Synthesis, structural characterization, cytotoxicity and encapsulation studies of N,N′-(1, 2-dicyano-1,2-vinylene)-bis(4-hydroxysalicylideneaminato) di(p-chlorobenzyl)tin as potential anticancer drug

Article abstract of DOI:10.1515/mgmc-2019-0010

Two new diorganotin(IV) complexes with the general formula (RC₇H₆)₂Sn(L) (where RC₇H₆ = p-ClBn, C1; and p-FBn, C2) were prepared based on the reaction of 2,3-bis(4-hydroxysalicylidene-amino)-maleic ni

Full text of DOI:10.1515/mgmc-2019-0010

Main Group Met. Chem. 2019; 42: 94–101
Research Article
Open Access
Nur Adibah Mohd Amin1, Rusnah Syahila Duali Hussen1,*, See Mun Lee2,*, Kae Shin Sim3 and
3
SSuyernialtohaseansNiasva,nesstanructural characterization, cytotoxicity
and encapsulation studies of N,Nʹ-(1, 2-dicyano-1,2-
vinylene)-bis(4-hydroxysalicylideneaminato)
di(p-chlorobenzyl)tin as potential anticancer drug
Keywords: organotin; antitumor; encapsulation; drug
formulation
https://doi.org/10.1515/mgmc-2019-0010
Received August 17, 2018; accepted March 14, 2019.
Abstract: Two new diorganotin(IV) complexes with the
general formula (RC7H6)2Sn(L) (where RC7H6 = p-ClBn,
C1; and p-FBn, C2) were prepared based on the reaction 1 Introduction
of 2,3-bis(4-hydroxysalicylidene-amino)-maleic nitrile (L)
with substituted dibenzyltin(IV) dichloride. The structu- Organotin(IV) complexes have captured the attention
res were confirmed by elemental analysis, Fourier trans- of many scientists in the past decade as potential
form infrared (FT-IR), proton and carbon nuclear magne- chemotherapeutic agents (Wang et al., 2014; Yao et al.,
13
tic resonance (1H and C NMR). They were tested against 2017). Studies have indicated milder toxicity behaviour
several cancer cell lines by using the MTT (3-(4,5-dimethyl- compared to cis-platin (Alama et al., 2009). The
thiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. C1, chemotherapeutic potential of organotin(IV) complexes
which was most effective against MCF-7 breast cancer cell is due to their apoptosis inducing behaviour and strong
line, was further investigated in formulation and encap- interaction with deoxyribonucleic acid (DNA) (Pellerito
sulation studies, including drug encapsulation efficiency, et al., 2005).
particle size, morphology and in vitro drug release. An
Recently, many researchers and chemists have great
encapsulation of about 90% was achieved with particles interest in structuring organometallic complexes with
of 128 nm average diameter. Field emission scanning elec- multidentate ligands (Burt et al., 2014; Yin et al., 2012). The
tron microscopy (FESEM) confirmed a spherical shape for synthesis of such ligands typically binds to the metal ion
the encapsulated C1. The cumulative drug release over a through phenolic oxygen, imine nitrogen, oxime oxygen or
period of 60 days in phosphate buffered saline (PBS) at pH oxime nitrogen. The chelate effect of multidentate ligands
7.4 was 75%. Based on these results, the formulated drug with metals makes the compounds more versatile with a
has the potential of a slow release drug for cancer chemo- wide range of application. The choice of the coordinated
therapy.
ligand is crucial for the biological effects of organotin(IV)
complexes in terms of solubility and bioavailability (Fani
et al., 2015). The coordinated ligands at the tin atom not
only can diminish drawbacks, but also embellish the
biochemical activity of organotin(IV) complexes (Kumar
et al., 2009). Azomethines on organotin(IV) compounds are
considered as privileged ligands due to their remarkable
biological properties (Pellerito, 2002) This may be due to
the fact that the C=N bond is capable to obstruct enzyme
activities(Sirajuddinetal., 2012). Moreover, theazomethine
can enhance the antibacterial activity by the influence of
structural factors, such as solubility, dipole moment and
cell permeability (Li and Shen, 2000). From literature
* Corresponding authors: Rusnah Syahila Duali Hussen,
Department of Chemistry, Faculty of Science, University of Malaya,
50603 Kuala Lumpur, Malaysia, e-mail: r_syahila@um.edu.my;
See Mun Lee, Research Centre for Crystalline Materials, School of
Science and Technology, Sunway University, 47500 Bandar Sunway,
Selangor Darul Ehsan, Malaysia, e-mail: annielee@sunway.edu.my
Nur Adibah Mohd Amin, Department of Chemistry, Faculty of
Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
Kae Shin Sim and Suerialoasan Navanesan, Institute of Biological
Sciences, Faculty of Science, University of Malaya, 50603 Kuala
Lumpur, Malaysia
Open Access. © 2019 Amin et al., published by De Gruyter.
