative molecular weight of 66,500 Da and contains 35 cysteinyl residues forming one sulfhydryl group and 17 disulfide bridges [32]. It is not a standard protein since it is extremely robust towards pH (stable in the pH range of 4–9), temperature (can be heated at 60 °C for up to 10 h) and organic solvents. When HSA is broken down, the amino acids will provide nutrition to peripheral tissues. These properties as well as its preferential uptake in tumor and inflamed tissue, its ready availability, biodegradability and lack of toxicity make it an ideal candidate for drug delivery [33,34].

3. Albumin nanoparticles Nanoparticles made of albumin offer several specific advantages: they are biodegradable, easy to prepare and reproducible. Due to the high protein binding of various drugs, the matrix of albumin nanoparticles can be used for effective incorporation of these compounds [35]. Covalent derivatization of albumin nanoparticles with drug targeting ligands is possible, due to the presence of functional groups (i.e. amino and carboxylic groups) on the nanoparticle surfaces [36,37]. Also they are expected to be well tolerated, which is supported by clinical studies with registered HSA-based particle formulations such as Albunex™ [38] and Abraxane™ [39,40]. Furthermore, protein nanoparticle preparations especially HSA appear to be a suitable agent for gene therapy, because it might avoid undesired interactions with serum that are often encountered after intravenous injection of transfection complexes [41,42].

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3.1. Preparation techniques The protocols to prepare albumin nanoparticles can be classified into three principal techniques; desolvation [18,26], emulsification [24,43,44], thermal gelation [45,46] and recently nano spray drying [47], nab-technology [48,49] and self-assembly [50,51] techniques were also used.

3.1.1. Desolvation (coacervation) In desolvation process, nanoparticles are obtained by a continuous dropwise addition of ethanol to an aqueous solution of albumin (pH 5.5) under continuous stirring until the solution became turbid. During the addition of ethanol into the solution, albumin is phase separated due to its diminished water-solubility [18]. The morphologically formed albumin particles being not sufficiently stabilized could consequently redissolve again after dispersion with water [26,52]. Therefore, coacervates were hardened by crosslinking with glutaraldehyde where the amino moieties in lysine residues and arginine moieties in guanidino side chains of albumin are solidified by a condensation reaction with the aldehyde-group of glutaraldehyde [53,54]. Fig. 1 illustrates the steps of albumin nanospheres preparation by desolvation method [55]. Weber et al. reported that the lowest required glutaraldehyde concentration for the production of stable nanoparticles was about 40% with a reaction time of 24 h for sufficient cross-linking of all amino groups [26]. In another study performed by Lin et al., methyl polyethylene glycol modified oxidized dextran (Dextranox-MPEG) was used for crosslinking of HSA nanospheres instead of glutaraldehyde creating a sterically stabilizing polyethylene oxide surface layer surrounding the nanospheres [56]. The Dextranox crosslinked nanospheres showed a significantly lower zeta potential and reduced plasma protein adsorption on the particle surface compared with glutaraldehyde crosslinked nanospheres [56]. To terminate denaturation, sodium metabisulfite may be added [57,58]. Alternatively, an aqueous solution of lysine was added to cap the free aldehydic groups [59]. After ethanol elimination by evaporation under reduced pressure, nanoparticles were purified by centrifugation to eliminate the free albumin and the excess cross-linking agent. The nanosuspension produced was freeze-dried using 5% mannitol as a cryoprotectant to obtain a fine powder of the nanoparticles [60]. The desolvation process of HSA for the preparation of nanoparticles was optimized by Weber et al. [26]. The results indicated that the particle size is monitored mainly by the amount of desolvating agent added and not the cross-linker [26]. The pH of HSA solution was also identified as a major factor determining the particle size. Varying this parameter, mean particle diameters could be adjusted between 150 and 280 nm, higher pH values leading to smaller nanoparticles [18]. A pump-controlled desolvation method was established by Langer et al. which enabled a controllable particle size in combination with a narrow size distribution [18]. Washing the particles by differential centrifugation led to significantly narrower size distributions [18,19]. Nguyen and Ko found that the intermittent addition of a desolvating agent (ethanol) to albumin solution can improve the reproducibility of albumin nanoparticles with a narrow particle size distribution [61].

Fig. 1. Preparation of albumin nanospheres by desolvation (simple coacervation) method. Modified from Ref. [55].

HSA can build dimers and higher aggregates because of a free thiol group present in the albumin molecule. However, the amount of dimerised HSA detected did not affect the particle preparation. Higher aggregates of the protein detected disturbed nanoparticle formation at pH values below 8.0. At pH 8.0 and above, monodisperse particles between 200 and 300 nm could be prepared [62]. As an alternative to blood derived albumin, recombinant HSA (rHSA), a genetically engineered protein expressed in yeast cells, has shown comparable safety, tolerability, pharmaco-kinetics and dynamics to native HSA [62]. Monodisperse rHSA nanoparticles could be prepared and enzymatic degradation of HSA and rHSA nanoparticles was possible over 24 h with different enzymes such as trypsin, proteinase K and protease. Furthermore, particle degradation in the presence of the intracellular enzyme cathepsin B confirms the biodegradability of the nanoparticles as a prerequisite of drug release after cellular uptake [62]. 3.1.2. Emulsification Emulsification technique has been extensively used for preparation of polymeric nanoparticles. Two main methods are used for stabilization of albumin nanospheres prepared by emulsification; thermal or chemical treatment [24,63]. Albumin nanospheres (0.3–1 μm) were formed by homogenizing the oil phase (e.g. cotton seed oil) containing the albumin droplets at a high speed then thermally stabilized by heating at 175 to 180 °C for 10 min [64]. This mixture was cooled and diluted with ethyl ether to reduce the oil viscosity to facilitate separation by centrifugation. Alternatively, in chemical stabilization, albumin aqueous solution was emulsified in cottonseed oil at 25 °C then denatured by resuspension in ether containing the cross-linking agent 2,3-butadiene or formaldehyde [63–65]. Crisante et al. prepared cefamandole nafate-loaded BSA nanoparticles by w/o single emulsion-chemical crosslinking with glutaraldehyde. BSA aqueous phase was added dropwise to a continuous phase consisted of cyclohexane containing glutaraldehyde and then homogenized at a high speed [43]. A reformative emulsion-heat stabilization technique was used by Yang et al. to prepare BSA nanoparticles entrapping the poorly soluble 10-Hydroxycamptothecin (HCPT) in order to improve its stability mainly in its active lactone form [44]. In this study, chemical crosslinking was replaced by thermal stabilization by adding the w/o single emulsion dropwise to castor oil at 140 ±5 °C [44]. The possibility of incorporating a w/o/w multiple emulsion-based ovalbumin nanoparticles in mucosal vaccines was investigated [66]. The nanoparticles contained florescent markers helped indicate the uptake and subsequent internal trafficking within macrophage cell cultures [66]. 3.1.3. Thermal gelation Thermal gelation is a sequential process that involves heat-induced unfolding followed by protein–protein interactions including hydrogen bonding, electrostatic, hydrophobic interactions and disulfide–sulfydryl interchange reaction [45,46,67]. In a study performed by Yu et al., spherical core–shell structure nanogels (about 100 nm) were manufactured using thermal gelation method where ovalbumin and lysozyme solutions were mixed at pH 5.3, the pH of the mixture solution was adjusted to 10.3 and the solution was subsequently stirred and heated [45]. The gelation property of BSA on heating has been also reported [68]. By heating a mixture of chitosan and BSA–dextran conjugates, biocompatible BSA–dextran–chitosan nanoparticles were formed [46]. BSA molecules gelate forming the core of the nanoparticles whereas chitosan chains are partly trapped in the nanoparticle core because of the electrostatic attraction between chitosan and BSA (Fig. 2). The rest of the chitosan and the dextran extend in the nanoparticle shell. Doxorubicin could be effectively loaded into the nanoparticles by diffusion after changing the pH of their mixture to 7.4 by virtue of the electrostatic and hydrophobic interactions between the nanoparticles and doxorubicin [46].

