Chitosan nanoparticles as adenosine carriers

July 8, 2017 | Autor: M. Kazemzadeh-Narbat | Categoria: Adenosine, Chitosan, Drug Delivery
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http://informahealthcare.com/mnc ISSN: 0265-2048 (print), 1464-5246 (electronic) J Microencapsul, Early Online: 1–7 ! 2015 Informa UK Ltd. DOI: 10.3109/02652048.2015.1046517

RESEARCH ARTICLE

Chitosan nanoparticles as adenosine carriers Mehdi Kazemzadeh-Narbat1,2,3, Marla Reid1, Marianne Su-Ling Brooks1, and Amyl Ghanem1 Department of Process Engineering and Applied Science, Dalhousie University, Halifax, Canada, 2Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA, and 3 Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA Journal of Microencapsulation Downloaded from informahealthcare.com by MIT Libraries on 06/12/15 For personal use only.

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Abstract

Keywords

The objective of this research project was to evaluate the potential use of chitosan (CS) nanoparticles (NPs) as a drug delivery system for the molecule adenosine. Adenosine is an essential drug used for treating several health issues especially irregular heart rhythm. However, due to its extremely short half-life in vivo (510 s), the effective delivery of adenosine in clinical applications is a significant challenge. In this research, adenosine was encapsulated into NPs formed by ionic gelation of CS. The encapsulation efficiency and loading capacity of 20% and 3% were obtained, respectively, by forming a complex between CS NPs and adenosine. The obtained CS NPs had a spherical shape in the size range of 260.6 ± 20.1 nm. Spectrophotometry analysis of the adenosine released in vitro showed an initial burst release phase, a plateau phase, followed by a steady release over a week.

Adenosine, chitosan, drug delivery systems, nanoparticles

Introduction As a wider variety of molecules are being investigated for their therapeutic benefit, drug delivery systems (DDS) are becoming increasingly important. DDS offer numerous advantages compared to conventional methods, including improved efficacy by maintaining a steady drug release in a therapeutic range, reduced toxic side effects, decreased drug dosages and frequency of administration and increased effectiveness of pharmaceuticals with short in vivo half-lives (Uhrich et al., 1999; Panyam and Labhasetwar, 2003; Goldberg et al., 2007; Kazemzadeh-Narbat et al., 2010, 2012, 2014; Kazemzadeh-Narbat et al., 2013; Gao et al., 2011; Ma et al., 2012). Nanoparticulate DDS offer advantages such as improved stability of the drug, and a higher dissolution rate because of their greater surface area-to-volume ratios. Moreover, nanoparticle (NP) DDS are able to cross cell membranes, enter the fenestration present in the epithelial lining and penetrate deep into tissues through fine capillaries. This capability allows improved delivery of therapeutics in the body. In addition, the small size of the particles regulates bio-distribution of drug and minimises the uptake by the reticuloendothelial system, making them less likely to be cleared through the liver or spleen (Ishida et al., 1999; Rabinow, 2004; Qiu and Bae, 2006). Over the past few decades, biodegradable polymeric NPs have attracted significant attention as potential DDS. In these systems, the drug is usually dissolved, entrapped, encapsulated or attached to a NP matrix with a general size varying from 10 to 1000 nm (Soppimath et al., 2001). Chitosan (CS) is a natural polymer with certain properties that make it suitable for developing NPs for drug delivery applications. Such examples are CS-based transdermal DDS, CS tablets and microcapsules/microspheres of

Address for correspondence: Mehdi Kazemzadeh-Narbat, 65 Landsdowne Street, Rm. 265, Cambridge, MA 02139, USA. Tel: +1(857)2221125. E-mail: [email protected]

History Received 8 November 2014 Revised 24 March 2015 Accepted 02 April 2015 Published online 8 June 2015

