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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5604_Библиотеки_им_академика_М_И_Перельмана.pdf
Carbon Nanomaterial-Incorporated Supramolecular Drug Delivery 135
dimensions, with lengths spanning from 5 to 100 mm and diameters ranging from 5
to 100 nm [41].
Carbon nanofibers (CNFs) possess a distinctive combination of structural characteristics, characterized by many infinitesimal and slender pores, rendering them
highly suitable for the sequestration of minute organic molecules [42]. This concept’s
underlying principle posits that the graphite platelets’ nonpolar basal regions
comprising the nanofiber structure are highly susceptible to establishing a robust
interaction with the organic impurity. Nonetheless, the adsorption of water molecules
is unlikely to occur at these specific sites, resulting in the material serving as a
discerning adsorbent [43]. The capacity to customize the structural attributes of
carbon nanofibers (CNFs) in a manner that confers upon the final product the distinctive dual characteristics of elevated surface area, conventionally linked with active
carbon, and a remarkable degree of crystalline perfection, akin to graphite, thereby
engendering high electrical conductivity, renders these materials highly suitable for
deployment as support media [44].
2.3 Graphene
Graphene is a two-dimensional material of carbon atoms arranged in a hexagonal lattice configuration. An important turning point in science was reached in
2004 with the isolation and characterization of graphene. Graphene has attracted
significant attention and generated great interest since its initial discovery, mostly
due to its exceptional qualities and potential for diverse applications. The emergence of novel quasi-particles is observed due to the intricate interaction between
electrons and graphene. This course’s key components of highest importance are
graphene nanoribbons and quantum dots. The particles demonstrate ballistic transport, a phenomenon in which electrons can travel distances of up to one micrometer
without encountering any scattering events [45]. Graphene demonstrates exceptional
electrical conductivity. The substance demonstrates a reduced degree of solubility in
aqueous solutions. As a result, several modifications have been introduced to generate
chemically modified graphene derivatives, such as layered graphene oxide (GO) and
graphene oxide. The application of graphene oxide (GO) and its derivatives in sol–
gel chemistry has been extensively utilized, particularly in producing biocompatible
nanocomposites [46].
Graphene (Fig. 1) and its related substances have been widely employed in
advanced medicine and drug delivery. Applying polymer surface modification to
graphene nanomaterials is a common technique utilized to enhance their compatibility with biological systems. Graphene nanomaterials exhibit responsiveness
toward various stimuli, including but not limited to magnetic fields, electric fields,
radiation, temperature, and pH. The regulation of drug release was achieved through
the management of stimuli that are internal as well as external. These stimuli
enhance the bioavailability of drugs, facilitate their crossing of biological barriers,
and mitigate their adverse effects [47].
136 N. T. Tuli et al.
Fig. 1 Schematic overview of various applications of graphene. Reproduced with permission from
Elsevier [48]
2.4 Carbon Quantum Dots
Carbon quantum dots (CQDs) are nanoscale carbon nanoparticles with dimensions
ranging from 1 to 10 nm (nm). In contrast to graphene or carbon nanotubes (CNTs),
these structures possess zero-dimensional characteristics. They exhibit pronounced
fluorescence and distinctive characteristics in optics, electronics, and chemistry.
The applications, such as optoelectronics, sensing, bioimaging, and drug delivery,
have garnered considerable interest [49]. The techniques utilized for synthesizing
CQDs can be categorized into two distinct classifications: “bottom-up” and “topdown” methodologies. These objectives may be attained by employing chemical,
electrochemical, or physical methods. Top-down strategies cover a range of techniques, including arc discharge, laser ablation, and electrochemical approaches,
which are employed to break down carbon materials into carbon nanoparticles
[50]. Contrarily, bottom-up strategies include template strategies, thermal pathways,
pyrolytic processes, hydrothermal and aqueous methods, supported synthetic techniques, reverse micelle techniques, microwave-assisted strategies, and substance
oxidation [51].
Carbon Nanomaterial-Incorporated Supramolecular Drug Delivery 137
2.5 Fullerene
Fullerenes are carbonaceous compounds with a distinctive molecular architecture characterized by carbon atoms’ cage-shaped or spherical configuration [52].
2
Fullerenes are special compounds with unusual features due to their sp
structure. These molecules, like C
and C76, have a cage-like shape that is unusually
60
carbon
symmetrical for their size. The synthetic fullerene that is most frequently encountered is C
, consisting of a total of 60 carbon atoms that are organized in a pattern
60
of 12 pentagons and 20 hexagons. These carbon atoms are interconnected by single
bonds (C5–C5) and double bonds (C5=C6). It is worth mentioning that each fullerene
structure consists of ‘n’ hexagons, wherein the number of carbon atoms is equal to
2n + 20. The concentration of C
has a dual behavior among reactive oxygen species (ROS), which allows it to
C
60
operate differently depending on the context [53]. For instance, C
and C70, formed at 1000°C, increases over time.
