The Evolution of 5 Therapeutic Drug Delivery Technologies

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The Evolution of 5 Therapeutic Drug Delivery
Technologies

Drug delivery technologies have enabled the development of many drugs that improve
patient health by enhancing the delivery of therapeutic agents to their target sites,
minimizing off-target accumulation, and promoting patient compliance.

A few decades ago, small molecule drugs were the main therapeutic agents. Since the
delivery of small molecule drugs depended heavily on their physicochemical properties,
which severely affected their bioavailability, research in delivery focused on how to
improve the solubility of drugs, control their release, expand their activity and tune their
pharmacokinetics (PKs). Over time, a new generation of therapeutic agents, including
proteins and peptides, monoclonal antibodies (mAbs), nucleic acids and live cells, has
offered new therapeutic possibilities. New therapeutic approaches pose additional
challenges, particularly in terms of stability (especially for proteins and peptides),
intracellular delivery requirements (especially for nucleic acids), and survival and
expansion (for live cells). Drug delivery strategies must evolve to meet these challenges.
This article will outline key innovations in five classes of therapeutic agents-small
molecules, nucleic acids, peptides and proteins, monoclonal antibodies (mAbs),
and live cells-and their clinical and commercial success.

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Figure 1: Therapeutic delivery challenges & delivery paradigms for improved therapeutic
function, Image source: Refernce 1

Small molecules

Small molecule drugs, such as chemotherapeutic agents, antibiotics and steroids, have
been identified, developed and used as drugs since the late 19th century. Due to the
smaller molecular weight of small molecule drugs, they can diffuse rapidly across many
biological barriers and cell membranes. These advantages allow small molecules to
diffuse through complex vascular systems and interact with virtually all tissues and cell
types in the body. However, in order to diffuse rapidly and enter the systemic vascular
system, small molecules must be freely soluble in biological fluids; therefore, this limits the
therapeutic effects of insoluble molecules. Approximately 90% of preclinical drug
candidates are low solubility compounds, so this remains a challenge. Strategies to
overcome low bioavailability have focused on improving drug solubility by modulating the
local microenvironment, particularly through the use of pH modifiers for small molecules
with considerable pH-dependent solubility. This has led to clinical success, as in the case
of intravenous ciprofloxacin, which is formulated with lactic acid to improve its solubility by
adjusting pH. Other strategies focus on altering the small molecules themselves to

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modulate their physicochemical properties to improve solubilization, diffusion, or
absorption.

Understanding how drugs are transported through the fasculature and into tissues or cells
led to the establishment of PK and pharmacodynamic (PD) principles. As the relationship
between PK/PD parameters and the efficacy, duration of action, and toxicity of small
molecule drugs became clearer, early efforts focused on controlling dose and dosing
regimens (i.e., infusion frequency and infusion rate) to improve drug efficiency. These
pioneering PK studies and clinical studies laid the foundation for the design of predictable
drug release kinetic systems that employ the following four drug release mechanisms:
dissolution, diffusion, osmosis, and ion exchange. Regulatory agencies have approved at
least 16 drug delivery systems based on osmotic release oral systems (the use of osmotic
pumps reduces the side effects associated with large changes in drug concentrations
caused by conventional dosing).

In addition, non-invasive controlled release systems, such as transdermal delivery
systems, have facilitated the long-term use of analgesics and smoking cessation agents,
thereby improving patient compliance. Systems based on nanoparticles and
microparticles have been used to overcome solubility challenges, allowing small
molecules to be transported to their site of action and reducing off-target side effects.
Nanoparticle therapies have been approved for a wide range of indications, from cancer
treatment to vaccination. The use of polyethylene glycol (PEG) has been found to be an
effective technique for extending the circulating half-life of particles and increasing particle
retention at the tumor site. This led to the formulation of PEGylated liposomal doxorubicin
(Doxil), the first nanoparticle therapy approved by the FDA in 1995. Since then,
nanoparticles have been extensively studied preclinically to address the challenges of
site-selective drug delivery. Delivery systems are now widely used to control the solubility,
dose, and other delivery parameters of small molecules, and subsequently for other
therapeutic agents.

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Peptides and proteins

Although drug delivery is based on the need to design for small molecules, their targets
represent only 2-5% of the human genome. Therefore, other therapeutic approaches are
needed. Peptides (2-50 amino acids) and proteins (50 or more amino acids) are extremely
selective for specific protein targets. Their size and diverse tertiary structures increase the
number of contact points with specific protein pockets, giving peptides and proteins higher
potency and lower toxicity than many small molecules. With the increased clinical use of
peptides and proteins, unique challenges limiting their delivery have emerged. Although
the complex structure of peptides and proteins improves their potency and selectivity
relative to that of small molecules, this also results in their poor stability. They are readily
degraded under environmental storage conditions, and in vivo, they are sensitive to
ubiquitous proteases, physiological temperature, and pH changes. In addition, peptides
and proteins can activate the immune system through the immunogenicity of antigens on
the protein structure or through their degradation, aggregation or post-translational
modifications. This usually leads to rapid clearance of the drug and immunogenicity-driven
adverse events.

