Novel Nanotechnology-based Drug Delivery Systems

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Novel Nanotechnology-based Drug Delivery
Systems

Drug delivery in vivo is often influenced by various physiological and pathological barriers,
including hepatic metabolism, renal filtration, immune clearance, and various organ and
tissue barriers (e.g., epithelial-endothelial barrier, extracellular matrix barrier, and cell
membrane barrier). In addition, the in vivo application of conventional chemical drugs is
often limited by low solubility, short retention time, suboptimal bioavailability, and poor
targeting ability [1,2]; while large molecule drugs, such as nucleic acids and proteins, are
more susceptible to rapid degradation by various enzymes in the circulation or tissues and
lose their effectiveness [3]. Therefore, finding less toxic drug carriers that can effectively
load drugs and deliver them to the target site has become a major challenge in drug
research, especially for poorly soluble or unstable active compounds.

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Figure 1. Major biological barriers and challenges to drug delivery in vivo, source:
reference [2]

In the last few decades, novel drug delivery systems have emerged, such as polyethylene
glycol (PEG), antibody-drug conjugates (ADC), adeno-associated virus (AAV), and
nanoparticles. Nanotechnology-based drug delivery systems have now been widely
developed to improve drug solubility and bioavailability, prolong retention time, and
enhance target delivery and cellular uptake, while minimizing side effects [4].

Figure 2. Nanotechnology Classification

This article focuses on the advantages and disadvantages of several commonly used
nano-delivery systems and the progress of research.

1. Lipid based nanoparticles

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Lipid-based nanoparticles are typically spherical and consist of at least one lipid bilayer
containing at least one internal water nucleus.

1.1 Liposomes

Liposomes were first discovered in the 1960s at the Babraham Institute, Cambridge
University. Liposomes are vesicles formed by concentric lipid bilayers. Lipids are
amphiphilic molecules with hydrophilic and hydrophobic components. When lipids come in
contact with water, the interaction of the hydrophobic segment of the molecule with the
solvent leads to the spontaneous formation of liposomal forms of lipids [5].

Figure 3. Structure of liposomes

Liposomes have many advantages as drug delivery systems.

1. One of the most important advantages of liposomes is their ability to fuse with cell

membranes and release their contents into the cytoplasm, which makes them a
novel carrier system suitable for targeted delivery.

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2. Liposomes are capable of storing drugs with different physicochemical properties

and can improve solubility, bioavailability and tissue distribution of encapsulated
drugs, reducing off-target side effects.

3. Liposomes can also improve the therapeutic index of encapsulated drugs by

increasing on-target accumulation and decreasing off-target distribution of drugs.

4. Liposomes can selectively deliver cytotoxic drugs to solid tumors and are

considered as suitable candidate carriers for drug delivery and cancer therapy in
nanomedicine.

5. In addition, the high flexibility of liposome structure and the potential for chemical

modification by combining various polymers, ligands and molecules are important
for enhancing the pharmacological value of drugs and improving the effectiveness
of anticancer drugs.

Liposomes have been extensively studied and used in applications such as cancer
diagnosis and treatment, vaccines, brain-targeted drug delivery and anti-microbial
therapy.

However, liposomes also have certain disadvantages, such as short half-life in blood,
limited clearance, high cost and complicated preparation methods, which limit the clinical
application of liposomes.

Doxil® was the first liposomal drug, approved by the FDA in 1995 for the treatment
of AIDS-related Kaposi's sarcoma, breast cancer, ovarian cancer, and other solid tumors.
In the last two decades, the development of liposomal drugs has grown exponentially [6].

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Figure 4. Approved Liposomal drugs, source: reference [6]

1.2 Exosomes

Exosomes are cell membrane-like lipid bilayer vesicles naturally formed and secreted by
various types of cells, 30 ~150 nm in size, usually found in different body fluids such as
saliva, blood, urine and breast milk, containing various substances including RNA, DNA,
glycolipids and proteins.

Exosomes play an important role in intracellular information exchange by delivering
various compounds through physiological mechanisms such as antigen delivery in
diseases such as immune response, neural communication, cancer, cardiovascular
disease, diabetes, and inflammation. Since these vesicles can be isolated from the
patient's body fluids, homologous exosomes have an advantage over the immune system
in that they can easily protect the contained drug from rapid clearance and deliver it to the
target site. As a result, investigations on exosomes as drug carriers for cancer and

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autoimmune diseases, diagnostic biomarkers for cancer, and even tissue regeneration
potential are emerging.

