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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5386_Библиотеки_им_академика_М_И_Перельмана.pdf
74
Nano Physical Pharmaceutics of Micelle-Based Systems
The micelle size is also related to polymer concentration and
segmented copolymer structure. For ABA type three segmented
copolymer (A is hydrophobic chain, and B is hydrophilic chain),
with the increase of polymer concentration, it is easy to interact
with other micelle cores to form larger micelles due to the
presence of some hydrophobic chains in the hydrophilic shell,
while the micelle size of AB or BAB type three segmented
copolymer formed at high concentration is small.
2.5.1.2 Critical micelle concentration
The CMC of segmented copolymers is an important parameter for
the thermodynamic stability of micelles, which is closely related
to their stability in vivo and is generally related to the hydrophobic
chain length (N
A
) and hydrophilic chain length (NB). This can be
calculated by Equation 2.25:
lnCMC = aN
A
+ bN
B
(2.25)
where a and b are constants related to external conditions.
Pimpha et al. designed and synthesized PLA-b-PEG-b-PLA with
and 3.60, a micelle with a hydrophobic core of PLA and a hydrophilic
shell of PEG could be formed at polymer mass concentrations
between 0.5% and 1.0%. When LA/EG decreases to 1.26, only at
higher polymer concentrations (>20 wt.%) can aggregates appear,
and no micelle structure is found by characterization. In general,
CMC gradually decreases with the increase of LA/EG ratio (i.e., the
increase of hydrophobicity of segmented copolymers).
A similar trend is found for the PEG-g-PCL graft copolymer,
with a gradual increase in CMC as the EG/CL ratio increases [31].
lower the grafting rate, the lower the corresponding CMC at the
same EG/CL ratio. Compared with linear segmented copolymers
with similar EG/CL ratios, graft copolymers have a lower CMC,
which is mainly due to their high dispersion degree and restricted
chain motion caused by side chain steric hindrance.
NPP of Polymeric Micelles in Drug Delivery
75
2.5.1.3 Zeta potential
When charged particles dissociate in solution, they attract
oppositely charged ions to the surface, where those close to the
There is a conceptual boundary, that is, when the particle moves
in the liquid, the ions inside the boundary move with the particle,
while those outside the boundary stay in place. This is called a
slipping plane, and the corresponding potential is called zeta
potential (z). This parameter characterizes the charge carried by
the particle surface and is generally measured by electrophoresis.
In this way, the electrophoretic mobility (U) of the particle in
potential can be calculated according to Equation 2.25 by
combining the known parameters solution viscosity η and dielectric
constant e.
∪
= z
(2.26)
/
Vlahos et al. studied the structure, the surface potential and
other properties of charged amphiphilic block copolymers (A5B30,
A10B
30
or A20B30) using molecular dynamics simulations with
the Langevin algorithm [33]. It was found that when the charged
chain segments were short and partially charged, the micelle
weight was at least bimodal in distribution, indicating the presence
of both small and large particle size micelles within the system.
The zeta potential was not a monotone function relative to the
length of the charged segment (NA), and had a more complicated
relationship with the charged ratio a. For micelles formed by
A5B
30
and A10B30, the zeta potential decreased as the ratio a
decreased, whereas for micelles formed by A20B30, the potential
when a was 0.4 was higher than that when a was 0.2 or 1. It was
found that the zeta potential increased with NA when the ratio
trend was found when the ratio was higher than 1.11.
76
Nano Physical Pharmaceutics of Micelle-Based Systems
2.5.2 Stability of Micelles
The stability of a micellar delivery system before it reaches the
targeting area is a critical parameter. How to maintain stable can
be challenging especially when facing the highly complex in vivo
environment, including high degree dilution after intravenous
surface areas of respective core-forming and corona-forming
chains (S
core/Nagg
and S
corona/Nagg
(Fig. 2.4) [23],
S
core
2
= 4pR
core
N
agg
corona
2
S
= 4pR
n
(2.28)
N
agg
with Rh= Dh/2. Decrease in S
corona/Nagg
indicated a strong
interaction between neighboring chains inside corona suggesting
density inside corona r and established their relationship with
stability using micelles formed by PBMA-b-PMA block copolymer.
The result shows that PMA chains inside corona lost their
mobilities with increasing r
AM
values leading to increased steric
repulsions, which prevented the interaction with proteins.
contributing to enhanced stability. The in vivo experiments also
S
corona/Nagg
showed much
higher tumor accumulation than those with low S
corona/Nagg
, due
to the strong entropic repulsion against biomacromolecules in
the circulation [34].
