How to broadly enable the design of antibody-targeted drugs with enhanced potency and optimized release profiles?
Self-assembling nanogel platform that separates drug carrying, targeting and release functions by encapsulating drugs without the use of linkers and binds targeting antibodies on the nanogel surface.
Development of a wide range of new targeted therapeutics with tunable pharmaceutical profiles (pharmacokinetics and pharmacodynamics) and drug release triggered by the microenvironment of specific tissues to treat cancer and other diseases.
Antibody-drug conjugates (ADCs) have emerged as a promising cancer therapeutic class by their ability to deliver potent drugs to tumor cells, while limiting off-target side effects. The linker chemistry is the linchpin for this technology. After a decade of development to create elegant linker chemistries that can stably connect a targeting antibody to a drug molecule and release that drug selectively at the tumor site, this approach remains limited to very few drug molecules with restrictive structural features.
UMass CBD researchers have developed a next generation targeting approach based on self-assembling, drug encapsulated polymer nanogels that do not require chemical changes to the active drug, can increase cargo capacity by at least 10X and thereby increase drug potency along with the therapeutic window by minimizing off target side effects. The nanogel structures can also be readily tuned to alter drug release rates over time or in response to the tissue microenvironment.
The nanogels have potential to achieve this high performance by efficiently integrating the targeting antibody with the protected drug without the need for a chemical linkage. This enables delivery of high drug concentrations without the need for cargo specific chemistries. Once absorbed, the drug is released through an environmental trigger, uniquely present in the cell or in a subcellular compartment at high levels. The tunability in polymer selection and associated features control the drug cargo capacity, protection, solubility and tissue-specific drug release profile.
This nanogel platform is built around fundamental design principles that allow flexibility and control of key parameters such as type of polymer, release rate, and ADMET profiles. For example, the release rate can be tuned inside of cells for either burst or controlled release by modulating the cross-linking. Because of this modular, chemistry-based discovery approach, the nanogel platform has the potential to provide a wider range and combination of features faster and at lower risk.
The UMass team has demonstrated initial proof-of- concept for this next generation approach in an animal model of cancer. In their studies, antibody-targeted, nanogel encapsulated doxorubicin produced tumor shrinkage vs. nanogel encapsulated doxorubicin alone at 10 percent of the dose of nanogel encapsulated doxorubicin alone. These preliminary studies demonstrate the promise of this innovative approach. Initial studies have also shown that there is no overt toxicity associated with these nanogels.