To overcome structural challenges, synthetic or humanized peptide analogs incorporate
unnatural amino acids or are linked to chemical fractions known to improve the half-life,
stability, receptor affinity, or toxicity of a peptide or protein. An example of the clinical
success of these efforts is desmopressin (DDAVP), an analogue of the natural peptide
therapy vasopressin (Vasostrict) but with a better half-life and stability.

The most successful strategy for reducing the immunogenicity of the protein and
extending its half-life is the use of PEG. PEGs can shield immunogenic epitopes
and increase the hydrodynamic diameter of the drug, thereby reducing its renal
clearance and prolonging its circulating half-life. Another strategy is to modulate the
microenvironment by introducing protease inhibitors that interfere with the degradation of
peptides or proteins in physiological fluids.

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Another strategy is to regulate the microenvironment by introducing protease inhibitors
that interfere with the degradation of peptides or proteins in physiological fluids. Peptides
and proteins exhibit size-based limitations in penetrating biological barriers due to their
size. This inspired the development of permeation enhancers (e.g., sodium
N-[8-(2-hydroxybenzoyl) amino caprylate]; SNAC) that modulate the microenvironment to
buffer gastric local pH or to positively improve transcellular absorption of peptides or
proteins. This strategy led to the approval of the first oral glucagon-like peptide
(GLP-1), semaglutide (Rybelsus) (Figure 2).

Figure 2: Amino acid-modified peptide with permeation enhancer (Rybelsus)

Antibodies

Antibodies are the dominant therapeutic agents today, with nearly 100 antibody drugs
currently approved. The structure of antibodies, which differs significantly from that of
other biological classes, allows for specific interactions between the therapeutic target and
the immune system. By binding to the target antigen, antibodies can neutralize it and
prevent signaling molecules from binding to it to initiate undesired cellular processes. In
addition, antibodies can interact directly with host immune cells to initiate phagocytosis,
antibody-dependent cytotoxicity, or complement-dependent cytotoxicity, thereby
triggering the death of undesirable cell populations. However, the unique characteristics of
antibodies capable of achieving these specific interactions may also lead to the production
of anti-antibodies, which may result in adverse events such as injection site rash, flu-like
symptoms and the development of autoimmune diseases. Muromonab-CD3 (OKT3) is an
example of this, being the first clinically approved (1986) murine-derived mAb, but it

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caused immune present-related adverse events. The drug was discontinued in 2010 after
better treatments entered the market. Subsequently, approval of antibody therapies was
delayed until the first decade of this century due to the immunogenicity of murine-derived
antibodies. During this decade, advances in antibody manufacturing allowed for changes
in the antibody structure itself allowing for the production of the first humanized
therapeutic antibody, daclizumab (Zinbryta), and the first fully human antibody,
adalimumab (Humira), produced through phage display technology, to be approved. In
addition, direct modification of the therapeutic antibody by PEGylation, a strategy
previously established for peptides and proteins, led to clinical approval of Certolizumab
pegol (Cimzia) in 2008.

Because the PK/PD of antibodies can be highly variable and their mechanism of action is
dependent on contact with the dynamic immune system, antibody therapy often requires
high doses and invasive administration. A delivery strategy that uses hyaluronidase to
modulate the local microenvironment by remodeling the subcutaneous gap has made
possible the subcutaneous injection of high doses of antibodies and their subsequent
absorption. This battle strategy led to the commercialization of hyaluronidase-based
antibodies.On February 28, 2019 the FDA granted marketing approval for
trastuzumab/hyaluronidase-oysk under the trade name Herceptin Hylecta. This novel
complex uses hyaluronidase to deliver trastuzumab ( Herceptin), facilitating its enhanced
dispersion in the subcutaneous space through hyaluronan degradation, thereby allowing
for greater injection volume and subsequent systemic absorption (Figure 3).On May 1,
2020, the FDA approved Darzalex Faspro, a subcutaneous dosage form of Johnson &
Johnson's CD38 antibody Darzalex. By replacing intravenous infusions with
subcutaneous injections, this system improves patient acceptance and convenience.

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Humanized mAb containing hyaluronidase for subcutaneous reconstruction (Herceptin
Hylecta)

Continued advances in small molecule and antibody modifications have led to the
development of antibody-drug conjugates (ADCs), which combine antibodies with
cytotoxic small molecules that can be administered in a highly targeted manner while
providing synergistic immunomodulatory functions.

Nucleic acids

While protein and peptide therapies have greatly expanded the number of available drug
targets, nucleic acids are capable of precisely controlling gene expression and can
therefore be used to silence or repair aberrant genes and drive expression of
therapeutically relevant genes. Because of the specific binding of nucleic acid sequences,
nucleic acids and gene editing tools, such as CRISPR, can be rationally designed to
therapeutically manipulate the human genome. fomivirsen (Vitravene), an antisense
oligonucleotide therapy (ASO) approach, was approved by the FDA in 1988 for the
treatment of cytomegalovirus retinitis complicated by AIDS patients. demonstrated the
potential of nucleic acid therapy. However, due to the inherent challenges of nucleic acid
delivery, the clinical success of first-generation ASO therapy was limited due to
insufficient levels of genetic suppression.