Attribution alone 4.0 License.
This work is licensed under the Creative Commons
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N.A.M. Amin et al.: Synthesis, structural characterization, cytotoxicity and encapsulation studies
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review, a study on the synthesis and characterization of a Meng et al., 2013; Tehfe et al., 2013), aluminium (Hao
new series of diorganotin(IV) dichloride with Schiff based et al., 2016) and copper(II) complexes (Hao et al., 2015),
ligand derived from tris(hydroxymethyl)aminomethane were confirmed with elemental analysis, IR and NMR
has been reported (Lee et al., 2015). All the mixed-ligand spectroscopy.
complexes have been evaluated with three types of
cancer lines, namely HT29 (human colon carcinoma cell
line), SKOV-3 (human ovarian cancer cell line) and MCF-7 2.2 Spectroscopic analysis
(hormone-dependent breast carcinoma cell line). Lee and
herco-workershaveconcludedthatmostofdiorganotin(IV) The strong C=N absorption of the ligand at 1626 cm-1
complex were found to have promising anticancer activity. was shifted to lower energy in the complexes, indicating
Even though organotin(IV) complexes have the coordination of azomethine nitrogen to the tin metal. The
potential to be a chemotherapeutic drug, they might characteristic absorption of the O-H bond in the complexes
be non-selective towards the targeted site, leading to showed that not all phenolic hydroxyl groups participated
severe side effects similar to most cytotoxic anticancer in the coordination to the tin metal. Two new bands, at
drug. A widespread strategy to reduce these unwanted 479-496 cm-1 and 536-543 cm-1, were assigned to the Sn-N
side effects is the encapsulation of the drug in carriers and Sn-C stretching vibration, supporting the bonding of
(Arias, 2008; Hamelers and de Kroon, 2007). Herein, we nitrogen and carbon to the tin atom. These findings are in
report the synthesis of diorganotin(IV) complexes with line with literature reports, which stated Sn-N and Sn-C
tetradentate ligands containing azomethine linkages vibrations in the region 475-495 cm-1 and 540-575 cm-1,
and investigations of their potential as anticancer drugs, respectively (Amini et al., 2016; Rehman et al., 2008).
including a formulation study on vesicular drug delivery.
The 1H NMR spectrum of complexes showed a new singlet
13
peak at 1.10 and 1.18 ppm, indicative of Sn-CH2. The C
NMR signals for the azomethine carbon in the complexes
were shifted significantly upfield with respect to the free
ligand to appear at 154.1 ppm. In addition, an upfield shift
was observed for the carbon carrying the oxygen at the
ortho-position, reflecting the tin-binding. A new peak at
around 9.0 ppm was attributed to the carbon of Sn-CH2,
2 Results and discussion
2.1 Synthesis
Two new complexes named as N,Nʹ-(1,2-dicyano-1,2- which suggested a bonding interaction between the
vinylene)-bis(4-hydroxysalicylideneaminato)di(p- organotin compounds and the ligand. The obtained data
chlorobenzyl)tin (C1) and N,Nʹ-(1,2-dicyano-1,2-vinylene)- were in good agreement with previously reported values
bis(4-hydroxysalicylideneaminato)di(p-
fluorobenzyl) (Lee et al., 2015).
tin (C2) were prepared by reaction of 2,3-bis(4-
hydroxysalicylidene-amino)-maleic nitrile (L) (Dumur
et al., 2014; Tehfe et al., 2013) with substituted dibenzyl 2.3 In vitro cytotoxic
tin(IV) dichloride and triethylamine in a molar ratio 1:1:2
in ethanol, as summarized in Scheme 1. The structure and The results for the in vitro cytotoxic are presented in
purity of C1 and C2 complexes, reflecting corresponding Table 1. Ligands and complexes were screened against
structures to previously reported zinc (Dumur et al., 2014; breast (MCF-7), lung (A549) and prostate (PC-3) cancer
R= p-ClBn (C1) and p-FBn (C2)
Scheme 1:ꢀThe general scheme for the preparation of the complexes C1 and C2.
