MIT chemists have developed a revolutionary drug delivery system that dramatically increases the amount of chemotherapy drugs that can be delivered directly to tumor cells. The new antibody-bottlebrush conjugates (ABCs) can carry hundreds of drug molecules per antibody, representing a significant advancement over current antibody-drug conjugates (ADCs) that are limited to carrying a maximum of about eight drug molecules.
Breakthrough in Drug Loading Capacity
The bottlebrush particles consist of a polymer backbone attached to tens to hundreds of "prodrug" molecules - inactive drug molecules that are activated upon release within the body. Using click chemistry, researchers can attach one, two, or three bottlebrush polymers to a single tumor-targeting antibody, creating conjugates with unprecedented drug-carrying capacity.
"We can use antibody-bottlebrush conjugates to increase the drug loading, and in that case, we can use less potent drugs," said Bin Liu, MIT postdoc and lead author of the study published in Nature Biotechnology. "In the future, we can very easily copolymerize with multiple drugs together to achieve combination therapy."
This enhanced payload capacity addresses a major limitation of current ADCs, which can only be used with very potent drugs - usually DNA-damaging agents or drugs that interfere with cell division - due to their restricted drug-carrying capacity.
Superior Efficacy in Preclinical Models
In mouse models of breast and ovarian cancer, the ABC particles demonstrated remarkable therapeutic efficacy. The researchers tested ABCs carrying various drug types including microtubule inhibitors (MMAE and paclitaxel), DNA-damaging agents (doxorubicin and SN-38), and experimental PROTAC drugs that selectively degrade disease-causing proteins.
The results showed that ABC treatment could eliminate most tumors using doses almost 100 times lower compared to traditional small-molecule drugs. "We used a very low dose, almost 100 times lower compared to the traditional small-molecule drug, and the ABC still can achieve much better efficacy compared to the small-molecule drug given on its own," Liu explained.
The ABC particles also outperformed two FDA-approved ADCs - T-DXd and TDM-1 - both of which target HER2-positive cells. This superior performance was achieved while using significantly lower drug doses, potentially reducing side effects.
Targeted Delivery Mechanism
Each ABC particle contains an antibody that targets specific tumor proteins. In this study, researchers used antibodies targeting HER2, a protein often overexpressed in breast cancer, and MUC1, commonly found in ovarian, lung, and other cancer types. The prodrug molecules are attached to the polymer backbone through cleavable linkers that respond to specific conditions within tumor cells.
After reaching a tumor site, some linkers break immediately, allowing drugs to kill nearby cancer cells even if they don't express the target antibody. Other particles are absorbed into cells with the target antibody before releasing their toxic payload, providing a dual mechanism of action.
Expanding Treatment Options
The technology's ability to deliver less potent drugs opens new therapeutic possibilities. Unlike current ADCs that require highly toxic payloads, ABCs can incorporate drugs like doxorubicin and paclitaxel, enhancing treatment customizability and enabling various drug combinations.
"We are excited about the potential to open up a new landscape of payloads and payload combinations with this technology, that could ultimately provide more effective therapies for cancer patients," said Jeremiah Johnson, the A. Thomas Geurtin Professor of Chemistry at MIT and senior author of the study.
Future Applications and Development
The modular design of ABC technology allows for easy adaptation to different cancer types by incorporating different targeting antibodies. More than 100 antibodies have been approved to treat cancer and other diseases, and theoretically any of these could be conjugated to create targeted therapies.
The research team plans to explore combination therapies using drugs with different mechanisms of action, potentially including immunotherapy drugs such as STING activators. They are also working on incorporating antibodies targeting EGFR, which is widely expressed in many tumors.
The versatility of the platform extends beyond drug delivery, as the bottlebrush structure can also incorporate imaging agents for real-time therapeutic tracking and photocatalysts for proximity-based labeling to study cellular interactions.
This research, funded by the National Institutes of Health, the Ludwig Center at MIT, and the Koch Institute Frontier Research Program, represents a significant step forward in precision oncology, potentially overcoming longstanding limitations of current antibody-drug conjugate technologies.
