Chapter 8. Hydrophobic Effect on the Structural Evolution of
8.8 Self-Assembly Map
On this basis, an interesting finding can be drawn from Figure 8-5, showing the plot of CAC and Wnf, max of ACC with different values of (XDH × XCn), where an intercept at product of (XDH × XCn) = 1.5 was observed. Below 1.5, assigned as Zone I, the values of CAC decreased readily with increasing (XDH
× XCn) up to 1.5 and reached a minimum value. The content of bound water, Wnf, max, in the ACC was increased only slightly in region of Zone 1. However, when the value of (XDH × XCn) exceeded 1.5 (i.e., Zone II), Wnf, max increases considerably to a level as high as 64% with increase of (XDH × XCn), whilst the CAC kept relatively constant. These findings strongly indicate that the hydrophobic effect was dominated by an interaction of both DH and Cn, rather than individual component alone. Further, the hydrophobicity associated with DH and Cn strongly affected the self-aggregation ability and the hydrophobizing water capacity of the ACC nano-aggregates. It is clearly demonstrated that a critical level of hydrophobicity that can effectively generate conspicuous changes in both CAC and Wnf, max is evidenced in the self-assembly map constructed in Fig. 8-5, when the composite effect of the degree of acyl substitution and acyl chain length, i.e., the product of (XDH × XCn), is closed to 1.5.
0 1 2 3 4 5 6
Upon self-assembly, the hydrophobicity of the ACC was detected to fatefully dominate the structural evolution of the nano-aggregates. Therefore, it is reasonably to believe from Eqns (8-1) and (8-5), together with Fig. 8-5, that the composite effect between the DH and Cn may play a key role in controlling the structural morphology of the resulting nano-aggregates. In Zone I of Fig.
8-5 (the region where the value of (XDH × XCn) is lower than 1.5), i.e., the nano-aggregates with Cn = 2 and DH = 0.5 showed a compact particle morphology with a relatively uniform size distribution of around 25 nm in diameter, as shown in Fig. 8-6a. This observation is similar to the case of the CC in previous work. However, when (XDH × XCn) exceeded 1.5, i.e., Zone II;
the resulting nano-aggregates exhibited entirely different structural morphology.
In the case of Cn = 6 and DH = 0.5, the ACC nano-aggregates shows a perfect spherical geometry with a size of about 100 nm, shown in Fig. 8-6b. After dehydration, the spherical nano-aggregates structurally collapsed (Fig. 8-6c)
and the broken nano-aggregates after electron-induced rupturing (shown in Fig. 8-6d), illustrated a hollow core, indicating such a class of nano-aggregate is virtually a capsule-like structure.
b
c d
a
50 nm 100 nm
20 nm 100 nm
Figure 8-6 TEM images of (a) C2-0.5, (b) C6-0.5, and C6-0.5 after dehydration; and (d) SEM image of the ACC nano-aggregates after electron-induced rupturing.
113
As revealed from the fluorescence probe test, the CAC values for the nano-aggregates with smaller (XDH × XCn) rapidly decreased till (XDH × XCn) approaching to 1.5. According to the poly-core model proposed by Wang et al., the amphiphatic potential drives the resulting ACC macromolecules to self-assemble into a micelle-like structure with hydrophobic groups turning into the core structure while the hydrophilic segments structurally turning into water environment to establish a shell structure, as schematic illustrated in the reaction scheme of A Æ B1 in Fig. 8-7, forming a spherical architecture with
minimal surface energy (as the drawing of B2 in Fig. 8-7). Furthermore, from experimental observation, it was discovered that the ACC with less hydrophobicity, e.g., Zone I where (XDH × XCn) <1.5, tends to form nano-particle dispersion.
- hydrophilic groups - hydrophobic groups - hydrophilic groups - hydrophobic groups
A
B1 B2
C1 C2
Figure 8-7 Schematic illustration of formation process of ACC nano-aggregates.
114
From a series of experimental observations, hollow structure exists only when the term of (XDH × XCn) >=1.5. As aforementioned, the hydrophobizing water capacity of the nano-aggregates increased rapidly as a result of increasing hydrophobicity in Zone II region. However, this would further cause structural in-stability when dispersed in aqueous solution due to the formation of an un-compatibilized interface between the aqueous phase and hydrophobic compartments of the ACC. Therefore, from the energy viewpoint, the ACC with higher hydrophobic nature, i.e., the compositions underlying the region of Zone II, prefers to self-aggregating into a more thermodynamically stable form as such that a sandwich structure with hydrophilic-hydrophobic-hydrophilic configuration can be expected, as
115
illustrated in the reaction scheme of A Æ C1Æ C2 of Fig. 8-7 where a final capsule-like structure can be developed, which is similar to that of bi-layer liposomal structure. On this basis, the ACC nano-capsules with hydrophilic layers residing in the outermost and inner regions of the capsules ensure a thermodynamic and colloidal stability in aqueous solutions, and this is evidenced from a stability test where the nano-capsules are well suspended in an aqueous suspension for 1-month period of time.
