Harvard University Academician Mitragotri: Pointing out the direction for drug delivery research

Drug delivery system refers to a technical system that comprehensively regulates the distribution of drugs in organisms in space, time and dosage. The goal is to deliver the right amount of medicine to the right place at the right time, thereby increasing the utilization efficiency of the medicine, improving the efficacy, reducing the cost, and reducing the toxic side effects. With the development of the treatment field, the drug delivery strategy and technology quickly adapt to Reflect the ever-changing demand for drug delivery.

Decades ago, small molecule drugs were the main category of treatment. Since the release of small molecules largely depends on their physical and chemical properties, which seriously affects the bioavailability of the drug, the release work is first to improve the solubility of the drug, control its release, expand its activity, and adjust its pharmacokinetics. dynamics.

Over time, a new generation of treatment methods, including proteins and peptides, monoclonal antibodies, nucleic acids and living cells, have provided new therapeutic functions. New functions bring additional challenges, especially in terms of stability (proteins and peptides), intracellular delivery requirements (nucleic acids), and viability and expansion (living cells). To meet these challenges, drug delivery strategies must continue to evolve.

In this review article, Harvard University Samir Mitragotri  and others evaluated the delivery challenges associated with five types of therapeutic drugs (small molecules, nucleic acids, peptides, proteins, and cells) and the development of drug delivery methods and commercial products. The pioneering approaches involved in driving the development of successful therapeutic products for both small and large molecules and the three-drug delivery paradigms that form the basis of contemporary drug delivery are discussed. The review was recently published in Nature Biomedical Engineering as “The Evolution of Commercial Drug Delivery Technologies” and has attracted wide attention.

Classification of drug treatment and delivery paradigms

For all drugs, the purpose of delivery is to deliver and release (passively or actively) the drug to the target site in the body and maximize the therapeutic effect by minimizing non-target accumulation of the drug. This can reduce drug toxicity by controlling drug PKs , Increase the accumulation of drugs in the target site, improve patient acceptance and compliance. Common drug treatment and delivery paradigms are classified as follows:

Small molecule drugs

Small molecule drugs can quickly expand through many biological barriers and cell membranes through biological fluids. These advantages enable small molecules to navigate the complex vasculature and interact with almost all tissues and cell types in the body. However, in order to quickly diffuse and enter the systemic vasculature, small molecules must dissolve freely in biological fluids. Therefore, this limits the therapeutic utility of poorly soluble molecules.

Approximately 90% of preclinical drug candidates are compounds with low solubility. The strategy to overcome low bioavailability focuses on over-regulating the local microenvironment to improve drug solubility. Such as intravenous injection of ciprofloxacin, which is formulated with lactic acid and is adjusted
pH value to improve its solubility. Other strategies focus on changing the small molecules themselves to adjust their physical and chemical properties to improve solubilization, diffusion or absorption. For example, the angiotensin-converting enzyme inhibitors Benazepril and Enalapril are commercially formulated with alkyl ester prodrugs, which can mask ionizable groups, thereby improving the absorption and bioavailability of the drug . At the same time, the commercial preparation of ritonavir, a key protease inhibitor for HIV treatment, is thiazole modified to improve its metabolic stability and water solubility.

Protein and peptide

Although the basis of drug delivery is based on the design requirements of small molecules, their targets only account for 2-5% of the human genome. Therefore, other types of treatment are needed. With the evolution of the human body, peptides and proteins have excellent selectivity for specific protein targets. Although the complex structure of peptides and proteins improves their effectiveness and selectivity, it also leads to their poor stability. They are easily degraded under environmental storage conditions and are sensitive to the ubiquitous proteases, changes in physiological temperature and pH in the body.

In order to overcome the challenges brought by its structure, synthetic or humanized peptide analogs are combined with unnatural amino acids or known chemical moieties to improve the half-life, stability, receptor affinity, or toxicity of the peptide or protein, and clinical success An example is desmopressin. In addition, due to the large size of peptides and proteins, they exhibit size-based limitations when penetrating biological barriers, which inspired the development of penetration enhancers.


The structure of the antibody allows a specific interaction between the therapeutic target and the immune system. By binding to the target antigen, the antibody can neutralize it, preventing signal molecules from binding to it and initiating undesired cellular processes. In addition, antibodies can directly interact with host immune cells to trigger phagocytosis, antibody-dependent cytotoxicity or complement-dependent cytotoxicity, thereby triggering the death of undesirable cell populations.

However, these specific interactions can also cause some adverse events, such as rash at the injection site, flu-like symptoms, and the development of autoimmune diseases. For example, Orthoclone OKT3, which is the first mouse-derived monoclonal antibody to be clinically approved , It caused adverse events related to its mechanism of action and its recognition by the immune system as foreign antigens.