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Fig. 2. Illustration of the formation of BSA–dextran–chitosan nanoparticles. Modified from Ref. [46].

3.1.4. Nano spray drying Spray drying is a well-established method commonly used in the pharmaceutical industry for producing a dry powder from a liquid phase. Unlike conventional spray dryers that use rotary atomizers and pressure nozzles for forming the spray droplets, the new Nano Spray Dryer utilizes a vibrating mesh technology for fine droplets generation [47]. Basically, the piezoelectric crystal driven spray head is incorporated with a small spray cap that contains a thin perforated membrane (spray mesh) having an array of precise micron-sized holes. When the piezoelectric actuator is driven at an ultrasonic frequency (i.e. 60 kHz), the mesh will vibrate upwards and downwards, injecting millions of precisely sized droplets from the holes and generating the aerosols [47]. In contrast to the common cyclone technology where particles smaller than 2 μm are typically not captured, particle separation in the Nano Spray Dryer involves the use of the electrostatic precipitator whereby the collection mechanism is independent of particle mass. Collection of fine particles with high efficiency is achieved with the novel electrostatic particle collector consisting of a grounded star electrode (cathode) and cylindrical particle collecting electrode (anode). The presence of a high voltage around the particle collector creates an electrostatic field that accelerates the deposition of negatively charged particles onto the inner wall of particle collecting electrode. This is followed by a discharging process [47]. Fig. 3 illustrates the functional principle of an electrostatic particle collector in the Nano Spray Dryer. Lee et al. utilized a feasible approach to prepare BSA nanoparticles in a single step using the novel Nano Spray Dryer (equipped with a vibrating mesh spray technology and an electrostatic particle collector) [47]. Optimized production of smooth spherical nanoparticles (median size: 460 ± 10 nm and yield: 72± 4%) was achieved using the 4 μm spray mesh at 0.1% w/v BSA concentration, 0.05% w/v surfactant concentration, drying flow rate of 150 L/min and inlet temperature of 120 °C [47]. 3.1.5. Nanoparticle albumin-bound technology (nab-technology) American Bioscience, Inc. has developed a unique albumin-based nanoparticle technology (nab-technology) that is ideal for encapsulating lipophilic drugs into nanoparticles. The drug is mixed with HSA in an aqueous solvent and passed under high pressure through a jet to form drug albumin nanoparticles in the size range of 100–200 nm [48,49]. Abraxane® (nab-paclitaxel;paclitaxel-albumin nanoparticle) with an approximate diameter of 130 nm is the first FDA approved nanotechnology based chemotherapeutic that has shown significant benefit in treatment of metastatic breast cancer. The market approval of Abraxane® can be viewed as a landmark not just for albumin-based drug delivery technology but also for nanomedicine [39,40,69,70]. Similarly, Kim et al. utilized nab-technology to prepare curcuminloaded HSA nanoparticles (CCM-HSA-NPs) with a size range of 130– 150 nm for intravenous administration [71]. HSA was dissolved in water saturated with chloroform. Separately, CCM was dissolved in

chloroform saturated with water. These two solutions were then mixed and homogenized at 20,000 psi for 9 cycles. The resulting colloid was rotary evaporated at 25 °C for 15 min under reduced pressure then lyophilized. CCM-HSA-NPs showed markedly a greater water solubility than CCM [71]. Several nab drugs are currently under development, including ABI-008 (nab-docetaxel) and ABI-009 (nabrapamycin) [48]. 3.1.6. Self-assembly Increasing the hydrophobicity of albumin by addition of a lipophilic drug and diminishment of primary amine groups on protein surface, could drive the self-assembly of HSA and formation of polymeric micelles [50]. Xu et al. prepared nanoscale HSA micelles for targeted delivery of doxorubicin [50]. The inner core was formed by albumin conjugated with doxorubicin via disulfide bonds. Additional doxorubicin was physically adsorbed into this core to attain a high drug loading capacity. This process gave rise to multimeric albumin aggregates that contain about 50 doxorubicin molecules per albumin with a mean diameter of about 30 nm [50]. In another study, a novel octyl-modified bovine serum albumin (OSA) has been synthesized based on the specific reaction between the aldehyde group of octaldehyde and primary amino group of albumin in order to improve the lipophilicity of albumin and thus form core–shell

Fig. 3. The functional principle of an electrostatic particle collector in the Nano Spray Dryer. Modified from Ref. [47].

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nanomicelles [51]. Lyophilized OSA powder was dissolved in double distilled water, ultrasonicated in a cooling bath followed by filtering through a 0.45 μm pore-sized microporous membrane. Paclitaxel was successfully loaded into OSA micelles by a dialysis method with a high drug-loading (33.1%) and entrapment efficiency (90.5%) due to the synergistic effect of micellar encapsulation and binding interaction between the drug and OSA [51]. By comparing the abovementioned methods for fabrication of albumin nanoparticles, it can be seen that emulsification technique requires organic solvents and removal of both the oily residues and surfactants. Furthermore, thermal stabilization is applicable only to drug molecules that are not heat sensitive. However, in chemical stabilization, the toxicity of the chemical crosslinking agents remains the main problem [65]. Therefore, desolvation process was developed as an alternative for the emulsification method since it is a robust and reproducible method for the denaturation of albumin [18]. Thermal gelation is a successful method to prepare albumin nanoscale hydrogels for loading and releasing drugs. The pH responsive property of the gel offers reversible sites to bind and release drugs, the cross-linking property can suppress dissociation upon dilution and the nanosize can respond to the environmental stimulation [67]. Nanoparticles prepared by nab-technology were designed to be safe and suitable for intravenous usage of poorly soluble drugs. Unlike the desolvation or emulsification methods, albumin bound nanoparticle technology does not require surfactants or polymeric materials for preparation. Furthermore, in desolvation or emulsification methods, the final state of the albumin differs from that produced by nab-technology. During chemical crosslinking processes, amines or hydroxyls present in HSA are cross-linked nonspecifically and during heat denaturation process, the structure of HSA is also irreversibly altered. In contrast, in nab-technology, the sulfhydryl residues of HSA may be oxidized (and/or existing disulfide bonds may be disrupted) to form new crosslinking disulfide bonds. However, the disulfide formation induced by homogenization does not substantially denature the HSA [48,49]. The self-assembly of chemically modified albumin to form nanoscale micelles can provide a high degree of drug loading as the hydrophobic core of micelles acts as a microreservoir for poorly water-soluble drugs [50]. Nano spray drying technique offers a new, simple and alternative approach for the production of nanoparticles. It offers the advantage of drying and particle formation in a single-step continuous and scalable process [47]. Furthermore, various particle properties such as particle size, bulk density and flow properties can easily be tuned via simple manipulation of the process parameters or spray dryer configuration [47].

