Geckeler K.E., Nishide H. (Eds.) Advanced Nanomaterials

2.4 Chemical Reactions 85

Figure 2.17 ). The right - hand image in Figure 2.18 shows a TEM image of such

hybrid nanoﬁ bers after the incorporation of Pd to a total of 18.4 wt - %. In fact, we

could tune the amount of Pd loaded into the nanotubes by adjusting the relative

amounts of the Pd - loaded nanotubes and Pd

2+

in a plating bath. As the Pd content

increased, eventually the hybrid ﬁ bers could not be dispersed in water. In addition

to Pd plating, we have also succeeded in the plating of Ni into the core of such

nanotubes, as evidenced by our recent success in preparing water - dispersible

triblock – Pd – Ni magnetic nanoﬁ bers [53] .

The use of a tetrablock copolymer for the above project seems to be an over kill,

as in the end the P t BA block was not used at all. This was, however, not by design.

Our initial plan was to fully degrade the PI block and then to hydrolyze the P t BA

block. We planned to introduce Pd(II) via its binding with the carboxyl groups of

PAA. The binding between Pd(II) and the residual double bonds of PI was a sur-

prise to us and should be useful in the future as a staining method for PI in the

elucidation of complex segregation patterns of block copolymers.

2.4.2

End Functionalization

In the “ supramolecular chemistry ” of nanotubes and nanoﬁ bers, the end - func-

tional groups should not be interpreted as the traditional carboxyl or amino groups,

etc. Rather, they should be other nano “ building blocks ” , including nanospheres

and nanoﬁ bers or nanotubes of a different composition. We ﬁ rst end - functional-

ized PS - PCEMA - PAA nanotubes by attaching to them water - dispersible PAA -

PCEMA nanospheres and spheres bearing surface carboxyl groups that were

prepared from emulsion polymerization [54] . Figure 2.19 shows the steps involved

in coupling the nanotubes and PCEMA - PAA nanospheres.

To ensure that the PAA core chains were exposed at the ends, we ultrasonicated

the pristine nanotubes to shorten them. The carboxyl groups of the nanotubes

were then reacted with the amino groups of a triblock PAES - PS - PAES, where

PAES denotes poly[4(2 - aminoethyl)styrene], in the presence of catalyst 1 - [3 -

Figure 2.19 End - functionalization of PS - PCEMA - PAA nanotubes by PAA - PCEMA nanospheres.

86 2 Block Copolymer Nanoﬁ bers and Nanotubes

Figure 2.20 TEM images of nanotube and emulsion nanosphere coupling products.

(dimethyl - amino)propyl] - 3 - ethylcarbodiimide hydrochloride (EDCI) and co -

catalyst 1 - hydroxy - benzotriazole (HBA). As PAES - PS - PAES was used in excess, it

was grafted onto the nanotubes mainly via one end only. We then puriﬁ ed the

sample. Nanotubes bearing terminal PAES chains were subsequently reacted with

the carboxyl groups on the surfaces of the nanospheres again using EDCI and

HBA as the catalysts. Coupling between the nanotubes and emulsion spheres

containing surface carboxyl group was achieved in a similar manner.

Figure 2.20 shows the typical products obtained from coupling the PAES - PS -

PAES - treated nanotubes with a batch of emulsion nanospheres bearing surface

carboxyl groups. The product in Figure 2.20 a resulted from the coupling between

one tube and one sphere. As the spherical “ head ” is water - dispersible and the

tube “ tail ” is hydrophobic, this structure may be viewed as a macroscopic coun-

terpart of a surfactant molecule or a “ super - surfactant ” . Figure 2.20 b shows the

attachment of two tubes to one sphere, which had fused with another sphere

probably during TEM specimen preparation. “ Dumbbell - shaped molecules ” were

formed from the attachment of one tube to two spheres at the opposite ends, as

seen in Figure 2.20 c. The products depicted in Figure 2.20 a – c co - existed regard-

less of whether we changed the tube to microsphere mass ratio from 20/1 to

1/20. At the high tube to emulsion sphere mass ratio of 20/1, the super - surfactant

and dumbbell - shaped species were the major products. At a mass ratio of 1/1

and 1/20, the dumbbell - shaped product dominated. Other than product control

by adjusting the stoichiometry, an effective method to eliminate the dumbbell -

shaped product was to use nanotubes labeled at only one end by PAES - PS - PAES.