Due to the immunogenicity of murine antibodies, subsequent antibody treatment approval was postponed to 2000. In the following ten years, advances in antibody manufacturing allowed the modification of the antibody structure itself, resulting in the production of the first humanized therapeutic antibody daclizumab for the treatment of adults with relapsing multiple sclerosis people.

Nucleic Acid

Nucleic acids can precisely control gene expression and can be used to silence or repair abnormal genes and drive the expression of genes associated with treatment. Due to the specific binding of nucleotide sequences, nucleic acids and recent gene-editing tools such as CRISPR can be reasonably designed for therapeutic manipulation of the human genome.

Nucleic acids are easily degraded by nucleases, which limits their half-life, and the human immune system recognizes and eliminates foreign ribonucleic acid and deoxyribonucleic acid. These challenges have led to innovations in nucleic acid bases, sugar rings, and chemical modifications at the 3’and 5’ends. . Make nucleic acid resistant to nuclease degradation, reduce immunogenicity and improve interaction with target cells.

Live cell therapy

Living cells are the latest generation of therapy. Live cell therapy uses the natural therapeutic functions of certain cell types to regulate or initiate key biological processes. For example, pluripotent stem cells can restore and heal tissues, reprogrammed immune cells can use the immune system for vaccination and cancer treatment, and microorganisms can interact with the microbiota to regulate mucosal immunity, metabolic processes and chronic inflammatory processes.

Living cells can also be modified. The most prominent example is chimeric antigen receptor T cells, which received clinical approval in 2017. They are genetically engineered cytotoxic T cells that target specific cancer-related antigens. The delivery of living cells presents unique challenges. The cells are much larger than all other types of therapeutic drugs, so they can be quickly trapped in the pulmonary capillaries and eliminated. For adoptive cell therapy, the size of living cells and the unfavorable tumor microenvironment result in low penetration of cells in solid tumors. This limits their current clinical application in hematological malignancies.

In addition, the viability, persistence, and maintenance of effective cell types depend to a large extent on the environment and the host of the delivered cells.

Three modes of drug delivery

We summarized three core drug delivery paradigms: drug modification, microenvironment modification, and drug delivery systems, and discussed how to apply these paradigms to cell therapy.

Drug delivery system integration

Drug modification

The modification of a drug includes chemical changes to its structure (such as functional groups, amino acids or accounting frameworks) and the combination of known parts or targeting ligands. Its purpose is to regulate the interaction between the drug and the molecules, cells and tissues in the body, As well as the interaction between the drug and the target site, so as to control the navigation and processing of the drug in the body, from the initial administration to its expected function, drug modification has been used to improve all the above-mentioned improved types of therapeutic drugs Delivery.

Microenvironment modification

Changes to the environment include a series of methods, from highly targeted changes in the site of action to systemic adjuvants that change the host environment. The changes in the environment represent a wide range of drug delivery strategies.

Drug delivery system

Modification of drugs and their microenvironment can adjust and optimize the activity of drugs. Drug delivery systems can combine these two strategies by establishing an interface between the drug and its microenvironment. These systems include hydrogels and polymer implants based on four mechanisms of controlled release (dissolution, diffusion, permeation, and ion exchange), as well as microparticles and nanoparticles, which allow particle surface modification to increase the half-life of the drug, and through and Specific interactions of the microenvironment target specific tissues.


Drug delivery has developed along with generations of therapies—from small molecules to proteins and peptides, to nucleic acids, and more recently to live cell therapy. In the development of drug delivery, established delivery methods are used to improve the second-team transformation of emerging treatment models, such as the application of controlled release and sustained release systems throughout the treatment range. Conversely, delivery strategies and technologies developed for new treatment modalities have been used to improve the delivery of treatments. For example, before being used to improve the delivery of small molecules, polyethylene glycol conjugation was developed for use in proteins.

Analysis of existing treatments and drug delivery methods reveals that there are three outstanding challenges: targeted drug delivery with single-cell resolution, overcoming biological barriers that limit the delivery of complex therapeutic molecules, and developing response environmental cues at a specific time and concentration in drug delivery system for rapid secretion of biomolecules in specific tissues.

Although these challenges will not prevent the implementation of most treatment methods, we believe that cell therapy can solve these problems at the same time and produce an effective single-dose drug delivery system.

In fact, cell therapy can provide a continuous source of complex biological agents, overcome biological barriers, and respond to host cues in a way that mimics natural biological processes. Therefore, cell therapy can be used as a dynamic delivery system as well as a kind of treatment method. Therefore, cell therapy is particularly suitable for the treatment or management of rare blood diseases, unresponsive cancers and metabolic genetic diseases.

Since they mimic key biological processes, advanced cell therapies can reduce the frequency of administration and the need or amount of certain medical interventions. If history is a guideline, cell therapy will use established methods to change the drug and its microenvironment in order to control the effect, efficacy, and toxicity of the drug.