CS for controlled drug release (Kumar, 2000). Some characteristics of CS such as its cationic nature, biodegradability, very low toxicity (LD50 of CS in laboratory mice is 16 g/kg body weight) and biocompatibility make it a promising candidate for biomedical and pharmaceutical formulations (Agnihotri et al., 2004; Kean and Thanou, 2010). CS is a weak base that can be diluted in aqueous acidic solution (pH 56.5), converting the glucosamine units into a soluble form of R–NH3+, allow ionic cross-linking with multivalent anions such as phosphates. CS NPs are formed by ionotropic gelation upon mixing with sodium tripolyphosphate (TPP) at appropriate ratios. This method is conducted under mild conditions, low temperature without organic solvents or toxic reagents used in chemical cross-linking (e.g. glutaraldehyde) that allows the encapsulation of fragile molecules, such as proteins (Rudzinski and Aminabhavi, 2010; Grenha, 2012; Rampino et al., 2013; Ganguly et al., 2014). Adenosine (C10H13N5O4) is an endogenous purine nucleoside that regulates many physiological functions particularly in the brain and heart (Sawynok and Liu, 2003; Hasko and Cronstein, 2004). The release of adenosine increases blood flow, respiration and reduction in cellular work particularly under conditions of energy deficiency (Drury and Szent-Gyo¨rgyi, 1929; Berne, 1980). The FDA has approved therapeutic use of adenosine under two formulations (AdenocardÕ and AdenoscanÕ ) (Paidas et al., 1989; U.S. Food and Drug Administration) for treating supraventricular tachycardia, and during cardiac stress tests in patients who cannot exercise adequately. Adenosine is injected intravenously for treating pain, controlling pulmonary hypertension, certain types of irregular heartbeat and controlling blood pressure during anaesthesia and surgery (Sawynok and Liu, 2003). Although the therapeutic impacts of adenosine are well recognised, systemic administration of adenosine may cause side effects such as suppression of cardiac function, decreased blood pressure and body temperature, hypotension and sedative side effects (Dunwiddie, 1999; Takahama et al., 2009). The main issue

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concerning administration of adenosine is however its extremely short half-life (less than 10 s) resulting in rapid clearance from the circulation via cellular uptake primarily by erythrocytes and vascular endothelial cells (Forman et al., 2006; Pagonopoulou et al., 2006). Because of such a poor stability, adenosine injection is given as a rapid intravenous bolus by placing the line as proximal as possible to the heart (e.g. at cubital fossa). Therefore, to enhance efficacy and to reduce side effects of adenosine in in vivo, a sustained delivery system for adenosine needs to be developed. This research describes the development of CS-based NP DDS for adenosine IV delivery. The characterisation of NPs was performed by monitoring particle shape and morphology, size distribution, surface charge and drug-loading capacity (LC). The release profile and stability of adenosine were also investigated.

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Materials and methods

%LC ¼

Preparation of blank and adenosine-loaded CS NPs Low molecular weight CS derived from crab shell with degree of deacetylation 90% was purchased from CarboMer Inc. CS NPs were prepared using the ionotropic gelation technique. Briefly, CS solution (1 mg/mL) was prepared by dissolving CS powder in 0.1 M acetic acid. The pH of solution (3.5) was adjusted to 5 using 20 wt% NaOH solution and the solution was allowed to stir for 2 h at 600 rpm at room temperature. Blank NPs were obtained upon the dropwise addition of a sodium TPP aqueous solution (2 mg/mL in distilled water) to the CS solution in a 1:5 volume ratio. The final solution was stirred at 600 rpm at room temperature overnight. Adenosine-loaded CS NPs were prepared in the same manner as blank NPs by adding the adenosine (1 mg/mL) to the CS solution after pH adjustment. NPs were collected by centrifugation (Thermo Scientific Sorvall WX Ultra, Asheville, NC) at 20 000 rpm for a period of 30 min. The amount of adenosine present in the supernatant was determined, and used to determine entrapment efficiency (EE). The NP pellets were used for characterisation, loading efficiency, swelling, release, sizing and surface charge studies. NP characterisation The size of NPs, the size distribution (polydispersity index, PDI) and the zeta potential of particles were measured using Zetasizer (Malvern Instruments, Malvern, UK) based on the dynamic light scattering method. Briefly, the NPs pellets recovered from centrifugation were sonicated in 10 mL of deionised water for 10 min to break up the particle aggregation and were stirred (300 rpm) at room temperature overnight. Subsequently, 0.5 mL aliquot was diluted and re-stirred for 3 h in 9.5 mL of deionised water for size determination in triplicate. The morphology of NPs was examined using field emission scanning electron microscope (FE-SEM, Hitachi 4700, Tokyo, Japan). To prepare the samples, a drop of solution containing NPs in water was mounted on a brass stub and left to air-dry. The NPs were made conductive using a very thin layer of gold–palladium for 30 s, and the images were captured at the voltage 3 kV. The visualisation of loaded CS NPs size and morphology was also evaluated in a dried state by transmission electron microscopy (FEI Tecnai TEM). Entrapment efficiency and loading capacity The quantity of adenosine entrapped within CS NPs compared with the initial adenosine loading was determined as the EE and calculated according to Equation (1). %EE ¼