The susceptibility of naked nucleic acids to degradation by nucleases and the expertise of
the human immune system in recognizing and removing foreign RNA and DNA limit their
half-life. In addition, nucleic acids need to be transported into the cytoplasm or nucleus of
the cell, thus requiring cellular internalization and endosomal escape. These challenges

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have led to innovations in the chemistry of modification of nucleic acid bases, sugar rings,
and the 3' and 5' ends of nucleic acids. This has enabled nucleic acid drugs to resist
nuclease degradation, reduced immunogenicity, and improved interactions with target
cells.In 2016, the next generation ASO drug Nusinesen (Spinraza) became the only
clinically approved drug for the treatment of spinal muscular atrophy. Preclinical
environmental manipulation can improve the intracellular targeting of nucleic acids. For
example, nucleic acid carriers can buffer cytosolic pH or form lipid complexes with the
cytosolic membrane, leading to cytosolic escape and cytoplasmic translocation. In
addition, cell-penetrating peptides have been used to disrupt or reorganize the inner
membrane to improve intracellular delivery of nucleic acids.

Advances in chemical modification of nucleic acids and drug delivery systems have also
led to the approval of siRNA therapies. 2018 saw the approval of Patisiran (Onpattro), the
world's first siRNA therapy, for the treatment of adult patients with hereditary
transthyretin-mediated amyloidosis polyneuropathy. It is a lipid-based nanoparticle
containing chemically modified siRNA for cellular targeting, uptake and endosomal
escape (Figure 4).The successful development of Onpattro was made possible by
decades of research into small molecule liposome formulations, optimization of
lipid-based nanoparticle size, charge and chemistry, and the use of PEGylation to improve
drug PK.

Chemically modified siRNA with ionizable lipids for endosomal escape (Onpattro)

More recent advances in nucleic acid delivery have been highlighted by the emergency
use authorization of the COVID-19 vaccine, which is based on chemically modified mRNA
delivered via PEGylated stabilized lipid nanoparticles.

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Live-cell therapy

Live cells are a new generation of therapeutic approaches that regulate or initiate key
biological processes by harnessing the natural therapeutic functions of certain cell types.
For example, pluripotent stem cells can restore and heal tissues, and reprogrammed
immune cells can harness the immune system for vaccination and cancer treatment.
Living cells can also be modified. The most successful examples are CAR-T cell therapies,
several of which have now received market approval. CAR-T cell therapies highlight the
features and benefits of cellular therapies: the innate ability to target disease sites, the
powerful activity at the site of action, and the ability to interface directly with the immune
system and to proliferate in the living body. Other FDA-approved adoptive cell therapies
are sipuleucel-T ( Provenge; for the treatment of prostate cancer) and cord-blood-derived
stem cells.

The delivery of live cells presents unique challenges. Cells are much larger than all other
types of therapeutic agents and thus can be rapidly trapped in lung capillaries and
eliminated. For pericyte therapies (especially immunotherapy), the size of live cells and
the hostile tumor microenvironment result in low cell penetration in solid tumors. This has
limited their current clinical application to hematologic malignancies. Furthermore, the
survival, persistence and maintenance of an effective cell phenotype are highly
dependent on the environment and host in which the cells reside. There are also
pragmatic issues related to the mass production of therapeutic live cells. On the one hand,
autologous therapies have a more favorable safety profile but require extraction,
processing and reinfusion from the same patient, which limits the scalability of the therapy.
On the other hand, allogeneic therapies can be more easily scaled up, but require
cold-chain storage and transport with stringent biocompatibility and sterility requirements.
Provenge faces challenges associated with its manufacture and administration after
approval, and its high cost and short shelf life hinder its widespread clinical adoption.
Many other live cell therapies need to overcome similar challenges. While cellular

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therapies remain challenging, we believe that they will improve over the next decade as
drug delivery technologies continue to advance.

Conclusion

With the development of small molecule drugs, proteins and peptides, antibodies, nucleic
acids and more recently live cell therapies, drug delivery systems have been passed down
with generations. Delivery challenges for each therapeutic approach have now been
improved through drug modifications and microenvironmental modifications (Figure 5).
During the development of drug delivery, established delivery methods have been applied
to improve emerging therapeutics, and with the development of novel drug delivery
systems, drug delivery technologies are playing an increasingly important role in the
treatment of cancer. As cancer treatment becomes more complex, there is still a need for
more refined drug delivery systems that can deliver multiple drugs with different chemical
compositions simultaneously.

Biochempeg provides a variety of PEG products or activated PEG derivatives, that are
crucial ingredients in the art of PEGylation. Biochempeg's dedicated and experienced
PEGylation group meets your unique PEGylation needs for proteins, peptides,
oligonucleotides, and small molecules. For detailed information about our PEGylation
services, please contact us at [email protected].

References:
1.The evolution of commercial drug delivery technologies.
2.Basics and recent advances in peptide and protein drug delivery.
3.Recent technologies in pulsatile drug delivery systems.
4.Drug delivery systems: an updated review.

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