propofol has been shown to bind to Sudlow's site II (in subdomains IIIA and B) in a cavity able to host the diiodophenol ring of a thyroxine molecule as well. The general anesthetic halothane also binds to Sudlow's site II and two further ligands are accommodated within the FA6 cleft, i.e., at the interface between subdomains IIA and IIB [75]. Because of the different abovementioned drug binding sites present in the albumin molecule, one of the major advantages of albumin nanoparticles is their high binding capacity of various drugs [24]. For water soluble drugs, drugs can be loaded to albumin nanoparticles either by incubation with the just-formed and hardened albumin nanoparticles or by incorporation of the drug into the solution of albumin prior to the formation and crosslinkage of the nanoparticles. A third method was via adding the drug to glutaraldehyde solution prior to the formation of the nanoparticles [54]. Fig. 5 illustrates the abovementioned loading methods of ganciclovir to BSA nanoparticle formulations. For model A (Incubation), unloaded nanoparticles incubated with ganciclovir increased the drug loading during the first 4 h of incubation. However, after this period of time, the amount of ganciclovir associated to nanoparticles remained almost constant (14.6 mg/mg). On the other hand, for model B (Incorporation), the nanoparticles offered a higher capacity to carry this antiviral drug (around 30 mg ganciclovir/mg nanoparticle). For model C, the mixture of ganciclovir with the protein and glutaraldehyde required a longer period of incubation to obtain similar drug loading values as model B [54]. Similarly, oligonucleotides and doxorubicin were loaded to BSA nanoparticles either via adsorbtion onto the surface of the pre-formed nanoparticles or incorporation in the nanoparticle matrix [76,77]. For water insoluble drugs, Zhao et al. prepared paclitaxel-loaded BSA nanoparticles using a desolvation technique [60]. For this purpose, paclitaxel, a water insoluble anticancer drug, was dissolved in ethanol which was then added as a desolvating agent to the aqueous albumin solution using a peristaltic pump followed by glutaraldehyde crosslinking. Drug entrapment efficiency and loading efficiency were approximately 95.3% and 27.2%, respectively [60]. In another investigation, the poorly soluble anticancer drug, 10-Hydroxycamptothecin, was successfully entrapped into BSA nanoparticles via emulsification technique with drug loading and encapsulation efficiency of 57.5% and 90.5%, respectively [44]. Nab-technology [69–71] and self-assembly [50,51] techniques were successfully developed for encapsulating poorly soluble drugs. The mechanism of drug association to albumin nanoparticles may include electrostatic adsorption of positively (e.g. ganciclovir) or

3.2. Drug loading HSA is best known for its extraordinary ligand binding capacity, providing a depot for a wide variety of compounds with favorable, noncovalent reversible binding characteristics for transport in the body and release at the cell surface [34]. HSA appears to be formed by three homologous domains (named I, II, and III). Each domain is known to be made up by two separate helical subdomains (named A and B), connected by random coil. According to Sudlow's nomenclature, bulky heterocyclic anions (e.g. bilirubin, anticoagulants like warfarin, nonsteroidal anti-inflammatory drugs like azapropazone, phenylbutazone and salicylate) bind to Sudlow's site I (located in subdomain IIA), whereas Sudlow's site II (located in subdomain IIIA) is preferred by aromatic carboxylates with an extended conformation (e.g. profens like ibuprofen, fenoprofen, ketoprofen and benzodiazepines like diazepam) (Fig. 4) [34,72,73]. These two pre-formed and stable high affinity binding sites account for the binding of most drugs at therapeutic concentrations, while higher drug concentrations might also involve other binding sites, with lower binding affinity and selectivity [34,74]. HSA is able to bind seven equivalents of long-chain fatty acids (FAs) at multiple binding sites with different affinities. Thyroxine binds to a pocket between domains I and III (Fig. 4). The general anesthetic

Fig. 4. HSA structure. The six subdomains of HSA are colored as follows: subdomain IA: blue; subdomain IB: cyan; subdomain IIA: dark green; subdomain IIB: light green; subdomain IIIA: red; subdomain IIIB: orange. Modified from Ref. [34].

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Fig. 5. Schematic representation of the different ganciclovir-loaded albumin nanoparticle formulations. Modified from Ref. [54].

negatively charged (e.g. oligonucleotide) molecules dependent on the high content of charged amino acids in the albumin primary structure [25,26]. On the other hand, a covalent linkage between ganciclovir and the albumin matrix in BSA nanoparticles was suggested by Merodio et al. who found that the presence of trypsin in the release medium slightly increased the drug concentration released from the nanoparticles [54]. However, the release of the drug was increased in acidic or basic media, due to the disruption of the covalent binding between ganciclovir and the protein matrix via glutaraldehyde. This suggestion was confirmed by thin layer chromatography study [54]. 3.3. In vitro studies Ovalbumin nanospheres (497 nm) prepared by a coacervation technique were loaded with the systemic antifungal drug amphotericinB as an alternative to liposomal preparation due to stability problems. Drug-loaded nanospheres were found to exhibit a biphasic release pattern with a cumulative release of 97.7% [78]. Arnedo et al. reported that desorption of the oligonucleotides from BSA nanoparticles was affected by pH and ionic strength of the medium indicating that electrostatic forces play a major role in the interaction between the negatively charged oligonucleotide and the positively charged amino groups on the surface of the nanoparticles [79]. The mechanism of prednisolone release from BSA nanospheres was found to be due to diffusion and erosion as observed by fitting the release data in different models [80]. In the study conducted by Das et al., it was shown that aspirin-loaded BSA nanoparticle formulation releases aspirin at a sustained rate for prolonged duration (90% at 72 h) compared to simple drug solution [81]. Similarly, 5-fluorouracilloaded BSA nanoparticles suspension maintained a constant release of drug for 20 h [82]. In a comparative study performed by Jain and Banerjee, ciprofloxacin hydrochloride-loaded nanoparticles were prepared using four different natural carrier materials; BSA, gelatin, chitosan and lipid (solid lipid nanoparticles) [83]. BSA nanoparticles appeared to be promising formulation due to their high zeta potential (N16 mV) and relatively high drug entrapment (48.20%) and ability to release the drug for prolonged durations up to 120 h (Fig. 6) [83]. Fluoresceinamine labeled HSA nanoparticles provoked little or no cytotoxicity and inflammation with an efficient uptake in human bronchial epithelial cells, thus these nanoparticles are suitable drug and gene carriers for pulmonary application [41]. Wartlick et al. reported that HSA nanoparticles were suitable carrier systems for protection of antisense oligonucleotides (ASOs) from nuclease digestion and thus enabled a sustained release [84]. The stabilization procedure mainly affects the enzymatic degradability of HSA nanoparticles. The enzymatic degradation is a crucial parameter for the release of an embedded drug.