The reversible dynamic balance between the free single
free single chains tended to dissociate and insert into the micelles
when the concentration of micelles was low, while micelles were
easy to fuse and re-split when the concentration of micelles was
high [35]. It has been reported that the dissociation rate of
micellar cores formed by chain segments with high Tg is much
lower than that of micellar cores formed by chain segments with
NPP of Polymeric Micelles in Drug Delivery
77
low Tg, which is due to the restricted movement of the high T
g
segment in the glassy state [36]. Therefore, micelles with T
g
higher than the normal body temperature tend to have limited
disintegration during circulation [15].
Interaction of micelles with proteins or cells in vivo is
another factor contributing to their instability in vivo, so avoiding
serum protein adsorption of micelles and reducing clearance
by the immune system is expected to enhance the stability of
micelles in vivo. Hydrophilic polymers with N and O atoms in the
polymer chain, such as PEG, polyacrylamide, polyvinyl alcohol,
poly(diethylenedioxazoline) and poly(vinylpyrrolidone), are able
to reduce adsorption by forming hydrogen bonds with water
molecules on the surface. The hydration layer helps to reduce
the free energy interface and increase the repulsion against
biomacromolecules, thus improving the stability of micelles. For
the circulation time and prevent protein adsorption with high
to a strong repulsive interaction of micelles and cells, hampering
its endocytosis process.
2.5.3 Drug-Loading Profile of Micelles
Drug-loading capacity is an important index to evaluate the
application of micelles in vitro and in vivo. At present, a variety
of methods to encapsulate drugs have been developed, such as
dialysis, W/O emulsion, solvent evaporation, co-solvent evaporation
and freeze-drying method. In general, the drug-loading capacity
between the polymer and the drug, and the driving force of
hydrophobic drug binding to the core can also be described by the
corrected Flory–Huggins equation. At the same time, other aspects
interaction, dipole-dipole interaction, hydrogen bonding and
lg SP = c + rR2 + sp2 + aSa2 + bSb2+ νV
x
(2.29)
78
Nano Physical Pharmaceutics of Micelle-Based Systems
heterogeneous phase, R2 is the molar refractive index of the
solvent (from London’s dispersion force), p2 is the ratio of
depolarization/polarization of the drug, Sa2 is the hydrogenbond acidity of the drug, S b2 is the hydrogen bond binding
alkalinity of the drug, Vx is the McGowan’s characteristic volume
from the molecular structure, and c, r, s, a, B, and ν are regression
Figure 2.4 Schemac illustraon of micellar structure and the parameters
related to the microstructure as described in Equaons 2.24, 2.27, and 2.28.
Based on the theory of linear solvent-free energy relationship
equation, to the core of a micelle, the drug needs to transfer its
free energy in water into the polymeric micelle.
hydrophobic/hydrophilic ratio, especially the hydrophobicity of
the core, the more hydrophobic, the higher drug-loading capacity
z as [39]:
r
3S
shell shell
z = =
(2.30)
V 4N pR
3
core ag g
NPP of Polymeric Micelles in Drug Delivery
79
Figure 2.5 The scheme illustrated the mechanism of drug loading and the
stability of micelle-drug delivery system in soluons (detailed data not shown
here). The equaons are dened from Equaons 2.27 and 2.30.
High z indicates a micellar structure with a relatively small
core and thick corona, which usually shows low drug-loading
capacity. The detailed process of drug loading and stability of the
micelle system is shown in Fig. 2.5. The inserted equations of c
and DG are illustrated in Chapter 1. The other parameters and
in Fig 1.16 in Chapter 1 and 2.28. The scheme gives us the basic
principles for making a stable and uniform delivery system
the experiments.
2.5.4 Endocytosis of Micelles
b-polyethylene
glycol as a model block copolymer, Doris et al. investigated the
by modifying hydroxyl, carboxyl and tertiary amine groups at the
terminal, respectively. It was found that micelles with cationic
surface charge had the fastest endocytosis, while those with anionic
surface charge showed the slowest endocytosis [40]. However,
all three micelles entered the cell by cytosolic cell-mediated
cytokinesis and had a similar behavior. Liu et al. designed and
80
Nano Physical Pharmaceutics of Micelle-Based Systems
synthesized a series of poly (2-ethyl-2-oxazoline)-b-polylactide
2.5.5 Drug Release Behavior of Micelles
We have found that the drug release behavior is dominated by
the thermodynamic detaching parameter ( c) cross-link density
(D R) [39], which can be categorized into
A larger R
core
leads to a higher c value, indicating a low drug
detachment. In the second step, the drug then passes through
the cross-linked area at the interface between the core and the
corona, which can be explained by a lattice model with the pore
size being r. This step is dependent on the r
shell
, and larger r
shell
corresponds to smaller r and smaller D. The third step involves
R
shell
means a longer
Jeong et al. used micelles formed by PEG-b-PBLG to encapsulate
clonazepam, and the increase in the mass fraction of the drug led
calorimetry result suggests that the drug tends to crystallize
However, the drug release curve measured in vitro does not take
in vivo environment into account, so it is only
partly correct. Generally speaking, the drug release behavior is
accelerated in vivo. For example, PEG-b-PCL micelles encapsulating
HCPT can be released in vitro within a few days, but it is removed
from plasma within a few hours after intravenous injection [43].