mass of adenosine entrapped in NPs  100 mass of initial adenosine

The mass of adenosine entrapped in NPs was measured in two ways. Adenosine concentration in the supernatant was determined based on the absorbance at 280 nm using UV–vis spectrophotometer (UV-1700 SHIMADZU, Kyoto, Japan), and compared to a standard curve of adenosine in supernatant, that was conducted in triplicate. The mass of entrapped adenosine was calculated by subtracting the amount of free adenosine in supernatant from the initial amount of adenosine loaded. In the direct method, the freeze-dried NPs were weighed (20 mg), and then dissolved in 5 mL aqueous hydrochloric acid (2 M), sonicated for 30 min and stirred for 3 h. The solution was then centrifuged at 20 000 rpm for 30 min and supernatant was collected and the concentration of adenosine was measured at 280 nm using UV–vis. The LC was calculated according to Equation (2).

ð1Þ

mass of adenosine entrapped in NPs  100 mass of nanoparticles

ð2Þ

Swelling behaviour The freeze-dried NPs were initially weighed (100 mg), and were rehydrated in PBS (pH 7.4) at ambient temperature for a period of 6 h. The swollen NPs were obtained by centrifugation at 10 000 rpm, and the excess liquid was removed by blotting with filter paper. The weight of swollen NPs was measured at time period 1, 2, 4 and 6 h. The swelling index was calculated at each time point by using Equation (3). SI ¼

WS  WD  100 WD

ð3Þ

where SI is the swelling index, WS is the weight of the NPs at time t and WD is the initial weight of dried NPs. Isoelectric point determination To understand the interactions between adenosine, CS and TPP in suspension, the effect of pH on particle surface charge of components was investigated using multi-purpose auto-titrator (MPT-2, Malvern Instruments, Westborough, MA). The solution pH in which the particle zeta potential was over 25 mV was considered as electrostatically stabilised. In this study, 0.25 M hydrochloric acid and 1 M sodium hydroxide were used as acid and base titrants, and the samples were stirred during the experiment. The isoelectric point values of adenosine in water (1 mg/mL), TPP in water (2 mg/mL), and CS in 0.1 M acetic acid (1 mg/mL) and CS NPs solution were measured separately, and the pH at which the zeta potential value crossed zero identified as IEP or point of zero charge. In vitro adenosine release studies The release of adenosine from CS NPs into 1 PBS (pH 7.4) at 37  C was measured according to the following procedure. Equal amounts of adenosine-loaded CS NPs solution (20 mL) were distributed into tubes and then centrifuged at 20 000 rpm for 30 min at room temperature. The pellets were re-suspended in 5 mL PBS and incubated separately on a magnetic stirrer with a stirring speed of 100 rpm at 37  C. The release of adenosine from the NPs into solution was monitored up to 7 days at predetermined time intervals (0, 10, 20, 30, 45, 60, 120, 180, 240, 360 min, and 1, 2, 3, 4, 5, 6, 7 days). At each time interval, one tube was removed and centrifuged at 20 000 rpm for 15 min at room temperature. The adenosine concentration in the release solution was analysed using UV–vis at 280 nm.

Chitosan nanoparticles as adenosine carriers

DOI: 10.3109/02652048.2015.1046517

Stability of CS NPs The stability of CS NPs was determined by measuring the particle size, particle size distribution (PDI) and surface charge at predetermined storage time durations (0, 1, 2, 3, 4, 5, 6, 8, 10, 12 and 14 days), at either ambient temperature or 4  C. Briefly, freshly prepared CS NPs pellets recovered from centrifugation were sonicated in 10 mL of deionised water for 10 min to break up the particle aggregation and were stirred (300 rpm) at room temperature overnight. Subsequently, 0.5 mL aliquot was diluted and re-stirred (3 h) in 9.5 mL of deionised water for the analysis in triplicate using Zetasizer (Malvern Instruments, Malvern, UK).

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Results and discussion The objective of this research was to develop a CS NP delivery system as a carrier for adenosine. In this study, the ionic gelation method was chosen to prepare CS–adenosine NPs. According to the ionic gelation process, CS NPs were prepared by the ionic interaction between a positively charged amino group of CS and a negatively charged counterion of TPP (P3 O5 10 anions). The greatest challenge in this work was to encapsulate acceptable quantities of adenosine despite the weak interaction due to charge repulsion between the cationic CS (pI  6.2–7) and positively charged adenosine at working pH. According to Calvo et al. (1997) to avoid the formation of any micro-particles of CS NPs specific concentrations of CS and TPP should be used. Therefore, a number of experiments were

Table 1. Increasing the rate of TPP improved the EE but caused a drastic increase in the size of NPs. CS:TPP

EE%

Size range (nm)

10:4 10:3 10:2

25–30 20–25 15–20

2208–6223 672–1250 147–373

Figure 1. Change of zeta potential with pH for the adenosine, CS, TPP, CS NPs loaded with adenosine using auto-titration. In addition to weak surface charge for adenosine, both adenosine and CS have very close isoelectric point.