These tubes were obtained by using ultrasonication to break up nanotubes that

contained end - grafted PAES - PS - PAES chains. For example, the ultrasonication

of the PAES - PS - PAES - grafted nanotubes for 8 h reduced the L

w

of a nanotube

sample from 701 to 252 nm and L

n

from 515 to 187 nm. The reaction between

the shortened tubes and the nanospheres at a tube to sphere mass ratio of 1/20

yielded almost exclusively the supersurfactant structure with unreacted nano-

spheres. The content of the multi - armed structure increased as the nanotube to

microsphere mass ratio increased.

More recently, we have used the same chemistry to couple PS - PCEMA - PAA

nanotubes with PGMA - PCEMA - PAA nanotubes [55] . Figure 2.21 shows the nano -

2.5 Concluding Remarks 87

tube multiblocks that we prepared. To facilitate the easy differentiation between

the two types of nanotubes, we loaded Pd nanoparticles into the PGMA - PCEMA -

PAA nanotubes. Using this method, we succeeded in preparing both nanotube

di - and triblocks with structures similar to di - and triblock copolymers. The

nanotube multiblocks should self - assemble in a manner similar to the block

copolymers.

2.5

Concluding Remarks

Block copolymer nanoﬁ bers and nanotubes can now be readily prepared with high

yields. Such nanoﬁ bers have interesting chemical and physical properties. More

pressing challenges in this area of research are to ﬁ nd and to realize the com-

mercial applications for these nanostructures. The latter will be greatly facilitated

with more participation from industrial partners.

On the fundamental research side, the construction and study of superstruc-

tures prepared from the coupling of different nano - and micro - components are a

very interesting and promising area of frontier research. The super - surfactants of

Figure 2.20 a may, for example, self - assemble as do surfactant molecules to form

supermicelles or artiﬁ cial cells, which contain structural order to several length

scales. The multi - armed structure of Figure 2.20 b and its analogues will be of

particular irrterest if the nanotubes are replaced by PS - PCEMA - PAA/ γ - Fe

2

O

3

hybrid nanoﬁ bers. Figure 2.22 shows, for example, just such an interesting struc-

ture, which can be prepared by attaching three PS - PCEMA - PAA/ γ - Fe

2

O

3

hybrid

nanoﬁ bers to one microsphere.

These ﬁ bers will attract one another in a magnetic ﬁ eld due to their magnetiza-

tion and thus grab a nanoobject. Such a nanoobject can be moved around by

focussing a laser beam on the microsphere that is trapped through an optical

Figure 2.21 TEM image of nanotube multiblocks.

88 2 Block Copolymer Nanoﬁ bers and Nanotubes

tweezing mechanism. The nanoobject can then be released at a desired spot by

turning off the magnetic ﬁ eld. Thus, such a device can function as an “ optical

magnetic nanohand ” . Last but not the least, studies on the concentrated solution

properties and nanoﬁ ber composite properties should be performed to see if there

are any novel desirable applications for these materials.

Acknowledgements

G. L. is very grateful for ﬁ nancial support from the Natural Sciences and Engineer-

ing Research Council of Canada, Defense Research and Development Canada,

Canada Research Chairs Program, Canada Foundation for Innovations, Ontario

Innovation Trust. G. L. would also like to thank Drs. Xiaohu Yan, Zhao Li, Sean

Stewart, Jianfu Ding, and Lijie Qiao for carrying out the work reviewed in this

chapter.

This Chapter has been published previously in:

Lazzari, Massimo / Liu, Guojun / Lecommandoux, Sebasti é n (eds.)

Block Copolymers in Nanoscience

2006

ISBN - 13: 978 - 3 - 527 - 31309 - 9 - Wiley - VCH, Weinheim

Figure 2.22 Schematic illustration of the operation of an optical magnetic nanohand.