Proteinase K and trypsin were suitable reagents to gain a fast and complete degradation of the nanoparticles without affecting ASO stability. Nanoparticles crosslinked with low amounts of glutaraldehyde, rapidly degraded intracellularly, leading to a significant accumulation of the ASO in cytosolic compartments of the tumor cells [84]. However, glutaraldehyde can lead to inactivation of ASOs through chemical crosslinking. Therefore, heat denaturation was used instead of using glutaraldehyde to prepare HSA nanoparticles loaded with ASOs against Plk1 (polo-like kinase 1) at a temperature of 105 °C for 10 min. A significant reduction of Plk1 mRNA and protein expression was observed [37]. HSA nanoparticles were also proved to be effective and safe carriers for delivering anticytomegaloviral compounds (ganciclovir and the phosphodiester oligonucleotide analog formivirsen) when administered by the intravitreal route and did not induce autoimmune reactions. The nanoparticles improved their antiviral activity and appeared to be fusogenic carriers able to target the nucleus of cells [25,85]. HSA nanoparticles enabled the delivery of a variety of drugs across the BBB into the brain. Therefore, the suitability of HSA nanoparticles for the transport of oximes across the BBB was suggested by Kufleitner et al. [86,87]. Due to its inability to rapidly cross the blood–brain barrier (BBB), obidoxime, an antidote for treatment of organophosphorous poisoning, was adsorbed to HSA nanoparticles. The in vitro release of obidoxime from nanoparticles showed a rapid release of the drug from the nanoparticles within 3 h [86,87]. Wacker et al. have established a

Fig. 6. In vitro drug release kinetics of ciprofloxacin hydrochloride-loaded nanoparticles in PBS (pH 7.4). Modified from Ref. [83].

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stable HSA nanoparticulate formulation of 5,10,15,20-tetrakis(mhydroxyphenyl) porphyrine (mTHPP) and chlorin (mTHPC), two wellknown photosensitizers used in photodynamic therapy of cancer [88]. Both preparations were able to generate singlet oxygen with low quantum yield. In contrast, efficient singlet oxygen generation was obtained when Jurkat cells were incubated with mTHPP and mTHPC loaded HSA nanoparticles indicating that the photosensitizer molecules were successfully released from the nanoparticles that were taken up by the cells. The nanoparticles protected these drugs from aggregation and oxidation processes until the particles are taken up by living cells and release their drug payload [88]. Concerning the stability of albumin nanoparticles, HSA nanoparticles showed no changes in particle size when stored in aqueous suspension for up to 6 months at 4 °C or also can be stored as a lyophilized powder [45,77]. A freeze-drying process was adopted to obtain a dry powder form for long-term stability of the pharmaceutical products [89]. Santhi et al. studied the effect of different cryoprotectors in prevention of the agglomeration of 5-fluorouracil-loaded BSA nanoparticles during freeze drying [90]. Glucose (5%) was observed to be relatively more effective in the prevention of particle agglomeration than the other cryoprotectors [90]. In another study, a particle growth of lyophilized HSA nanoparticle formulations was observed in the absence of cryoprotectants while in the presence of different cryoprotective agents sucrose, trehalose and mannitol, aggregation of HSA nanoparticles during freeze-drying was prevented [91]. Sucrose and trehalose were superior to mannitol, especially with regard to the long-term storage stability results [91]. Kumar and Jain [92] used pectin-modified HSA nanoparticles and found that a small quantity of pectin suppressed the agglomeration of the nanoparticles. This effect may be attributed to the pectin segments present on the surface of nanoparticles [92]. 3.4. In vivo studies BSA nanoparticles could serve as a rational liver-targeted drug delivery system. The results of a body distribution study in rats showed the ‘passive’ liver targeting potential of 10-Hydroxycamptothecin (HCPT)–BSA nanoparticles where 59.6%, 52.9% and 55.3% of the examined amount of HCPT accumulated in liver at 1, 4 and 24 h after injection, respectively [44]. Similar results were observed by Li et al. [80] and Kapoor et al. [93] where sodium ferulate- and prednisolone-loaded BSA nanoparticles, respectively, showed a much higher drug distribution into liver, compared with drug solution after intravenously injected to mice. The biodistribution of methotrexate-loaded BSA nanoparticles in mice showed a markedly high increase in drug distribution to the lungs, liver and spleen compared to the free drug [94]. BSA nanoparticles were shown to be suitable carriers to target gamma-interferon (IFN-γ) to macrophages and thus potentiating their therapeutic activity [95]. Whereas the encapsulation of IFN-γ inside the matrix of nanoparticles completely abrogated its activity, adsorbed IFN-γ increased the bactericidal effect induced by RAW macrophages activated with free IFN-γ, along with a higher production of nitric oxide in BALB/c-mice infected with Brucella abortus[95]. In another study, BSA nanoparticles loaded with the antibiotic (cefamandole nafate) were developed. The nanoparticles were able to adsorb high antibiotic amounts due to their high surface/volume ratio. However, they released cefamandole in an uncontrolled fashion, leading to a rapid loss of its antibacterial activity. It was found that when cefamandole-loaded BSA nanoparticles were entrapped in a carboxylated polyurethane, improvements in the release control were obtained. The polymer matrix acting as a diffusion barrier controlled the drug elution and prolonged the antimicrobial activity of the systems up to 8 days [43]. In a platelet aggregometric study, Das et al. clearly showed that the amount of aspirin diffused from aspirin-loaded BSA nanoparticles at the end of 48 h was sufficient to prevent platelet aggregation [81]. Santhi et al. observed that BSA nanosphere-bound 5-fluorouracil produced a better cytotoxic effect than the free drug against HEp-2