60
can produce
60
oxygen upon being exposed to ultraviolet (UV) rays, making it an appealing option
for photodynamic therapy (PDT) [54].
2.6 Carbon Nanohorns
A special type of carbon nanostructure known as a carbon nanohorn (CNH) (Fig. 2)
is distinguished by its horn-like morphology. The carbon nanomaterials, including
graphene, fullerenes, and carbon nanotubes (CNTs), belong to the same family as
the subject in question [55]. Curved graphene sheets are stacked into a conical or
horn-like structure to make CNHs. These objects have a porous surface of graphene
edges and a hollow interior. CNHs come in various diameters, typically between a
few nanometers and several micrometers in diameter [56]. One of its key characteristics is the high surface area that carbon nano horns possess due to their distinct
form. The huge surface area of these materials makes them highly appealing for
several applications, such as energy storage, catalysis, drug administration, and
sensors [57]. Various methods, including arc discharge, laser ablation, and chemical vapor deposition (CVD), can be employed to synthesize carbon–nitrogen hybrid
materials (CNHs). These techniques enable the control of the final CNHs’ size, shape,
and surface characteristics.
2.7 Carbon Nano-Onions
Carbon nano-onions (CNOs) are a specific class of fullerene characterized by the
arrangement of graphitic layers in a quasi-spherical or polyhedral configuration,
exhibiting a remarkably s mall interlayer gap. Distances between graphitic layers
(0.335 nm) and graphitic planes (0.334 nm) are quite close to one another [59].
138 N. T. Tuli et al.
Fig. 2 Functionalization of carbon nanohorns. Reproduced with permission from John Wiley and
Sons [58]
Production methods for carbon nanoparticles have been documented extensively.
Nevertheless, the prevailing methodologies employed in the production of these
materials encompass arc discharge conducted between two electrodes immersed in
a water medium, pyrolysis, ion implantation, chemical vapor deposition (CVD),
thermal annealing of ultra-dispersed nanodiamonds, thermal annealing of ultradispersed nanodiamonds and electron-beam irradiation. The size, form, polyhedral arrangement, and core composition (whether dense or hollow) of the resulting
nanostructures exhibit variations contingent upon the specific preparation procedure
employed for the onion-like structures. The distinct multilayered architecture of
carbon nano onions (CNO) is because each layer comprises very few carbon atoms.
Size and properties can vary since the number of layers might range from very few
to very many [60].
Carbon Nanomaterial-Incorporated Supramolecular Drug Delivery 139
2.8 Nano-Diamond
Carbon atoms are arranged into tiny diamond-like nanostructures called carbon
nanodiamonds. These entities are sometimes known as diamond nanoparticles or
nanodiamonds. Typically, their dimensions span from only a few nanometers to
several tens of nanometers. Diamond is a special kind of carbon with outstanding
qualities like extreme hardness, high thermal conductivity, and superior optical qualities. These characteristics are improved even more at the nanoscale and provide
extra benefits for a variety of applications [61]. Carbon nanodiamonds can be
produced using several methods, such as high-pressure techniques, chemical vapor
deposition (CVD), high-temperature (HPHT) treatment, and high-pressure techniques, explosion-based processes. Nanodiamonds made using each technique have
unique properties, such as the size of particles, functionalization of the surface, and
crystal quality. These nanoparticles find extensive utilization across diverse domains,
such as medicinal applications, quantum sensing and computation, energy storage,
mechanical reinforcement, and optical applications [62].
3 Supramolecular Chemistry in Drug Delivery
3.1 Principles of Supramolecular Chemistry
Supramolecular chemistry studies (supra)molecular phenomena between inorganic,
organic, and physical chemistry. It is commonly described as the “molecular science
of information encoding and processing” [63]. Using this concept to create massive
ensembles of molecules, supramolecular chemistry bridges the gap between the
picometer size of molecules and the nanoscale world. Thus, the principles of
nanotechnology’s chemical “bottom-up” approach must be understood. Supramolecular interactions constitute the foundation of many fundamental biological processes,
including cell division, signal transmission, biocatalysis, memory formation, and
data processing. Simple self-assembly mechanisms are responsible for most of the
construction of enzymes, membranes, viruses, and many other complex structures
with physiologically important activities [64]. Metallo phthalocyanines and metalloporphyrins are outstanding precursors in supramolecular chemistry, and their rapid
evolution led to assemblies with varied topologies and features (electro-, photo- and
catalytic capabilities, etc.) [65]. The fundamental principles of host–guest chemistry are revealed by the “lock and key” interaction between enzymes and the
chemicals that support them. Most drug-receptor interactions in medicine occur at
the supramolecular level [66]. Supramolecular medicine was developed due to the
convergence of molecular assembly and supramolecular chemistry, two domains that
have traditionally worked in silos [67]. It can be defined as developing supramolecular formulations of diagnostic and therapeutic substances for disease diagnosis,
prevention, and treatment. After progressing from the development, we have arrived