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performed in this research in order to determine the appropriate conditions for the incorporation of the adenosine into the CS NPs. The interaction of adenosine with different CS-TPP formulation was investigated spectrophotometrically based on encapsulation efficiencies. A successful adenosine entrapment into NPs below the average size of 300 nm was achieved between 15% and 20% by dissolving the adenosine in a CS (1:1) after pH adjustment at 5, followed by the addition of the TPP (2 mg/mL) to the CS solution in a 1:5 weight ratio (Table 1). This optimum TPP:CS ratio might be related to the poly-functional cross-linking property of TPP that can create five ionic cross-linking points with amino groups of CS. It is believed that the TPP:CS 1:5 results in the most compact particle structure due to the most efficient cross-linking of amino groups (Zhang et al., 2004). Also, it has been previously reported that CS NPs formed at solution pH 5 have a smaller size and a higher particle zeta potential because NH2-groups of the CS are mostly protonated and are better accessible to interact at this pH (Gan et al., 2005). The appearance of the solution changed from a clear to opalescent solution when TPP was added to the CS solution, indicating a change of the physical states of the CS to form NPs. It was also observed that increasing the concentration/ rate of TPP would result in a more turbid NP suspension, which improves the EE at the expense of increasing the nanometer size range of NPs (Table 1). Also, when the initial CS concentration was increased above a critical value more viscous agglomerates formed instantaneously causing sedimentation tendency of the suspension. Mean encapsulation efficiencies decreased with increases in adenosine initial loading. Also real adenosine loading was calculated to be 3 ± 0.4% with respect to the CS NPs. Limited EE and LC of adenosine loaded CS NPs may be attributed to the weak positively charged adenosine molecules (nearly neutral, isoelectric pH 7), therefore, its electrostatic interaction with CS cations was minimised (Figure 1). In addition, the isoelectric point of adenosine was determined very close to that of CS, which can further limit the ionic interaction between two molecules (Figure 1).

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Figure 2. (a) The SEM micrograph of CS NPs incorporated adenosine prepared according to the ionotropic gelation technique. The volume ratio of TPP solution to the CS solution was adjusted to 1:5, (b) by increasing the volume ratio of TPP, the size of NPs increased significantly and (c) TEM image of an air-dried single spherical adenosineloaded CS NP at 150 000 magnification.

Figure 3. Malvern size distribution diagram of NPs obtained with CS/TPP by ionotropic gelation technique (mean size: 260.6 ± 20.1 nm). The adenosine-loaded NPs exhibited a heterogeneous dispersion with relatively wide particle size distribution.

Electron microscopy images of CS-TPP NPs incorporating adenosine are shown in Figure 2. NPs were inclined to agglomerate with each other, this phenomenon happened because it reduced the surface area, and free surface energy. The adenosine-loaded NPs had a uniform relatively smooth surface with non-porous spherical structure. Mean particle size, PDI and zeta potential values of 260.6 ± 20.1 nm, 0.53 ± 0.1 and +29.2 ± 0.5 mV were obtained, respectively. The adenosine-loaded NPs exhibited a heterogeneous dispersion with relatively wide particle size distribution (Figure 3), as indicated by PDI values slightly above 0.5. By passing the CS NPs through a syringe filter with specific pore size the homogeneity dispersion can be improved, which was not applied in this research as the particles were mostly in the proper size range (markedly below 500 nm). Figure 2(b) shows the effect of the addition of TPP concentration/rate on particle size increase. Comparing these values to the unloaded NPs showed that the adenosine loading did not significantly alter the values. Figure 4 shows the swelling rate over time of adenosine-loaded CS NPs, which is linear versus time.