1.3 Solid Lipid Nanoparticles (SLNs)

In lipid-based delivery systems, phospholipids are important components due to their
various properties, such as amphiphilicity, biocompatibility and multifunctionality. However,
all of them have disadvantages such as complex production methods, low encapsulation
rates, and difficulty in large-scale manufacturing, so solid lipid nanoparticles came into
being.

Figure 5. Structure of SLNs

SLNs are colloidal nanoparticles with a lipophilic nucleus consisting of a lipid matrix that is
solid at room and body temperature and first appeared in the early 1990s. Depending on

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the production method, SLNs range in size from 50 nm to 1000 nm, and the choice of lipid
also influences the drug delivery properties.

SLNs can encapsulate very high amounts of lipophilic drugs as well as hydrophilic drugs
and nucleic acids, making them versatile drug delivery vehicles. SLNs can also be
modified or loaded with proteins and antigens and further administered via parenteral
routes or alternative routes such as oral, nasal and pulmonary.

The lipid matrix improves protein stability, avoids protein hydrolysis, and releases proteins
in a controlled manner at specific sites to improve bioavailability and stability, enhance
pharmacokinetics and pharmacodynamics, and reduce drug toxicity and immunogenicity.

The SLN preparation process does not use organic solvents, which is biocompatible and
can be repeated for mass production. However, the main drawback of SLN is the drug
excretion and relatively high water content (70-99.9%) after polymer modification during
storage. In addition, the encapsulation efficiency of SLN is influenced by the solubility of
the drug in the lipid matrix, the composition of the lipid matrix, and the state of
polymerization of the lipid matrix [7].

1.4 Lipid nanoparticles (LNP)

Lipid nanoparticles are submicron capsules with an aqueous nucleus developed on the
basis of liposomes. Lipid nanoparticles encapsulating nucleic acids are commonly
referred to as LNPs and are currently the predominant non-viral gene delivery system in
clinical trials. LNPs can encapsulate many types of nucleic acids, including but not limited
to DNA, ASOs, siRNA, microRNA, and mRNA.

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Figure 6. reference [9]

Since naked RNA or DNA molecules degrade rapidly after injection, as a result they will
not accumulate in the target tissue and cannot penetrate into the target cells even if they
reach the target tissue [8]. Moreover, the immune system can recognize and destroy
carriers containing genetic information. Thus the delivery of nucleic acid drugs is a central
issue that hinders the widespread implementation of gene therapy based on RNA and
DNA polymers.

LNPs serve as a nucleic acid drug delivery system that overcomes the major obstacles in
gene therapy, namely nucleic acid degradation and limited cellular uptake. The LNPs
consist of four main components: a neutral phospholipid, cholesterol,
a polyethylene-glycol (PEG)-lipid, and an ionizable cationic lipid,

Many of the structural and biological properties of LNPs are not attributed to a single lipid
component alone, but to a combination of lipids. These components promote the
formation of monodisperse nanoparticles, improve the stability of nanoparticles, achieve
efficient nucleic acid encapsulation, and aid cellular uptake. At the same time, LNPs act
as protective capsules for nucleic acid drugs, preventing enzymatic degradation until

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nucleic acid delivery to the cytoplasm of the target cell and promoting intranuclear body
escape of nucleic acid cargo.

The LNP delivery system is critical to the success of the COVID-19 vaccine. In the
COVID-19 vaccine, the mRNA encodes an antigen, specifically a modified SARS CoV-2
spike-in surface protein, which triggers an immune response, including the production of
neutralizing antibodies. Delivering via LNP avoids eliciting an unwanted immune response
[9].

LNP technology is now a leading non-viral technology with its powerful and efficient
formulation process, as well as its advantages in potency, payload and design flexibility,
making possible the enormous potential of gene therapy.

1.5 PEGylated Liposomes

PEGylated liposomes are another important type of lipid-based nanoparticles. It consists
of two structural domains: a hydrophilic polyethylene glycol polymer bound to a
hydrophobic lipid anchor.