cancer cell lines [90]. The anti-tumor efficacy of fluorouracil-loaded nanospheres was investigated in DLA tumor-induced mice models and the percentage of tumor inhibition was relatively higher in animals treated with nanosphere-bound drug than with the free drug [90]. Arnedo et al. found that the phosphodiester oligonucleotides (PO)-loaded BSA nanoparticle formulations significantly increased the antiviral activity of PO against MRC-5 fibroblasts infected with human cytomegalovirus [76]. BSA nanoparticles partially protected PO against enzymatic degradation and improved their presence in the nucleus increasing its efficiency [76]. Coadministration of bioadhesive polymers (hyaluronic acid, mucin, sodium carboxymethylcellulose and polyacrylic acid) with pilocarpine-loaded BSA nanoparticles increased the residence time of the nanoparticles in the eye [58]. The drug bioavailability with the best results for miotic response and IOP reduction was observed with mucin. The polymers interacted strongly both with the albumin nanoparticles and with precorneal mucus resulting in an improved adhesion to the precorneal/conjunctival mucin layer and hence to a prolongation of the residence time of the medication in the eye [58]. In another study, HSA nanoparticles were found to sustain the hydrocortisone transport through porcine cornea [96]. The distribution study of hydrocortisone-loaded nanoparticles showed a higher drug level in the inflamed eye of rabbits than in the healthy eye due to increased cell permeability as a result of inflammatory processes [96]. Dreis et al. investigated the influence of doxorubicin-loaded HSA nanoparticles on cell viability in two different neuroblastoma cell lines (UKF-NB3, IMR 32) [77]. Doxorubicin loading to HSA carrier system did not result in a reduced biological activity; the inhibition of cell growth is comparable or even better compared to a doxorubicin control solution [77]. Noscapine, a widely used cough suppressant, has recently been shown to cause significant inhibition and regression of tumor volumes. Therefore, the incorporation and delivery of noscapine-loaded HSA nanoparticles to breast cancer cell line (SK-BR-3) was reported [97]. Noscapine-loaded HSA nanoparticles were found to have the potential to deliver a maximum amount of noscapine to target sites at a rate and concentration that permits optimal therapeutic efficacy while reducing any undesirable side effects to a minimum [97]. 3.5. Accumulation of HSA nanoparticles in tumors The enhanced uptake of albumin-based nanoparticles in solid tumors is mediated by the pathophysiology of tumor tissue, characterized by angiogenesis, hypervasculature, a defective vascular architecture and an impaired lymphatic drainage [98–100]. Also due to transcytosis initiated by binding of native albumin to a cell surface, 60-kDa glycoprotein (gp60) receptor (albondin) as well as binding of albumin to SPARC, an extracellular matrix glycoprotein that is overexpressed in a variety of cancers. Albumin binds to the gp60 receptor, which in turn results in binding of gp60 with an intracellular protein (caveolin-1) and subsequent invagination of the cell membrane to form transcytotic vesicles (Fig. 7). Tumor uptake in preclinical models can be easily visualized by injecting the dye evans blue that binds rapidly and tightly to circulating albumin and makes subcutaneously growing tumors turn blue within a few hours post-injection [69,70]. Nanoparticles made of HSA represent a promising strategy for targeted delivery of anticancer drugs to tumor cells by enhancing the drug bioavailability and distribution, diminishing their toxicity and reducing the body's response towards drug resistance. Albumin nanoparticles prepared by nab-technology were reported to utilize albumin receptor (gp60)-mediated transcytosis through microvessel endothelial cells in angiogenic tumor vasculature and targets the albumin-binding protein SPARC [48,49]. The superior antitumor activity of nab-paclitaxel was found to be due to increased transendothelial gp60-mediated transport and increased intratumoral accumulation as a result of the SPARC–albumin interaction [48,49,69,70]. In a preclinical study using radiolabeled paclitaxel, endothelial binding of paclitaxel

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Electrospinning is a simple technique used to form long, ultrafine fibers in the form of a non-woven web [101]. Electrospun biodegradable nanofibers used as drug carriers [102] and for post-operative local chemotherapy [103] have thus become promising new developments. Edible electrospun nanofibrous thin film could be fabricated from blend solutions of ovalbumin and cellulose acetate with the addition of Tween 40 to modulate the solution properties (Fig. 9) [29]. These edible protein–polysaccharide composite nanofibers could provide new functionalities with respect to in vivo-controlled release of nutraceuticals and drugs. In the gastrointestinal tract they can withstand the stomach's severe acidic conditions and release the bioactive material at the alkaline pH of the intestine [29]. Nanoparticles based on thiolated alginate (ALG-CYS) and disulfide bond reduced bovine serum albumin (BSA-SH) have been synthesized by a coacervation method and stabilized by disulfide bond formation [104]. These nanoparticles were evaluated as delivery systems for tamoxifen where maximum drug release (23–61%) took place between 7 and 75 h and the amount of drug released can be modulated with the percentage of ALG-CYS in the particle. After fitting several mathematical models, a fickian release behavior for all the formulations was declared [104]. Emulsion solidification method was used to prepare fluorouracil-

loaded sodium alginate-BSA nanoparticles. By incorporating I125 within the nanoparticles, radioactive counting in different organs of rats was possible after oral administration. The nanoparticles were mainly distributed in the liver, spleen, lungs and kidneys and slightly in brain [105]. Verrecchia et al. prepared poly(lactic acid/albumin) “PLA/HSA” nanoparticles by emulsification-solvent evaporation and microfluidization [106]. The albumin molecules did not damage, therefore the nanoparticles are not more immunogenic than native albumin in solution. The PLA/albumin nanoparticles were well tolerated during in vivo studies where daily i.v. injection in rats did not produce apparent adverse effects. However, the time necessary to clear the PLA/albumin nanoparticles from the plasma was very short (about 90% was eliminated from the blood stream in 5 min) [106]. HSA–PEI–DNA nanoparticles consisting of DNA, HSA and polyethylenimine (PEI) were formed and tested for transfection efficiency in vitro with the aim of generating a nonviral gene delivery vehicle [107]. The nanoparticles containing the pGL3 vector coding for luciferase as a reporter gene were formed by charge neutralization and displayed a low cytotoxicity when tested in cell culture. These nanoparticles combined a high transfection potential with a good biocompatibility and low cytotoxicity which may be suitable for i.v. administration [107]. Ternary proticles are nanoparticles (around 200 nm) prepared by self-assembly from oligonucleotides (ONs), protamine free base and human serum albumin. HSA serves as a protective colloid in the nanoparticle suspension [108]. These nanoparticles are promising candidates for ONs delivery to cells because they are stable for several hours in solutions, efficiently taken up by cells and even after cellular uptake, they easily release the ONs [108,109]. Recently, lipoprotein-based nanoparticles have offered several advantages as drug vehicle being biocompatible and stable in the circulation. The recognitions with the low density lipoprotein receptors (LDLR) overexpressed in some tumor cells offer a great potential for tumor-targeting delivery of lipoprotein-based nanoparticles [110]. Therefore, Xu et al. developed a novel lipoprotein-mimic nanocarrier composed of a modified protein–lipid nanocomplex (mP-LNC) [111]. The core was formed of lipid nanoparticle prepared by solvent evaporation method. The hydrophilic shell was formed of BSA where its amino groups were covalently modified by ursodeoxycholic acid (UA) to improve the binding efficiency of albumin with the hydrophobic lipid core. Using coumarin-6 as a fluorescence probe in normal and cancer liver cells, it was found that the uptake of mP-LNC was higher in hepatic carcinoma cells than in normal liver cells. This indicates that the recognition of UA and bile acid receptor played an important role in the targeting delivery and energy driven endocytosis process of the nanocomplex. Besides the receptor effect of targeting ligand, the effect of albumin on cellular uptake enhancement of mP-LNC may also coexist [111].