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Smart Nanoassemblies of Block Copolymers for Drug

and Gene Delivery

Horacio Cabral and Kazunori Kataoka

91

3

3.1

Introduction

In Nature, various complex architectures are formed from a limited choice of

building units such as lipids or amino acids. These natural assemblies form a large

variety of biological devices with speciﬁ c cellular functions. Conversely, synthetic

polymers can be prepared from a wide range of monomers, and these macromol-

ecules can construct singular architectures and shapes. The interest in these

structures relies on their characteristic sizes in the mesoscopic range ( < 100 nm),

and that their constitution and shape lead to materials with particular properties

and functions. Nevertheless, these artiﬁ cial structures could not yet attain the

complexity achieved by the natural assemblies.

One particular example of man - made nanoassemblies is that of block copoly-

mers. The reason for using block copolymeric systems to prepare nanostructures

is their simplicity to form nanoscale objects with expected shapes and sizes,

without any additional trigger. Block copolymers consist of two or more covalently

bonded blocks with different physical and chemical properties. In addition, each

block should have the features to control the self - assembly process. The driving

force for core – shell - structured self - assembly consists of repulsive interactions

between incompatible domains, such as the case of amphiphilic diblock copoly-

mers, which contain a hydrophobic and a hydrophilic block. Moreover, the cova-

lent link between the blocks is responsible for the microphase separation, and

prevents the system from further separation on a macroscopic scale. The self -

assembled nanostructures can be ﬁ nely tuned to a variety of morphologies by

altering the molecular parameters of the block copolymers or the environment

(Figure 3.1 ). These self - assembled block copolymer systems have already been

found to be appropriate for several applications in nanotechnology, including

detergents, paints, electronics, cosmetics, lubricants, tissue engineering, and drug

delivery, as determined by the morphology of the structures [1 – 3] .

In an attempt to create synthetic structures that somehow approach natural

assemblies in terms of their complexity, functionality, and performance,

Advanced Nanomaterials. Edited by Kurt E. Geckeler and Hiroyuki Nishide

ISBN: 978-3-527-31794-3

92 3 Smart Nanoassemblies of Block Copolymers for Drug and Gene Delivery

nanostructures have been designed to respond in a controlled manner to external

stimuli. Stimulus - responsive nanostructures, which are also referred to as “ smart, ”

“ intelligent ” , or “ environmentally sensitive ” nanostructures, are systems that

exhibit sharp changes in response to physical stimuli such as heat, ultrasound,

and light, or to chemical stimuli such as pH, ions in solution, and chemical sub-

stances. These responses depend on the stimulus applied, and they may comprise

modiﬁ cations in the properties of the assemblies such as shape, volume, and

permeation rates.

3.2

Smart Nanoassemblies for Drug and Gene Delivery

An “ ideal ” drug carrier should emulate a system that is capable of residing in vivo

for long periods of time, targeting particular cell types, incorporating a large set

of therapeutic agents, and releasing those molecules in the appropriate environ-

ment. Micelles, rods, or polymersomes have been used as carriers of therapeutic

agents to target speciﬁ c sites in the body [3, 4] . Moreover, several micellar delivery

systems for anticancer drugs are currently undergoing clinical trials [5] . Rods,

threads, and ﬁ bers have also been shown to be useful as support media for cell

growth in vitro , and have been used to direct nerve regrowth in vivo or as the basis

of more complex mechanical systems [6 – 8] .

Polymeric self - assembled nanostructures have a great potential to reach patho-

logical sites while avoiding biological barriers in the human, due to their nano-

Figure 3.1 Block copolymer nanoassemblies. Several

structures ranging from 10 nm to 10 000 nm can be formed

using block copolymers as the building units.

3.3 Endogenous Triggers 93

scopic size (typically between 10 and 100 nm). It has been determined that the

so - called enhanced permeability and retention ( EPR ) effect plays a major role in

tissue targeting to, for example, tumor tissues [9, 10] . The EPR effect is attributed

to the angiogenic tumor vasculature, which has a higher permeability compared

to normal tissues due to its discontinuous endothelium, and to the somewhat

undeveloped lymphatic drainage in tumors. These characteristics lead to the

extravasation of colloidal particles in tumor and other inﬂ amed tissues, and their

subsequent retention there. Moreover, the polymeric nanostructures must circu-

late in the bloodstream for a sufﬁ cient time in order to achieve this targeting. Thus,

the surface properties of polymeric micelles represent important factors as they

determine the biological fate of the material. The reduction of nonspeciﬁ c recogni-

tion and uptake by the reticuloendothelial system ( RES ) is critical for the prolonged

circulation of the carrier. Colloidal carriers bearing hydrophilic polymers on the

surface of particles have been shown to reduce the opsonization and subsequent

uptake by the RES cells of the liver, spleen, and bone marrow [11 – 13] .