Doxorubicin loading
To investigate the drug-loading capacity of the ACC nano-aggregates, doxorubicin (DOX), a clinically important anti-cancer drug, was employed as a model molecule, and loaded into the ACC nano-capsules. Since DOX molecule contains an amino group with a pKa of 8.6, it is expected that DOX can form polyelectrolyte complex with the carboxymethyl groups of ACC [28].
Figure 8-8 shows the plots of the DOX encapsulation efficiency (EE) in the ACC nano-aggregates with different values of (XDH × XCn). For CC, it showed only 26.3% encapsulation efficiency (EE) due to the physical interaction between DOX molecules and carobxymethyl groups, as demonstrated in pervious work [126]. After acyl modification (where Cn=2), DOX encapsulation efficiency of the ACC nano-aggregates was slightly reduced from 26.3% to 24.5% with increase of DH from 0 to 0.5. This decrease of EE is due to a decrease in the population of functional group, i.e., carboxymethyl groups, along the ACC chains. This is further evidenced from Fig.8-1 where the intensity of the characteristic peaks at 1730 cm-1 is reduced, indicating a reduction of intermolecular interaction between carboxymethyl dimers as the Cn was increased. However, the EE of the ACC nano-aggregates for the DOX
is increased considerably with the composite effect of both acyl chain length, i.e., Cn =6, 10, and 12 and the degree of acyl substitution, to a value of about 56%. This finding clearly suggests a considerable improvement in chemical and/or physical affinity between the nano-capsules and the DOX, thus, resulting in an enhancement of drug load efficiency by more than 200%
compared to the CC composition.. However, it should be noted that optimal encapsulation efficiency has not yet practiced for the ACC through other processing skills in this study, instead, the current experimental outcomes of the EE are simply illustrating the power of the hydrophobic nature and a successful design of hydrophobic interactions, i.e., the effect of (XDH × XCn), of the ACC nano-aggregates, that can be used as an indicator for better drug loading manipulation.
0 1 2 3 4 5 6
20 30 40 50 60
(X
DH*X
Cn)
EE ( % )
CCCn=2 Cn=6 Cn=10 Cn=12
Figure 8-8 DOX encapsulation efficiency of ACC nano-aggregates with various values of (XDH × XCn).
116
117
Chapter 9
Conclusion
9.1 electric-sensitive of clay/chitosan hybrids
1. The increased cross-linking density with considerable increase of clay content improved the mechanical properties of hybrids, but restricted the swelling-deswelling kinetics.
2. After repeatedly on-off switch operation of a given electric field, a relatively constant deswelling-swelling behavior for over 10 times on-off operation can be reached for the hybrids with higher Cclay (>0.5 wt %), compared to that of the pure CS.
3. The release kinetics of vitamin B12 displays a pseudo-zero order release and the release mechanism shifted from diffusion-controlled towards swelling-controlled mode when lower MMT content (1 wt %) was added.
However, as MMT contents exceed 1 wt %, both diffusion exponent n and responsiveness to electrical stimulation were decreased.
4. The resulting nanostructure of the nanohydrogels can be well manipulated to keep the pulsatile release profile relatively constant after repeated on-off switching operations.
5. The nanohydrogels with 2 wt % MMT addition was demonstrated to exhibits excellent anti-fatigue behavior and better pulsatile release compared to that of the pure CS.
9.2 electric-sensitive of TEOS/CS nanoparticles
1. The nanoparticles with particle size of 50-130 nm composed of chitosan (CS) and tetraethyl orthosilicate (TEOS) were obtained through emulsion and
118
sol-gel process.
2. LC and AE were effectively enhanced by increasing the TEOS content.
3. The existence of TEOS network structure significantly altered the release behavior from swelling-controlled to diffusion-controlled mechanism.
4. Burst release from nanoparticles was occurred when the electrical field was applied. This release behavior provided a new drug delivery system to precisely and effectively control the release of protein.
9.3 Acylated-carboxymethyl chitosan nanocapsule
1. A simple and direct method that amphiphilic CHC hollow nanocapsules were developed in aqueous system without the aid of surfactants, organic solvents, emulsion phases, or template cores.
2. Higher hexanoyl substitution promoted larger nanocapsules, ca. 200 nm in diameter, whilst a reduced zeta potential was correspondingly detected, and vice verse, forming smaller nanocapsules, ca. 20 nm in diameter.
3. An encapsulation efficiency of 46.8% was reached, and a corresponding drug release from the nanocapsules for a time period exceeded 7 days can be achieved in vitro.
4. Evolution of resulting self-aggregation structure of the ACC has been explored where a transformation from solid nano-particle to hollow nano-capsule of the ACC was observed as a result of hydrophobic effect, i.
e., a product of (XDH × XCn), induced from acyl substitution (amount and chain length), exceeded a critical value of 1.5.
5. An improved affinity and capacity of doxorubicin drug encapsulation can be technically designed according to the nature of the resulting nanocapsules for controlled delivery.