It can prolong the drug circulation time, as PEGylated long-circulating liposomes (stealth
liposomes), which prolong the blood circulation time of liposomes. This is because
polyethylene glycol polymers represent a spatial barrier that prevents the binding of
plasma proteins (conditioners), which not only evade capture by the reticuloendothelial
system, but also improve passive targeting.

It is now widely used in liposome formulations. PEGylation is considered to be the most
successful method to achieve extended cycling of nanoformulations, but repeated doses
of PEG-modified liposomes accelerate their clearance in vivo, which is mediated by
specific anti-PEG IgM. The modification of functional molecules leads to a non-T

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cell-dependent acute immune response. Therefore its clinical application still faces many
challenges.

2. Polymer-based nanoparticles

Polymer-based nanoparticles can consist of biodegradable and biocompatible polymers.
Many nanoparticles exist in polymeric form, such as dendrimers, micelles, protein NPs,
nanogel, etc. Synthetic or natural polymer-based nanoparticles are biocompatible,
non-immunogenic, non-toxic and biodegradable.

2.1 Micelles

In a specific environment, some molecules containing both hydrophilic and hydrophobic
groups can self-assemble, isolating their non-polar regions from the aqueous phase or
isolating their polar regions from the organic phase, resulting in a variety of structural
phases, such as micelles, vesicles, microemulsions, liquid crystal dispersions, etc. These
self-assembled particles are dispersed in the solvent in a thermodynamically stable state,
ranging in size from a few nanometers to tens of nanometers, and can be used as carriers
for a variety of drugs.

Figure 7. Self-assemble drug delivery system, source: reference [11]

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Micelles are generally the simplest conjugated structures of amphiphilic molecules
commonly found in solution. Micelles are formed spontaneously by amphiphilic or
surfactant molecules under certain concentration and temperature conditions, and their
molecules consist of two regions with different properties, which have opposite affinities to
their solvent. When micelles are used as drug carriers for aqueous phase media, insoluble
non-polar drug molecules can be wrapped inside the core of the micelle, while polar
molecules are adsorbed on the outer shell of the micelle.

Diblock polymers, triblock polymers, multiblock polymers, graft polymers, and
stimuli-responsive polymers can form different types of monopolymeric micelles, which
act as drug carriers to promote the dissolution of hydrophobic molecules, prolong the
release of various drugs, and prevent the rapid clearance of the reticuloendothelial
system.

Hybrid polymeric micelles are combinations of two or more amphiphilic molecules, such
as lipid bilayers that dissolve and form hybrid micelles composed of surfactants and polar
lipids after the addition of surfactants. Hybrid micelles also have more potential for
development in terms of in vivo stability, drug loading and regulation of drug uptake and
release [10].

The advantages of micelles as drug carriers are [11].

1. Increased drug solubility and improved bioavailability of drugs.
2. Reduction in drug toxicity and other adverse drug reactions.
3. Modification of drug biodistribution by enhancing drug permeability and helping to

cross physiological barriers.

4. Extended half-life of drugs in the circulation.

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5. Enhanced tissue interstitial permeability and passive targeting of drugs with the

help of high permeability and retention effect of leaky vascular system.

6. Effectively protect the drug activity in vivo and avoid the side effects of the drug in

non-target tissues.

At present, micelles have been widely used as drug carriers for small molecule drugs,
nucleic acid drugs, peptides and protein drugs, etc. The routes of administration include
oral, injectable, transdermal, oral and nasal administration, involving antitumor therapy,
treatment of neurological diseases, fungal infections, diabetic-induced keratopathy and
other fields.

Figure 8. Application and development of micelles

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Conclusion

Drug delivery systems have a wide range of applications. In recent years,
nanoparticle-based drug delivery has made significant progress in disease treatment. A
large number of clinical trials based on nanomedicine technologies are underway, with
liposome-based drug delivery systems accounting for the majority of clinical trials. The
development of drug delivery systems with novel delivery systems requires the synergistic
support of multiple assay technology platforms (mass spectrometry, immunoassay, cell
biology, and molecular biology platforms, etc.), making the development of bioanalytical
technologies a long way to go.

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Protein and Peptide Drugs, AAPS PharmSciTech 20 (2019) 190.

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