Fig. 8. Binding of CrEL-paclitaxel and nab-paclitaxel to live human umbilical vascular endothelial cells. Modified from Ref. [70].

Fig. 9. SEM micrographs of the electrospun nanofibers from the ovalbumin and cellulose acetate blend solutions containing Tween 40. Modified from Ref. [29].

Fig. 7. Albumin receptor-mediated uptake of intravascular constituents and transcytosis across the vascular endothelium. (A) Albumin receptor (gp60) binds albumin which in turn results in binding the induction of caveolin-1; (B) caveolin-1 induces membrane budding and internalization, trapping free and protein-bound plasma constituents; (C) formation of caveolae, leading to transcytosis and extravascular deposition of the caveolae contents. Modified from Ref. [70].

increased 9.9-fold and transport of paclitaxel across the endothelial cell monolayer increased 4.2-fold with nab-paclitaxel compared with cremophor EL-paclitaxel (CrEL-paclitaxel) (Fig. 8) [69,70]. Similarly, Kim et al. investigated the potential mechanisms responsible for the enhanced accumulation of curcumin (CCM) in tumors from CCM-loaded HSA-NPs prepared by nab-technology [71]. The endothelial transcytosis of CCM-HSA-NPs was completely suppressed by β-methyl cyclodextrin, a known inhibitor of caveolar mediated transcytosis [71]. 4. Albumin nanocomplexes

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5. Surface-modified albumin nanoparticles Because of the defined primary structure of albumin, albumin-based nanoparticles offer various possibilities for surface modification due to the presence of functional groups (i.e. carboxylic and amino groups) on the surface of the nanoparticles [26,36,37]. Conjugation of surfacemodifying ligands to the surface of albumin nanoparticles is usually achieved through covalent bond formation between the ligands and the functional groups on albumin surface. However, surface coating or electrostatic adsorption techniques may be also utilized for surface modification of the nanoparticles. In the albumin–ligand combinations, the protein acts as a biodegradable carrier for drug delivery whereas the ligand is used for modifying the pharmacokinetic parameters (e.g. surfactants), enhancing the nanosystem stability (e.g. poly-L-lysine), prolonging its circulation half-life (e.g. PEG), slowing the drug release (e.g. cationic polymers) or as a targeting agent (e.g. folate, thermosensitive polymers, transferrin, apolipoproteins and monoclonal antibodies).

coating BSA nanoparticles to be a suitable substitute for PEI. Short interfering ribonucleic acid (siRNA) and BMP-2 were encapsulated in PLL-coated BSA nanoparticles as model drugs [115,119]. The PLL coating was found to enhance proteolytic resistance producing more stable nanoparticles. The aqueous solution stability of nanoparticles increased with increasing PLL molecular weight and concentration which was demonstrated by the continuous release of FITC–BSA from 0.9 kDa PLLcoated BSA nanoparticles in phosphate buffer (pH 7.4) and almost no release of FITC–BSA from 4.2, 13.8 and 24 kDa PLL-coated BSA NPs after 3 days (Fig. 10) [115]. It can be seen that polymers capable of forming brush-like structures on nanoparticle surfaces that might reduce van der Waals based interactions among the nanoparticles, thereby stabilizing them [119]. 5.3. Thermosensitive polymers

The hematological, cardiac and testicular toxicities of doxorubicin could be effectively reduced by binding the drug to HSA nanoparticles surface coated with polysorbate 80 [112]. The most probable explanation of the lower cardiotoxicity is the favorable alteration of the drug pharmacokinetics produced by surfactant coating. It was demonstrated that coating of the nanoparticles with polysorbate 80 increased the AUC as well as decreased the volume of distribution, clearance and cardiotoxicity of doxorubicin [113]. It is also possible that the lower testicular toxicity of surfactant-coated nanoparticles is explained by a less efficient uptake of the surfactant-coated and consequently less opsonized particles by the Sertoli cells that have a phagocytotic function. Accordingly, the uncoated particles being more prone to phagocytosis are more hazardous for the Sertoli cells. Inside the cell, these particles degrade and release the drug that then exerts its cytotoxic effect, thus causing more pronounced damage of the epithelium [114].

Shen et al. developed a new thermal targeting anti-cancer drug carrier by conjugating the thermo-responsive poly(N-isopropylacrylamide-coacrylamide)-block-polyallylamine (PNIPAM-AAm-b-PAA) to the carboxylic group on the surface of albumin nanospheres through carbodiimide (EDC) coupling technique [120]. The anti-cancer drug, adriamycin, was entrapped into the unconjugated (AN) and conjugated albumin nanospheres (PAN) during the particle preparation [121]. Compared with AN, the release rate of adriamycin from PAN in trypsin solution was slower and decreased with increasing the conjugation amounts or molecular weight of PNIPAM-AAm-AA, which suggested that the existence of a steric hydrophilic barrier on AN made digestion of AN more difficult. Moreover, the release of adriamycin from PAN above the cloud-point temperature of PNIPAM-AAm-AA became faster due to shrinkage of the hairy thermosensitive polymer. When incubated with the human hepatocellular carcinoma HepG2 cells, PAN could target cancer cells above the cloud-point temperature of PNIPAM-AAm-AA, whereas it cannot below this temperature. These results might reflect the thermal targetability of PAN that may selectively accumulate onto solid tumors that are maintained above physiological temperature due to local hyperthermia [121].