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N.A.M. Amin et al.: Synthesis, structural characterization, cytotoxicity and encapsulation studies
Table 1:ꢀAnticancer screening result of the ligand and its complexes process of the bilayer (Kulkarni et al., 1995). As reported
in comparison with known drugs.
in the literature, the highest %EE can be attained when
a large surface area of thin film was produced (Amselem
Compound
Cytotoxicity (IC50 in µg/mL)
et al., 1990). High %EE can also be contributed by the
concentration of drug used. Previous studies have
demonstrated that %EE of drug was found to increase
from 80% up to 96% with increasing concentration
of docetaxel (Hammadi et al., 2017). Liu et al. have
found that formulation of paclitaxel with different
concentration of 1,2-dilauroylphosphatidylocholine
(DLPC) used in the nano-emulsification process has
affect %EE from 15% (0.01% w/v) up to 56% (0.04% w/v)
(Liu et al., 2010). The microencapsulation vesicle method
was used to encapsulate 5-fluorouracil, ibuprofen and
flurbiprofen. Results show that %EE of non-polar drugs
A549
PC-3
MCF-7
L
28.1 0.4
11.1 0.7
23.2 1.1
2.6 0.1
3.9
5.4 0.1
18.9 0.9
2.5 0.1
16.9 0.3
18.3
6.1 0.2
1.7 0.1
18.7 0.1
9.5 0.3
8.4
C1
C2
Cis-platin
Cis-platina
PTXb
5.3
3.4
5.1
a adapted from (Gumulec et al., 2014; Ma et al., 2016; Mroueh et al.,
2015)
b adapted from (Fang et al., 2011)
cell lines and compared with cis-platin as positive have high compared to polar drugs, the % EE of water-
control. The experimental IC50 for cis-platin was in soluble 5-fluorouracil showed 12-15% while lipophilic
reasonable agreement with the previously published ibuprofen and flurbiprofen was around 90% (Nii and
value (Gumulec et al., 2014; Mo et al., 2016; Mroueh Ishii, 2005). Therefore, the thin film hydration method,
et al., 2015). The data indicated C1 as an effective drug using high concentration of C1 in the formulation and C1
against breast cancer cells, while C2 was most effective as non-polar drug are all the factors contributed to the
against the prostate cancer cell line. Where, both tin high %EE of C1.
complexes were more effective than cis-platin at their
most responsive target cells. Interestingly, the reverse
application proofed unfavourable, in these cases the 2.5 Particles size distribution
sole ligand was more active than the tin complex.
Neither C1 nor C2 exhibited promising activity against The particle size distribution of the encapsulated C1
lung cancer. In fact, besides the indicated application indicated a size of 130 20 nm with 100% intensity. Based
fields above, both complexes only demonstrated about on the reviewed literature, the typical particle size for
ten times lower activities compared to cis-platin in lung formulations of hydrophobic anticancer drugs, such as
cancer cell line, thereby indicating the biological activity paclitaxel (PTX) loaded drug carriers, is below 150 nm
as highly cell-type specific. The IC50 obtained for C1 for (Mo et al., 2016). Previous findings have proved that drug
MCF-7 was three times lower than the reported activity of carriers, sized in the range of 100-200 nm, have a good
pacilitaxel (PTX), (Fang et al., 2011). It also exceeded the chance to be circulated in the organism for a longer time
activity of a previously reported monobenzyltin Schiff (Dhand et al., 2014).
base complex (2.5 0.5 µg/mL) (Fani et al., 2015). These
data demonstrate the potential of C1 for breast cancer
therapy. Therefore, C1 was further investigated for drug 2.6 Morphology analysis
formulation and release studies.
