Release date:2021/7/15 9:56:18

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.

therapeutic  delivery challenges & delivery paradigms for improved therapeutic function
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 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.      

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.

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 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 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.

Humanized mAb containing hyaluronidase for subcutaneous reconstruction   (Herceptin Hylecta)
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 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.

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


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

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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