The in vitro release profile of CS–TPP NPs in PBS (pH 7.4) is shown in Figure 5. The release profile suggests two different mechanisms, that is, diffusion of adenosine molecules and degradation of polymer matrix. The particles incorporating adenosine showed a burst release of about 42% during the first hour, followed by a very slow release of 5% (almost a plateau) over the next 3 days, and 37% release over the following 4 days. The first stage of release profile can be associated with the adsorbed adenosine dispersing close to the CS NP surface, which easily diffuse out in the initial incubation time following first-order elimination kinetics. The CS NPs have a large specific surface area that can adsorb adenosine, and desorb during this the initial release period. The second sustained slow release might be due to swelling of the compact structure of CS NPs and release of adenosine by diffusion through swelled pores. The third stage of release may be related to the release of encapsulated adenosine in sub-surface layer of CS nano-spheres under hydrolytic degradation. The best model describing the release at this stage fits the zero order (y ¼ 0.006x + 19.287).

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DOI: 10.3109/02652048.2015.1046517

Figure 4. The swelling kinetics over time of adenosine-loaded CS NPs at room temperature.

Chitosan nanoparticles as adenosine carriers

This complies with the consensus understanding of protein release from CS particulate systems includes three mechanisms: (a) protein desorption from the surface of particles, (b) protein diffusion through the swollen polysaccharide matrix and (c) protein release because of polymer erosion (Zhou et al., 2001). It should be noted, however, that CS is expected to degrade faster in vivo due to the presence of enzymes such as a-amylase or lysozyme (Lopez-Leon et al., 2005). For pharmaceutical applications, the storage stability is a great concern. Because of high surface energy, CS NPs colloidal solution is thermodynamically unstable (Gan et al., 2005). Therefore, it is important to know the stability behaviour of CS NPs suspension over time. The stability test performed on adenosine incorporated CS NPs showed no significant increase in particle size (ranging 240–450 nm) during 14 days of storage at room temperature and at 4 C (Figure 6). However, a slight increase (not significant) was measured for samples kept at room temperature. Likewise, the surface charge of both groups remained unchanged (ranging 27–35 mV) over 14 days (Figure 7). The positive zeta potential values of CS NPs

Figure 5. Adenosine release profile in PBS (pH 7.4), (a) short term and (b) long term.

Figure 6. Particle size and PDI of adenosineloaded CS NPs suspended in PBS and stored at room temperature (RT) and 4  C for two weeks (n ¼ 3). No significant difference was observed in particle size and PDI for a period of 14 days.

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Conclusion

Figure 7. The surface charge of CS NP stored at room temperature and 4  C remained nearly unchanged (ranging 25–37 mV) over 14 days.

This research demonstrates that non-toxic biodegradable CS NPs are promising carriers for weak cationic adenosine drug with an extremely short half-life in vivo. The EE and size of adenosine in ionically cross-linked CS /TPP NPs were significantly affected by the mass ratio of CS to the TPP agent. For the sake of adenosine IV delivery, this work has focused on NPs with a size 300 nm at 5:1 CH:TPP mass ratio. The obtained NPs had spherical shape with an average particle size of 260.6 ± 20.1 nm, and zeta potential value of +29.2 ± 0.5 mV. The release mechanism showed an average burst release (42% within 1 h) that can be attributed to the sudden release of drug from the matrix surface with a slow prolonged release within a week, driven by initial adsorption, swelling (almost 350% in 6 h) and degradation of the CS matrix. An important observation was that later phase CS NPs degradation caused a second wave of significant release, indicating the presence of remaining adenosine molecules entrapped inside the NP structure. The NPs showed an excellent physical stability both at room temperature and at 4  C, with no apparent agglomeration and severe size and surface charge increase over a period of two weeks probably due to strong repulsive forces between high surface potential of the particles. Further experiments are suggested to optimise the formulations, and biocompatibility of CS NPs.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

References

Figure 8. Colloidal dispersion of CS NPs after 30 days incubation at room temperature (RT) and at 4  C. CS NPs could precipitate after being stored undisturbed for a few days, but they were simply re-dispersed by gentle shaking.

indicate the presence of amino groups of CS on the surface. Such a high and positive zeta potential provide suitable electrostatic stabilisation created by repulsive forces between NPs during prolonged circulation time. A stable positivity of the NPs is critical for their interaction with the negatively charged cellular membrane components and the triggering the paracellular permeation of the adenosine (Sadeghi et al., 2008). Adhesion of NPs to one another in a colloidal dispersion may form aggregates with larger size, which may settle out under the influence of gravity. Both suspensions showed a similar colloidal stability after storage for two weeks. It was observed that the CS NPs could spontaneously precipitate after being stored undisturbed for a few days, however, they can be simply re-dispersed by gentle shaking. Adenosine-loaded CS NPs can be simply freeze-dried in order to improve the storage stability. The CS NPs dispersion remained colloidally identical after two weeks, indicating that the particles have repulsive forces strong enough to resist further aggregation (Figure 8).

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