140 N. T. Tuli et al.
at the stage where we can create adaptable materials, morphing with spatiotemporally sensitive features [68]. Supramolecular chemistry’s fundamental principles
and concepts encompass several terms, such as non-covalent contact, molecular
recognition, and self-assembly.
3.1.1 Non-covalent Interactions
Reversible development and disassembly of supramolecular aggregates rely on
noncovalent interactions among the molecular ingredients of the building. Small
(binding energy 1–10 kcal/mol) non-covalent interactions include solvent effects
(e.g., hydrophobicity), stacking, dispersion, cation interactions, and dipole–dipole,
whereas large (binding energy 10–90 kcal/mol) noncovalent interactions include
coordinative and electrostatic interactions. Inductive and dispersive attractive forces
form a weak covalent bond. Electrostatic interactions are compelling due to the attractive force between oppositely charged dipoles or ions. Hydrogen-connected arrays
have a high degree of stability due to the cumulative effect of multiple hydrogen
bridges despite the individual binding energy of each bridge being very moderate
[69]. Within supramolecular chemistry, the contact of metal coordination is regarded
as a “noncovalent” interaction, although often encompassing a substantial covalent element in the binding process. Both “stability” and “lability” are required in
ligand–metal interaction. Sometimes, it is referred to as “Metallo supramolecular
chemistry,” this field studies molecules that contain metal ions. Recently, reversible
covalent bonds like esterification, disulfide, or imine synthesis have been integrated
into the dynamic combinatorial chemistry framework, expanding supramolecular
chemistry capabilities [64].
3.1.2 Molecular Recognition
Molecular recognition occurs when two molecules interact because their electronic
and geometric characteristics are complementary. The lock and key principle, as seen
in Fig. 3, involves the insertion of a solid substrate into a solid receptor, analogous to
fitting a key into a lock. This model oversimplifies molecular recognition events and
does not represent the real thing perfectly. Dynamic behavior with rapidly balancing
forms is a common feature of molecules. A flexible molecular species chooses a
single geometry after interacting with other species. The classic lock and key principle
defines the interplay between pieces, which is determined by their preorganization
(form) and stiffness. When examining the distinctions between molecular recognition
and supramolecular chemistry compared to many examples in traditional “covalent
chemistry,” entropy emerges as a pivotal factor. The concept of the lock-and-key
model served as the foundational principle for the field of host–guest chemistry.
The discovery that metal cations serve as templates to produce crown ethers and
that the ethers can selectively complex the cations led to a rich new study area. The
complementarity of species is not the only factor in a host’s ability to selectively bind
Carbon Nanomaterial-Incorporated Supramolecular Drug Delivery 141
Fig. 3 The lock and key
principle, wherein the lock
governs a receptor while the
grooves complement the key,
corresponding to the
substrate. Reproduced with
permission from ACS [70]
its molecular guests. The oxygen donors in crown ethers typically take an “outward”
conformation, where they can interact with polar solvents. When introducing a cation,
the donor atoms must rearrange themselves to face the enclosed metal ion. As a result,
the lock and key idea cannot be taken at face value but rather must be evaluated with
other “induced-fit-mechanisms.”
Host-guest chemistry now studies the interaction of cations, neutral compounds,
and anions. Ion pairs are useful for extracting harmful wastes or enriching valuable
compounds from mixes. Host-guest chemistry also affects modern sensor technologies. In supramolecular chemistry, molecular identification pertains to the initial
interactions between host and guest molecules, particularly those involving simple
crown cryptand-type compounds. However, this phenomenon also affects other
biological processes when a receptor and substrate interact.
3.1.3 Self-Assembly
Rigorous self-assembly holds paramount importance in supramolecular chemistry,
but directed (templated) self-assembly is also frequently observed. The process of
strict self-assembly promptly results in the formation of a precisely defined aggregate.