5.2. Cationic polymers

5.4. Polyethylene glycol (PEG)

Albumin nanoparticles prepared by coacervation are usually stabilized by glutaraldehyde crosslinking. However, the use of glutaraldehyde for controlling nanoparticle resiliency is a concern since this compound is cytotoxic and it may react undesirably with the therapeutic agents entrapped within the nanoparticles [115]. Coating the protein nanoparticles with biomaterials may be a superior way to provide protection against enzymatic degradation where the physical adsorption of a macromolecule will eliminate the need to utilize hazardous crosslinkers [115]. Therefore, anionic BSA nanoparticles were surface coated with cationic polymers such as polyethylenimine (PEI). Bone morphogenetic protein-2 (BMP-2) could be encapsulated in PEI-coated BSA nanoparticles with its release was controlled by the PEI coating concentrations [116,117]. The surface charge of the particles was shifted from negative to neutral or slightly positive which may reduce the plasma protein adsorption on particle surfaces and thus facilitate in vivo application of nanoparticles. However, the osteoinductive activity of BMP-2 encapsulated in nanoparticles was not readily achieved in a rat ectopic model, and this undesirable result was attributed to the toxic effect of the PEI on locally present cells [117]. In a study performed by Zhang et al., polyethylene glycol (PEG) substitution was shown to effectively reduce the toxicity of PEI [118]. A more effective bone formation in the rat ectopic model was achieved with BMP-2 encapsulated in BSA nanoparticles coated with PEI–PEG compared with those coated with PEI which was attributed to the improved biocompatibility and physiochemical properties [118]. Another cationic polymer, poly-L-lysine (PLL), was explored for

Chemical coupling of polyethylene glycol (PEG) to proteins or particles (PEGylation) is known to prolong their circulation half-life by greater than 50-folds, reduce their immunogenicity and also promote their accumulation in tumors due to enhanced permeability and retention effect [122]. mPEG-Succinimidyl Propionate (mPEG-SPA) was used for PEGylating the amino groups of BSA nanoparticles [122]. The release of 5-fluorouracil from the PEGylated BSA nanoparticles was almost slower than non-PEGylated ones, probably due to existence of a PEG layer around PEGylated particles which makes an extra resistance in opposition to drug diffusion [122]. Surface-modified HSA nanoparticles were prepared from two poly(ethylene glycol)–HSA conjugates: poly(thioetheramido acid)–poly(ethylene glycol) copolymer-grafted HSA and methoxy poly(ethylene glycol)-grafted HSA (HSA–mPEG) [123]. Rose Bengal (RB) was used as a model drug for encapsulation into the nanoparticles. The drug loading in HSA–mPEG nanoparticles was much lower due to less drug–protein binding sites available in the HSA– mPEG molecule as compared to the HSA. Compared with unmodified nanoparticles, the slower release of RB from the surface-modified HSA nanoparticles in the presence of enzymes suggested that the existence of a steric hydrophilic barrier on the surface of the nanoparticles made digestion of the nanoparticles more difficult [123].

5.1. Surfactants

5.5. Folate Folic acid is a low molecular weight (441 Da) vitamin whose receptor is frequently overexpressed in human cancer cells. This receptor has been identified as a tumor marker, especially in ovarian carcinomas and it is

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Fig. 10. Stability of PLL-coated BSA nanoparticles based on release profile of FITC–BSA from coated BSA nanoparticles measured in phosphate buffer (pH 7.4). The MWs of PLL used for coating onto BSA nanoparticles were 0.9 (A), 4.2 (B), 13.8 (C) and 24 (D) kDa, with their concentrations being 0.1(●), 0.3 (○) and 1.0 (▼) mg/ml, respectively. Modified from Ref. [115].

highly restricted in most normal tissues [124,125]. As a targeting device to the tumor cells, folic acid presents advantages as follows. First, it is stable, inexpensive, nonimmunogenic compared with proteins such as monoclonal antibodies and compatible with organic solvents used during the preparation process. Second, folic acid binds to the folate receptors at cell surfaces with very high affinity and is internalized by receptormediated endocytosis [126,127]. Folic acid carboxylic group was covalently conjugated to the amino groups on the surface of albumin nanoparticles using 1-ethyl-3-(3dimethylaminopropyl) carbodiimide (EDC) coupling technique [59]. The increased nanoparticle uptake into cancer cells suggests that folate-conjugated albumin nanoparticles represent a drug delivery system that shows specificity for cancer cells [128]. Therefore, many anticancer drugs were loaded into folate-conjugated albumin nanoparticles including doxorubicin [59], paclitaxel [60], cisplatin [129], vinblastine sulfate [130], mitoxantrone [131] and epigallocatechin-3gallate [132]. Fluorescein isothiocyanate labeled folate-conjugated BSA nanoparticles were taken up to SKOV3 cells (human ovarian cancer cell line). This uptake was inhibited by an excess of folic acid, suggesting that the binding and/or uptake were mediated by the folate receptor [133–135]. Similarly, folate-decorated paclitaxel-loaded BSA nanoparticles could effectively targeted a human prostate cancer cell line [60]. Shen et al. reported that folate-conjugated doxorubicin-loaded BSA nanospheres were incorporated into HeLa cells (tumor cells) only after 2 h incubation, whereas HeLa cells failed to incorporate the unconjugated nanospheres after 4 h incubation [59]. Aortic smooth muscle cells (AoSMC) viability was higher when compared to viability of HeLa cells if the cells were treated with folate-conjugated doxorubicin-loaded BSA nanoparticles, suggesting that these nanoparticles were selective for HeLa cells (with FA receptor alpha, FRα) and non-selective for AoSMC cells (without FRα) [59]. Folate-conjugated magnetic HSA nanoparticles loaded with cisplatin showed an obvious sustained-release effect where the half release time (t1/2) of cisplatin from cisplatin solution and nanoparticles was 65 min and 24 h, respectively [129].

Ulbrich et al. prepared folate-modified HSA nanoparticles with the folic acid was attached to the nanoparticles surface either by adsorption or by covalent coupling [128]. Folic acid adsorption to HSA nanoparticles increased their binding and uptake to cancer cells to a much lesser extent compared to folate-conjugated HSA nanoparticles. The fluorescence intensity of two cell lines 101/8 and UKF-NB-3 incubated for two different incubation times (4 h and 24 h) with covalently folateconjugated HSA nanoparticles was significantly higher, especially after 24 h, than that of cells incubated with folic acid adsorbed onto the surface of the nanoparticles (Fig. 11). The figure also showed that the fluorescence intensity in the cells exposed to nanoparticles (unmodified, folate-adsorbed and covalently folate-conjugated HSA nanoparticles) increased with incubation time [128]. 5.6. Peptides Cancer cells from various entities have been reported to express high levels of αvβ3 integrin, a membrane receptor for extracellular matrix ligands such as vitronectin and fibronectin [136,137]. Since cyclic arginine–glycine–aspartic acid (RGD) peptide is a ligand with high binding affinity to αvβ3 integrin, RGD peptide-anchored sterically stabilized BSA nanospheres (RGD-SN) bearing 5-fluorouracil were prepared for targeting the tumor vasculature [138]. RGD-SN were compared with Arginine–Alanine–Aspartic acid (RAD) peptideanchored sterically stabilized BSA nanospheres (RAD-SN) and BSA nanospheres without peptide conjugate (SN). RGD-SN were significantly effective in the prevention of lung metastasis, angiogenesis and in effective regression of tumors compared with free fluorouracil, RAD-SN and SN (Fig. 12) [138]. In another study, PEGylated HSA nanomicelles formed by selfassembly were surface conjugated with cyclic RGD peptides to guide selective delivery of doxorubicin to cells expressing the αvβ3 integrin. A cyclic RGD peptide was conjugated to the micelle PEG chains [50]. When incubated with human melanoma cells (M21+) that express the αvβ3 integrin, higher uptake and longer retention of doxorubicin was