The morphology of formulated drug was examined by field
emission scanning electron microscopy (FESEM). The
2.4 Percentage encapsulation efficiency
FESEM image in Figure 1 indicated a spherical shape for
the formulated drug of C1. In commercial nanoparticles,
The encapsulation efficiency (%EE) of C1 based on shape and surface are the two important elements for
mixed vesicle (cationic-nonionic surfactant system) and efficient drug delivery. From the reported literature, most
prepared by thin film hydration method was found to be of the nanoparticles of anticancer drug revealed a fine
about 90%. This value is relatively high. High %EE can spherical shape and various degrees of smooth surface
be due to the method of preparation, concentration of (Bandi et al., 2017). Spherical nanoparticles are more
the drug in the formulation and the polarity of the drugs. favourable because of several factors, which includes the
In thin film hydration method, larger surface areas of the ease of production and also controlling on bio circulation
film are convenient because they accelerate the hydration (Mitragotri, 2009).
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that paclitaxel incorporated in poly-L-co-D,L-lactic
acid (PLDLA) microspheres released 90% of the drug
for 30 days period. Thus, the data obtained denote that
PLDLA microspheres are promising carriers for paclitaxel
(Martins et al., 2014). To sum up, these findings agree with
those earlier published in the literature for mixed vesicles
which can control the release of drugs (Jiang et al., 2012).
3 Conclusion
Two new complexes have been synthesized by the
condensation reaction of 2,3-bis(4-hydroxysalicylidene-
amino)-maleic nitrile and substituted dibenzyl tin
(IV) dichloride in an appropriate molar ratio. The
in vitro cytotoxic assay revealed the potent effect
of C1 against MCF-7, justifying its selection for the
further formulation studies. The complex can be
encapsulated in high efficiency in nanosized carriers
of spherical shape. The determined cumulative drug
release of 75% within 60 days in PBS buffer at pH 7.4
is comparable with commercially known anticancer
drug paclitaxel. These results suggest that a vesicular
formulation of N,Nʹ-(1,2-dicyano-1,2-vinylene)-bis(4-
hydroxysalicylideneaminato) di(p-chlorobenzyl)tin has
potential for cancer chemotherapy.
Figure 1:ꢀThe FESEM image of the encapsulated C1.
100
90
80
70
60
75
50
39
40
30
20
10
0
0
10
20
30
40
50
60
70
Time, days
Figure 2:ꢀIn vitro release profile of encapsulated C1 in 60 days.
Experimental
2.7 In vitro drug release study
The infrared spectra of the compounds were recorded
using the ATR technique on a Perkin Elmer System
The in vitro released profile of encapsulated C1 is displayed 400 spectrophotometer from 4000 to 450 cm-1 at
in Figure 2. The release of C1 from the carriers displayed room temperature. The H and 13C NMR spectra were
1
a biphasic release pattern (Hasan et al., 2013). The initial recorded on a JEOL ECX 400MHz FT-NMR spectrometer
release was about 40% at the end of the 8th day. The early in DMSO-d6 and CDCl3. The data are provided on the δ
rapid release of hydrophobic drug might be related to scale relative to SiMe4. Elemental analyses were carried
adsorbed drug on the surface of the formulation, which out on a Thermofischer Scientific FlashSMART CHNS/O
is subject to the spontaneous diffusion in the dissolution analyzer.
medium. This process is termed as a burst effect (Allison,
2008). Among drug-based nanoparticles formulations,
burst release effect is typically common (Xin et al., Synthesis of ligand, L
2010). The previous literature also indicates that vesicles
formulations containing hydrophobic drugs exhibit Dieter et al. have described the preparation of L (Dieter
similar release patterns (Xu et al., 2007). For another et al., 1983). From the literature, a hot ethanolic solution
subsequent 50 days, the remaining complex which of 1 mmol of diaminomaleonitrile was added to 2 mmol of
was captured in the structure was further released in a 2,4-dihydroxybenzaldehyde. The mixture was refluxed
controlled manner. The amount of percentage cumulative for 2-3 h producing a reddish orange mixture at the end
drug release was found to be 75% for 60 days in PBS pH 7.4 of the reaction. The mixture was filtered and a reddish
as a medium. A recent studied by Martin et al., concluded orange precipitate was obtained upon cooling to room
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1
temperature. The solid product obtained was then C=N), 1196 (s, C-O). H NMR (DMSO-d6, ppm): 6.28-6.32
recrystallized from methanol.
