Drug delivery efficiency plays a crucial role in disease treatment, and so solving its challenges remains one of the most important tasks in the industry. Many methods exist to deliver drugs into the body, such as oral, submucosal, parenteral, transdermal, and pulmonary, among others. Yet most pharmaceuticals face similar problems; a low level of macromolecular absorption, slow onset of action, non-specific delivery, and the potential for off-target side effects.
Most approaches that attempt to address these issues depend on physiological differences between healthy and diseased tissues, or on the existence of tissue-specific markers, which can vary between patients and between disease indications. This variability limits the development of generalized therapies and has driven the current emphasis on precision medicine approaches to drug development.
In addition, there are some indications where even more focused drug delivery could potentially enable better outcomes with fewer side effects, such as for the treatment of discrete tumors, local sites of pain, or narrowly focused, deep-seated infections.
Localized drug delivery refers to technology used to limit the presentation of a drug to a desired body site for its release and absorption, or the subsequent transport of the active ingredients across the biological membranes to the site of action. The aim of such approaches is to improve the bioavailability of the drug at the site of disease, reduce dosing frequency, and minimize systemic side effects.
The development of a successful strategy for localized drug delivery requires an understanding of the transport of drugs or drug carriers to a target site after administration, as well as issues relevant to disease-specific targets and the body’s response to a drug delivery system.
Overall, an effective drug delivery system encompasses the following key steps: retention of the drug by a delivery vehicle; evasion of the body’s attempts to clear that drug or carrier; precise targeting to the desired delivery site; and release of the drug from its delivery vehicle.
One localized drug delivery approach that has been studied for several decades is based on the use of liposomes. In such methods, the drug is encapsulated inside liposomes that emit the drug via diffusion or by liposomal degradation. Liposomal encapsulation reduces many of the side effects associated with certain drugs by preventing their release at undesirably high concentrations. By attaching targeting ligands to liposomes, it is possible to direct them to an intended location. Liposomal systems have been approved by regulatory authorities for the treatment of Kaposi sarcomas, ovarian cancer, and fungal infections.
Another localized delivery strategy involves the use of nanoparticles. Because of their small size, nanoparticle-encapsulated drugs can pass through certain biological barriers. A high density of therapeutic agent can often be encapsulated, dispersed, or dissolved within these delivery vehicles.
There are two main methods to transport drug-loaded nanoparticles to localized diseased sites: passive and active targeting.
Passive targeting works through an increased permeability and retention effect that makes tumor cells preferentially absorb nanoparticle bodies by exploiting abnormalities of tumor vasculature, namely hypervascularization. Drugs administered intravenously escape renal clearance. Being unable to penetrate through tight endothelial junctions of normal blood vessels, their concentration builds up in the plasma rendering them long plasma half-life. More importantly, they can selectively extravasate in tumor tissues due to its abnormal vascular nature.
Over time, the tumor concentration of drug will build up reaching several folds higher than that of the plasma due to lack of efficient lymphatic drainage in solid tumor. In active targeting, nanoparticles are functionalized with ligands such as antibodies, proteins, and peptides that interact with receptors overexpressed at the target site.
In recent years, the concept of “self-triggered” drugs has emerged. These delivery systems function by means of a signal at the target site that spurs release of the drug. Such release signals can be related to pH, the presence of specific enzymes, temperature changes, ultrasound, or molecular markers that guide drugs to the target site and control their release.
One example of this approach is a new technology based on the principle of bio-orthogonal chemistry—abiotic chemical reactions that do not interfere with the physiological environment. Bio-orthogonal-activating compounds are covalently incorporated into an implantable polymeric gel. This drug-activating gel can be injected at the specific site in the body where therapy is required, allowing for a precisely targeted interaction with circulating pro-drugs. A pro-drug with attenuated activity is captured by the gel due to specific chemical interactions and subsequently released as the active drug. The pro-drugs are thus transformed into active therapeutic agents in a regionally defined manner.
In published preclinical studies1, this technology has been used to control the toxicity of doxorubicin, a commonly used chemotherapy medication, by precisely targeting the action of the drug to the tumor site itself. In mice bearing human fibrosarcoma xenografts, conventional doxorubicin treatment led to initial shrinkage of tumors, followed by recurrence and tumor growth.
In contrast, the site-activated drug treatment resulted in sustained remission in the median of mice treated. In addition to a better outcome, the local activation strategy also generated fewer side effects. Anemia and suppressed immune system function are the side effects that most often limit the use of doxorubicin, but neither was a problem in the mice treated with the site-activated drug. Other undesirable side effects such as weight loss also were not observed.
The enhanced safety of the local activation approach allowed the doxorubicin pro-drug to be administered at more than three times the maximum tolerated dose of standard doxorubicin therapy, with no observable adverse effects. This combination of better outcome and fewer side effects has the potential to allow doctors to safely increase the chemotherapy dose employed and thereby make it more effective in shrinking and eliminating tumors.
These studies illustrate the benefits of localized drug activation, but multiple challenges remain for their clinical application in many indications. Among them is drug delivery across the blood-brain-barrier (BBB). One method currently under study uses advanced ultrasound techniques that disrupt the BBB briefly so medications can be delivered to brain tumors directly, potentially negating the need for surgery.
Targeted Intracellular delivery of therapeutic agents is another area of high interest for the future. While there has been some success recently, notably with antisense agents, challenges for such delivery remain as each cell protects itself from foreign agents. Researchers have been working on many therapeutic agents that can be delivered not just to the cell, but also to a particular compartment of that cell to achieve better activity, e.g. proapoptotic drugs to the mitochondria, antibiotics and enzymes to the lysosomes, and various anticancer drugs and gene therapies to the nucleus.
The technologies described here represent the tip of the iceberg for the development of new drug delivery systems. From both a financial and a global health care perspective, the promise of administration methods that allow localized treatment will change the future of medicine.
1Mejia Oneto J., Khan I., Seebald L., Royzen M. 2016. In Vivo Bioorthogonal Chemistry Enables Local Hydrogel and Systemic Pro-Drug To Treat Soft Tissue Sarcoma. ACS Central Science 2016 2 (7), 476-482.
About the Authors
Jose Mejia-Oneto is the Founder and Chief Executive Officer of Shasqi. He completed a Ph.D. in organic chemistry at Emory University and an MD degree from the University of Minnesota, followed by residency studies in orthopaedic surgery at UC Davis, before starting Shasqi in 2015.
Nathan A. Yee is a Senior Chemist at Shasqi. He completed a Ph.D. in chemistry at UC Berkeley in 2017, with a focus on chemical biology.
Valeria Revilla is a Senior Scientist at Shasqi, specializing in micro and molecular biology. She holds an M.S. degree in biotechnology from the Ensenada Center for Scientific Research and Higher Education, Mexico.
Filed Under: Drug Discovery