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Fig. 11. Internalization and uptake of HSA nanoparticles examined by laser confocal microscopy. Modified from Ref. [128].

observed. Once accumulated in cells, both the covalently linked and the noncovalently absorbed doxorubicin were readily released from albumin carrier by a combination of reversal of disulfide bonds by intracellular thiols and by proteolytic processes in endosomes and lysosomes [50]. In the study conducted by Karmali et al., tumor-homing peptides (CREKA), a pentapeptide (cysteine–arginine–glutamic acid–lysine– alanine) and (LyP-1), a cyclic nine-amino acid peptide, were used to target abraxane (nab-paclitaxel) to tumors in mice [139]. Peptide– abraxane conjugates were prepared by coupling peptides to abraxane through their cysteine sulfhydryl group using a sulfo-SMCC (sulfosuccinimidyl 4-[N-maleimidomethyl] cyclohexane-1-carboxylate) crosslinker. When CREKA-abraxane was injected intravenously into mice bearing MDA-MB-435 human cancer xenografts, it accumulated in tumor blood vessels forming aggregates that contained red blood cells and fibrin. Self-assembled mixed micelles carrying the homing peptide on different subunits accumulated in the same areas of tumors as LyP-1abraxane, showing that Lyp-1 can deliver intact nanoparticles into extravascular sites. LyP-1-abraxane produced a statistically highly significant inhibition of tumor growth compared with untargeted abraxane [139].

5.7. Apolipoprotein As a brain targetor, apolipoprotein E (Apo E) was covalently bound to HSA nanoparticles to enhance the delivery of drugs across the blood– brain barrier [140,141]. For the conjugation to occur, sulfhydryl groups were introduced into the apolipoproteins then the thiolated lipoprotein solutions were added to activated HSA nanoparticles and stirred for 12 h at room temperature. After intravenous injection into mice, only the Apo E-modified nanoparticles were detected in brain capillary endothelial cells and neurones, whereas no uptake was detectable with unmodified nanoparticles (Fig. 13) [140]. In another study, Apolipoprotein E3, A-I as well as B-100 was covalently attached to HSA nanoparticles loaded with loperamide, a drug that normally does not cross the blood–brain barrier [141]. After intravenous injection in mice, all the Apo-modified nanoparticle preparations yielded considerable antinociceptive effects after 15 min and lasted over 1 h, whereas the loperamide solution achieved no effect [141]. 5.8. Transferrin The surface of HSA nanoparticles encapsulating azidothymidine, a water-soluble antiviral drug, was modified by anchoring transferrin as a ligand for brain targeting. For the conjugation to occur, the nanoparticles were activated with the heterobifunctional crosslinker NHS-PEG-MAL-5000 then thiolated solution of transferrin was added to sulfhydryl-reactive HSA nanoparticles and incubated under shaking for 18 h at room temperature. A significant enhancement of brain uptake and localization of azidothymidine was observed for transferrin-anchored HSA nanoparticles[142]. In another investigation, transferrin or transferrin receptor monoclonal antibodies TfR-mAb (OX26 or R17217) were covalently coupled to HSA nanoparticles loaded with loperamide [36]. After intravenous injection, loperamideloaded transferrin- or TfR-mAb-coupled HSA nanoparticles achieved strong antinociceptive effects in mice demonstrating that these modified nanoparticles represent very useful carriers for the transport of drugs into the brain [36]. 5.9. Monoclonal antibodies

Fig. 12. Antitumor efficacy of control, fluorouracil and different nanosphere formulations of the drug in mice bearing B16F10 melanoma. Arrow represents the time of injection. Modified from Ref. [138].

Monoclonal antibodies (mAb) have emerged as an interesting group of ligands for specific tumor targeting. The human epidermal growth factor receptor-2 (HER2) serves as a tumor targeting marker for the treatment of patients with metastatic breast cancer. Therefore, the surface of HSA nanoparticles was modified by humanized anti-HER2

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Fig. 13. Micrographs of the hippocampus region of SV 129 mice after the injection of Apo E-modified nanoparticles. 15 min after intravenous injection, the nanoparticles (dark spheres indicated by arrows) could be seen inside the endothelium cells (a and b). (a) shows a cross section of a vessel in the hippocampus region of a SV 129 mouse 15 min after nanoparticle injection. Some nanoparticles (arrows) can still be seen in the lumen of the vessel. (b) shows a higher magnification of the same vessel with the endothelium cell membrane forming a coated pit adjacent to a nanoparticle. Modified from Ref. [140].

specific antibody trastuzumab (Herceptin®) through avidin–biotincomplex formation between the biotin-binding protein (NeutrAvidin) attached to the nanoparticles and the biotinylated antibody [35]. Attachment of the trastuzumab-conjugated HSA nanoparticles to the surface of HER2-overexpressing cells (cell lines BT474, MCF7 and SK-BR3) was time and dose dependent allowing an effective internalization of the nanoparticles by these cells via receptor-mediated endocytosis [35]. Steinhauser et al. used trastuzumab-modified HSA nanoparticles to provide a cell specific targeting of the antisense oligonucleotides (ASOs) to HER2-overexpressing breast cancer cells [37,143]. The ASOs were directed against Polo-like kinase 1 (Plk1) and were able to cause a significant down-regulation of the Plk1 mRNA and Plk1 protein after incubation with the nanoparticle formulations [37]. It has been shown that many malignancies like colorectal, head, neck, non-small cell lung ovarian, breast and prostate cancers, as well as glioma, show an overexpression of the epidermal growth factor receptor (EGFR) on their surfaces. Thus, cetuximab, a humanized IgG1 mAb targets EGFR and was approved for the treatment of colorectal cancer by FDA in 2004 [144]. Therefore, cetuximab-modified HSA nanoparticles are a promising carrier system for drug transport. A specific accumulation targeting the EGFR could be shown in EGFR-expressing colon carcinoma cells [144]. DI17E6, a monoclonal antibody directed against αv-integrins, was covalently coupled to HSA nanoparticles loaded with doxorubicin [145]. The thiolated antibody was coupled with sulfhydryl-reactive nanoparticle suspension to achieve a covalent linkage between antibody and the nanoparticle system. The target-specific nanoparticles specifically targeted αvβ3 integrin positive melanoma cells showing increased cytotoxic activity compared to the free drug [145].

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