(m, 4H, Aryl), 7.47-7.50 (m, 2H, Aryl), 7.73-7.75 (m, 2H, Aryl),
13
8.39 (s, 2H, CH=N), 9.85 (s, 2H, OH). C NMR (DMSO-d6,
ppm): 113.7 (C1, C1’), 165.6 (C2, C2’), 102.6 (C3, C3’), 163.0
(C4, C4’), 109.1 (C5, C5’), 133.3 (C6, C6’), 163.7 (C7, C7’), 124.7
(C8, C8’), 113.7 (C9, C9’).
Synthesis of organotin compounds
Preparation method is based on the literature without
modification(Sisidoetal.,1961):3to5dropsofwaterwere
added to 5 mmol of tin powder and kneaded together. N,Nʹ-(1,2-dicyano-1,2-vinylene)bis(4-hydroxy-
The tin powder was suspended in 50 mL of toluene under salicylideneaminato)di(p-chlorobenzyl)tin (C1)
efficient stirring and the mixture was heated to about
110°C. Then, 5 mmol of substituted benzyl chloride Dark brown solid, Yield: 0.26 g (37%), m.p: 210-212°C
was dissolved in toluene and added drop wise into (dec.). Anal. Calc. for C32H22Cl2N4O4Sn: C, 53.67; H, 3.10; N,
the suspension mixture for 3 min while refluxing 7.82. Found: C, 53.59; H, 3.39; N, 7.66%. IR (cm-1): 3306 (b,
was continued for an additional 3 h. After that, fine OH), 2239, 2213 (s, C≡N), 1603 (s, C=N), 1210 (s, C-O), 543
1
colourless crystals started to appear on the surface of (m, Sn-C), 479 (m, Sn-N). H NMR (DMSO-d6, ppm): 1.10
the solution. The mixture was filtered while it was hot. (s, 4H, Sn-CH2), 6.24-6.34 (m, 4H, Aryl), 7.38-7.90 (m, 10H,
The greyish residue which remained at the bottom of Aryl), 8.10 (s, 2H, CH=N), 9.87 (s, 2H, OH). 13C NMR (DMSO-
the flask was dissolved, extracted with acetone and d6, ppm): 9.0 (Sn-CH2), 113.7 (C1, C1’), 151.5 (C2, C2’), 102.9
filtered. The second filtrate and the solution were (C3, C3’), 160.8 (C4, C4’), 109.2 (C5, C5’), 124.8 (C6, C6’),
evaporated under diminished pressure producing a 154.1 (C7, C7’), 127.8 (C8, C8’), 114.2 (C9, C9’), 129.0, 129.3,
yellow solid.
131.0, 131.6, 136.6, 114.8 (R).
Synthesis of diorganotin complexes
N,Nʹ-(1, 2-cyano-1,2-vinylene)bis(4-hydroxy-
salicylideneaminato)di(p-fluorobenzyl)tin (C2)
1 mmol of L and 2 mmol of Et3N were dissolved in 20 mL
of hot ethanolic solution. The solution was refluxed for Reddish brown solid, Yield: 0.64 g (96%), m.p: >360°C
1 h 30 min until clear light brown solution was formed. (dec.). Anal. Calc. for C32H22F2N4O4Sn: C, 56.25; H, 3.25; N,
Then, 1 mmol of di(p-chlorobenzyl)tin dichloride and 8.20. Found: C, 56.17; H, 3.64; N, 8.38%. IR (cm-1): 3307 (b,
di(p-fluorobenzyl)tin dichloride to produce C1 and C2 OH), 2241, 2208 (s, C≡N), 1599 (s, C=N), 1210 (s, C-O), 536
1
respectively was dissolved in 20 mL of ethanol and added (m, Sn-C), 496 (m, Sn-N). H NMR (DMSO-d6, ppm): 1.18
in the solution. The mixture was filtered and the filtrate (s, 4H, Sn-CH2), 6.32-6.42 (m, 4H, Aryl), 7.09-7.96 (m, 10H,
was dried by rotary evaporator to get dark brown powder. Aryl), 8.27 (s, 2H, CH=N), 9.92 (s, 2H, OH). 13C NMR (DMSO-
The numbering scheme for the NMR assignment was d6, ppm): 9.0 (Sn-CH2), 115.6 (C1, C1’), 151.5 (C2, C2’), 102.7
shown in Figure 3.