The development of smart nanoassemblies that dynamically morph their prop-

erties due to sensitivity to chemical or physical stimuli, magniﬁ es to an even

greater extent the signiﬁ cance of block copolymer nanostructures in biological

applications. In this way, smart polymeric nanostructures can respond either to

pathological or physiological endogenous stimuli present in the body, or to exter-

nally applied stimuli such as temperature, light, or ultrasound. One sophisticated

and rational approach is a conversion of the core - forming segment of polymeric

micelles from a hydrophobic to a more hydrophilic state under a stimulus, which

causes an eventual dissolution of the micelles. The therapeutic agent should be

stably associated with the hydrophobic core, and release of the drug would be

expected to occur along with destabilization of the nanostructure. Irreversible

changes in the structure of the nanoassemblies can be induced by cleavage of the

covalent bonds, whereas reversible changes can result from changes in hydrogen -

bonding capability, in the solubility - temperature of polymers, the protonation, the

pH - sensitivity of polymers, and from changes in the redox potential.

In this chapter we will introduce smart nanoassemblies as applied to drug and

gene delivery ﬁ elds, organized in groups depending on their stimuli sensitivity.

3.3

Endogenous Triggers

3.3.1

p H - Sensitive Nanoassemblies

3.3.1.1 Drug Delivery

The mildly acidic pH of solid tumors and inﬂ ammatory tissues [14] (pH ∼ 6.8), and

the pH of the endosomal and lysosomal compartments of cells [15] (pH 5 – 6),

provides a potential trigger for the release of systemically administered drugs from

a pH - sensitive carrier, as blood and normal tissues have a pH of 7.4. Moreover,

as macromolecular carriers enter the cells via endocytosis and are localized in

94 3 Smart Nanoassemblies of Block Copolymers for Drug and Gene Delivery

the endosomes or in the lysosomes [16] , the pH represents a very useful stimulus

for the design of drug carriers that release their contents only within the intracel-

lular environment. Conversely, drug - loaded nanoassemblies that are stable at

low pH (i.e., in the stomach) and degrade at near - physiological pH (i.e., in the

intestines) are very attractive for controlled drug release following their oral

administration.

pH - sensitive nanoassemblies can be constructed by the use of an acid - labile

bond between the drug and the carrier polymer. As drug release is dependent on

the chemical or enzymatic hydrolysis of the bond between the drug and the

polymer backbone, drug release from these nanoconstructs is usually slower than

that of physically loaded drugs. Recently, pH - sensitive doxorubicin ( DOX ) - loaded

polymeric micelles were prepared by chemically conjugating DOX to the side

chain of poly(ethylene glycol) - b - poly(aspartic acid) (PEG - b - P(Asp)) copolymers via

an acid - labile hydrazone bond (Figure 3.2 ) [17] . These micelles speciﬁ cally released

DOX at endosomal pH conditions (pH 5.0), whereas DOX was retained in the

micelle core at physiological pH. These pH - sensitive DOX micelles were very

effective against subcutaneous murine colon adenocarcinoma 26 in vivo , while

their toxicity proved to be negligible due to minimal drug leakage [18] .

Gillies et al. reported the construction of PEG - b - P(Asp) functionalized with tri-

methoxybenzylidene acetals as acid - labile linkages [19] . The cyclic benzylidene

acetals and the copolymer backbone increased the hydrophobicity of the core due

to the aromatic rings, while the acetal groups hid the polarity of the diol. Although

these micelles were relatively stable at physiological pH, hydrolysis of the acetal

bonds occurred at pH 5. In addition, the generation of diols increased the

hydrophilicity of the polymers. During this process, disassembly of the micelles

occurred as the hydrophobic dye was released.

Figure 3.2 PEG - P(ASP(Hyd))/DOX conjugate forming

pH - sensitive micelles. At endosomal pH, the micelles release

DOX molecules [17] .

Geckeler K.E., Nishide H. (Eds.) Advanced Nanomaterials

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