119
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Curriculum Vitae K. H. Liu (Kun-Ho Liu) Advisor: Prof. San-Yuan Chen
Department of Materials Science Engineering, National Chiao Tung University
1001 Ta Hsueh Road, Hsinchu, TAIWAN 300 Email: [email protected]
I. B. S.: I-Shou University (1997-2001), Kaohsiung, Taiwan.
Major: Materials Science and Engineering
II. M. S.: National Chiao Tung University (2001-2003), Hsinchu, Taiwan Major: Materials Science and Engineering
Prof.: San-Yuan Chen
Research Topic: Growth process and physical characteristics of Zn-ZnO nanocrystals via thermal reduction
III. Ph.D.: National Chiao Tung University (2003-2008), Hsinchu, Taiwan Major: Materials Science and Engineering
Prof.: San-Yuan Chen
Research Topic: Study on the nanostructural evolution and controlled drug release behavior of chitosan nanocomposites.
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Publications
Kun-Ho Liu Patent:
z 雙性幾丁聚醣衍生物之空心圓球及使用其之醫藥用雙性幾丁聚醣衍生物複 合物(Hollow sphere of amphiphilic chitosan derivatives and amphiphilic chitosan derivative complex using the same for medical use), Taiwan patent, Japan patent, and the United State patent, in press.
SCI Paper:
1. Kun-Ho Liu, Chin-Ching Lin, and San-Yuan Chen, Growth and Physical Characterization of Polygon Prismatic Hollow Zn-ZnO Crystals. Cryst.
Growth Des. 5 (2005) 483-487 (Impact Factor: 4.046)
2. Kun-Ho Liu, Ting-Yu Liu, San-Yuan Chen, and Dean-Mo Liu, Effect of clay content on electrostimulus deformation and volume recovery behavior of a clay–chitosan hybrid composite. Acta Biomater. 3 (2007) 919–926 (Impact Factor: 3.113)
3. Kun-Ho Liu, Ting-Yu Liu, San-Yuan Chen , and Dean-Mo Liu, Drug release behavior of chitosan–montmorillonite nanocomposite hydrogels following electrostimulation. Acta Biomater. 4 (2008) 1038–1045 (Impact Factor:
3.113)
4. Kun-Ho Liu, Ting Yu Liu, Dean-Mo Liu, and San-Yuan Chen, Electrical-Sensitive Nanoparticle Composed of Chitosan and TEOS for Controlled Drug Release, J. Nanosci. Nanotechno. (2008) in press (Impact Factor: 1.987)
5. Kun-Ho Liu, San-Yuan Chen, Dean-Mo Liu, and Tse-Ying Liu, Self-Assembled Hollow Nanocapsule from Amphiphatic Carboxymethyl-hexanoyl Chitosan as Drug Carrier. Macromolecules 41 (2008) 6511-6516 (Impact Factor: 4.411)
6. Kun-Ho Liu, San-Yuan Chen, Dean-Mo Liu, Hydrophobic Effect on the Structural Evolution of Acylated-Carboxymethyl Chitosan and its
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Self-Assemble Forming of Doxorubicin-loading Nanocapsule. In Prepared.
7. Chin-Ching Lin, Kun-Ho Liu, and San-Yuan Chen, Growth and characterization of Zn–ZnO core-shell polygon prismatic nanocrystals on Si, Journal of Crystal Growth 269 (2004) 425–431 (Impact Factor: 1.950) 8. Ting-Yu Liu, Shang-Hsiu Hu, Kun-Ho Liu, Dean-Mo Liu and San-Yuan
Chen, Preparation and characterization of smart magnetic hydrogels and its use for drug release, J. Magn. Magn. Mater. 304 (2006) e397-e399 (Impact Factor: 1.212)
9. Ting-Yu Liu, Shang- Hsiu Hu, Kun-Ho Liu, Dean-Mo Liu and San-Yuan Chen, Study on controlled drug permeation of magnetic-sensitive ferrogels:
Effect of Fe3O4 and PVA, J. Control. Release 126 (2008) 228-236 (Impact Factor: 4.756)
10. Ting-Yu Liu, Shang- Hsiu Hu, Kun-Ho Liu, Dean-Mo Liu and San-Yuan Chen, Instantaneous Drug Delivery of Magnetic/Thermal Sensitive Nanospheres by a High Frequency Magnetic Field, Langmuir (2008) revised (Impact Factor: 4.009).
11. Ting-Yu Liu, Kun-Ho Liu, Dean-Mo Liu, San-Yuan Chen and I-Wei Chen, Temperature-sensitive Nanocapsules for Controlled Drug Release Caused by Magnetically Triggered Structural Disruption. Adv. Funct. Mater. (2008) in Press. (Impact Factor: 7.496)
International Conferences:
Kun-Ho Liu, Ting-Yu Liu, Dean-Mo Liu and San-Yuan Chen, Ultra-fast reactive drug release system composed of electrical-sensitive chitosan and TEOS-IPN hybrid nanoparticle under applied DC electrical fields, NIPER-NANO-2006-Nanotechnology in advanced drug delivery Conference (2006) Chandigarh, India.