Similar results were found in earlier studies, where polymeric
micelles showed loss of integrity within 1 hour after intramuscular
or subcutaneous injection [44, 45]. This is mainly due to the sudden
dilution of the drug-loaded micelles and protein absorption,
which promotes rapid drug release. Figure 2.6 shows the detailed
For hydrophobic drugs like PTX or DOX released from the micelle
NPP of Polymeric Micelles in Drug Delivery
81
system, the drug is processed in three steps as shown in Fig. 2.6.
The release process is illustrated from the top right panel to the
disassociation of drug from the hydropobic core, that is, the drug
detachment. The second step is the kinetic penetration of drug
through the cross section between the core and the shell, where
the highly entangled polymer chains result in many small pores
D
actually the shell thickness of the micelle. Generally, for a Brown
drug passing through thickness is too low to be considered. Thus,
for the drug release of the micelle system, the accumulated release
time and concentration is dominated by the thermodynamic
detaching and the mesh size in the core–shell cross section. The
function that describes these factors are shown in Fig. 2.6.
Figure 2.6 The mechanism of drug release in the micelle system. From top
right panel to boom panel: (1) the thermodynamic disassociaon of drug
(small yellow ball) from the hydropobic core; (2) the kinecally penetraon
of drug through the cross secon between the core and the shell; and (3) the
diusion distance, namely, the thickness of the shell.
82
Nano Physical Pharmaceutics of Micelle-Based Systems
For charged drug-loaded micelles, the drug release is not
induce the disintegration of micelles. For example, micelles can be
destabilized through ion exchange with compounds such as salts
and heparin. Similarly, polymer-metal complex micelles can
dissociate by substitution of ions in the medium for metals in
the ligands [15].
drug, nucleic acids and proteins) delivered by carriers like micelles,
liposomes, nanogels, PLGA microspheres and organic–inorganic
complex particles in solutions, we systemically summarize and
analyze series of the key physical-chemistry properties, propose
covering the in vitro/vivo gap of nanoformulations.
2.5.6 Drug Release Behavior of Stimuli-Responsive
Micelles
Driven by the aim to develop a smart drug delivery system,
various stimuli-responsive polymeric micelles were prepared and
such as temperature, pH and light have been applied to induce
the disassembly or morphology changes of micellar aggregates,
2.5.6.1 pH-responsive micelles
while the mesenchyme cellular environment of tumor tissues is
removal and rapid glycolysis leading to lactic acid accumulation,
which provides an important theoretical basis for the development
and application of pH-responsive nanocarriers [48]. Such drugloaded micelles are stable under normal physiological environment,
and the hydrophobic drugs encapsulated in the core hardly leak
after long-term systemic circulation, but they are less stable under
low pH environment, in which the structure will be disrupted and
NPP of Polymeric Micelles in Drug Delivery
83
Currently, pH-responsive micelles are mainly designed through
chain segments with ionizable chemical groups to assemble into
micelles that remain deprotonated/deionized at physiological pH,
and are protonated and disintegrate at acidic pH with the change
in hydrophilic/hydrophobic ratio of the micelle and the release
of the drug [49, 50]. Polymers with side chains containing
carboxylic acid groups are the most common class of pH-responsive
polymers, including polyacrylic acid (PAA) and polymethacrylic
acid (PMA) [14]. The second approach uses acid-sensitive chemical
bonds to achieve pH response, that is, the acid-sensitive chemical
bonds are introduced between the drug and the polymer or
inside the polymer, and the drug is released by hydrolysis under
acidic conditions. Common acid-sensitive chemical bonds include
hydrazone, imine, oxime, acetal, vinyl ether and catechol ester
the location and drug release principles of chemical bonds:
(1) chemical bonds located at the connection of two blocks, and
the separation of the two after hydrolysis leads to micelle
disintegration and drug release; (2) chemical bonds connect
hydrophobic chain segments of polymers to hydrophobic groups,
to a decrease in the hydrophobicity of the inner core and drug
release through solubilization; (3) chemical bonds connect drugs
2.5.6.2 Redox-responsive micelles
The environment inside the cell is highly reducing, with the
concentration of the major reducing agent glutathione (ɣ-Glamylcysteinyl-Glyine, GSH) reaching about 100 times that in the
extracellular environment. However, tumor cells have higher GSH
concentrations (up to four times the normal cytoplasm) due to
their high activity and low metabolism, as well as the structural
hypoxia of solid tumors, which provides ideas for the design of
bond is a common redox-sensitive chemical bond, which is often
used to connect the hydrophobic and hydrophilic segments of
amphiphilic block copolymers to synthesize redox-responsive