(C3, C3’), 163.7 (C4, C4’), 109.2 (C5, C5’), 131.9 (C6, C6’), 154.1
(C7, C7’), 128.9 (C8, C8’), 114.1 (C9, C9’), 130.7, 130.8, 129.0,
129.6, 133.7, 115.4 (R).
2,3-bis(4-hydroxysalicylidene-amino)-maleic nitrile (L)
Reddish orange solid, Yield: 2.55 g (78%), m.p: 264°C Cytotoxicity screening
(dec.). IR (cm-1): 3306 (b, OH), 2239, 2212 (s, C≡N), 1626 (s,
Ligand, C1 and C2 complexes were screened against
several cancer cell lines, breast (MCF-7), lung (A549)
and prostate (PC-3) cancer cells. Cells were maintained
in basic culture medium, containing 10% FBS and 1%
penicillin/streptomycin and 0.5% amphotericin B, and
were cultured at 37°C under a humidified atmosphere
in a CO2 incubator. The cells were seeded in a 96-well
microtiter plate at a concentration of 7,000 cells
per well. After 24 h, the cells were treated with the
Figure 3:ꢀThe numbering scheme used for NMR assignment.
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samples and incubated for an additional 72 h. DMSO the amount of free drug in the supernatant (Olerile et al.,
was used to dilute the samples, with the final dilution 2017).
containing a maximum of 0.5% DMSO. At the end of
the incubation period, 20 µL of MTT working solution
(5 mg/mL) was added into each well and the 96-well Drug release studies
microtiter plate was incubated for another 3 h. After
the incubation period is over, the medium was removed The release of C1 was measured by applying dialysis
completely and replaced with 200 µl DMSO. The plate tubing method. 5 mL of encapsulated C1 was sealed in
was stirred using a shaker for 15 min to dissolve any a dialysis bag and suspended in 50 mL of PBS (pH 7.4).
precipitants. The absorbance values were measured The container that contained the dialysis bag was
at 570 nm, with a reference wavelength of 650 nm on placed in water bath at 37°C. At predetermined time
a Multiskan GO UV/Vis microplate spectrophotometer intervals (0 h up to 60 days), 1 mL of the medium was
from Thermo Scientific (Waltham, MA, USA) withdrawn and replaced with an equal volume of fresh
(Mosmann, 1983).
PBS. The absorbance of C1 was obtained from UV-Vis
spectrophotometer at 327 nm and concentration is
calculated based on the calibration curve. The result
is displayed in cumulative % drug release vs. time.
Encapsulation of C1
The vesicles were prepared by thin film hydration
methods. The surfactant was prepared by mixing dodecyl
trimethylammonium bromide and 2-hexyl-decyl lactoside
in ratio 30:70 respectively. Then, C1 was added to the
mixed surfactant with concentration is fixed at 5 mM
and the total concentration of the mixed surfactants are
1 mM; the details of the glycolipid surfactant can be found
in the literature (Hussen, 2012; Mak et al., 2015). C1 and
the mixed surfactants were dissolved in ethanol and the
solvent was subsequently removed on a rotary evaporator,
yielding a thin lipid film on the wall of a round bottom
flask. The thin film was thoroughly dried to remove any
Visualization of the particle loaded C1
The prepared encapsulated C1 was centrifuged to separate
the non-encapsulated C1. Then, the pellet was collected,
dried on a membrane and then coated with platinum.
Then the sample was loaded into the FESEM chamber and
it was subsequently viewed under FESEM. The surface
was scanned and photomicrographs were taken at an
accelerating voltage of 30 kV.
traces of ethanol. Then, the thin film was hydrated in 5 mL Acknowledgment: The authors are thankful to the
of phosphate buffer saline pH 7.4. The hydrated film was University of Malaya for financial support of this
further used to investigate related characterization on the research under grants PG239- 2016A and RP17A-14AFR.
formulated drugs.
Special thanks to Prof. Dr. Lo Kong Mun from Research
Centre for Crystalline Materials, School of Science and
Technology, Sunway University, 47500 Bandar Sunway,
Selangor Darul Ehsan, Malaysia for his keen interest,
continuous support and his kind help in providing
Percentage encapsulation efficiency (%EE)
The percentage of encapsulation efficiency (%EE) of facility.
vesicles was determined by ultracentrifugation. The
resulting dispersion was separated by centrifugation at
15000 rpm for 30 min. The absorbance of the supernatant
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