The use of templates or alternative mechanisms for species control in guided selfassembly. In ideal scenarios, self-assembly has a cooperative nature. The aggregate
acquired exhibits thermodynamic stability, surpassing other species with differing
structures and compositions. Self-assembled aggregates depend heavily on component geometry. Symmetry allows incommensurate binding sites or building block
geometries to develop huge container-type molecules that resemble Platonian or
Archimedean solids [71]. In an ideal instance, two or more molecular components
should aggregate due to an alteration in enthalpy, corresponding to bond energy
provided by bond formation. Entropy should discourage aggregation since only one
species is created from many, resulting in a highly ordered aggregate. Environmental
variables like solvents must be addressed. Dissociating solvent molecules from single
units during aggregation makes oligomerization entropically favorable. The enthalpy
contribution is reduced to the differential between solvent molecules and complimentary moieties. Most assemblies have small thermodynamic differences. Secondary
stabilizing factors, including conformational constraints, templating, and others, help
produce one well-defined species.
142 N. T. Tuli et al.
Figure 4 depicts the host’s four binding pockets, focusing on a central guest
binding pocket. Biological systems like substrates and enzymes comprise host-guest
complexes. Large (usually macrocyclic) ligands host metal cations in coordination
chemistry. A host with a stable molecular cavity and sites for binding guests can
accommodate guests both in solution and in the solid state. Solid-state architectures
and solutions will likely be equivalent. Solid-state inclusion compounds behave as
crystalline solids since their guest remains trapped in a cavity created by a hole in
the host lattice [70].
Fig. 4 The development of a supramolecular structure utilizing the following molecular building
pieces (binding positions shown as circles): a host-guest complexity, b lattice inclusiveness, and
c corresponding molecule self-assembly. Reproduced with permission from ACS [70]
Carbon Nanomaterial-Incorporated Supramolecular Drug Delivery 143
3.2 Advantages of Using Supramolecular Structures in Drug
Delivery
Supramolecular interactions, which can be tuned and reversed, give materials ranging
from nano- through macroscopic sizes to provide a wide range of desirable characteristics. Supramolecular biomaterials provide many advantages over conventional
biomaterials, some of which are described below (mechanical tunability, modularity,
biomimicry, and responsiveness).
3.2.1 Mechanical Tunability
The traditional network concept of polymeric gels enables modification of distance
or crosslink density to tune the mechanical characteristics of covalently polymeric
substances. The concepts discussed can be effectively utilized in the development of supramolecular polymers. Adjusting the ratio of self-assembling subunits
or including a molecular identification pattern in the polymer framework makes
it possible to manipulate the material properties with relative ease. The macroscopic features of polymeric systems can be controlled by rationally designing
recognition patterns that use diverse and synergistic supramolecular interactions
[72]. Supramolecular interactions are constantly changing and limited by association/dissociation timeframes. Whether via supramolecular motif stacking or interchanging molecular recognition, the lifespan of a bonded complex and active and
inactive contacts might affect the material’s behavior. Hence, the mechanical characteristics of supramolecular materials are influenced by various parameters, including
the polymer’s molecular weight (or the effective length of a one-dimensional
assembly), the manner of binding, the valency and spacing of interacting units,
and both the kinetics and thermodynamics of the binding process. The generation of
anisotropy can be achieved through the precise alignment of the components of materials, while the cytocompatibility can be modified by adjusting the binding forces.
These capabilities apply to materials with long-range directionality.
3.2.2 Modularity
Systems can be built by conjugating several capabilities, including supramolecular
interaction specificity, without affecting thermodynamics, self-assembly, or kinematics. This enables the development of modular and universally applicable material
platforms assembled in a “mix and match” fashion without altering the fundamental
material characteristics. Supramolecular materials, such as stacking and polymeric
cross-linking motifs, have a modular structure that allows fine-tuned manipulation
of composition, bioactivity, functioning, and “multiplexing” signals or targeting
groups. Maintaining the character of the supramolecular motif is essential when
adopting a mix-and-match strategy; this includes ensuring that all molecules share
144 N. T. Tuli et al.
the same equilibrium constant Keq. This strategy has been used for nanoparticles,
two-dimensional substrates, and hydrogels to create biomaterials with many functions [73]. Modularity in the supramolecular design allows for easy adaptation to
various targeting ligands or bioactive epitopes through straightforward adjustments
to the formulation ratios of individual components. Large proteins are built using
peptide-linked-sheet motifs as linear fiber-building elements (Fig. 5).
Fig. 5 Hydrogels and nanostructures made of recombinant proteins. a Recombinant proteins (fluorescent proteins) with a -sheet-fibrillating domain and short oligopeptides can form self-assembling
peptide nanostructures with gradated and ratiometric protein integration. b Mixing GFP, dsRed,
and eGFP ratio-metrically gives the hydrogel a progressive color. Mutating the sheet-fibrillating
fusion domain (Tmut) changes hydrogel color, showing that this domain is important for protein
inclusion. Reproduced with permission from Nature Materials [74]