Microneedle Patch Delivery of PROTACs for Anti-Cancer Therapy

Proteolysis-targeting chimera (PROTAC) is an emergingtechniquefor degrading disease-related proteins. However, the current PROTACssuffer from inadequate solubility and lack of organ targeting, whichhas hampered their druggability. Herein, we report direct and sustaineddelivery of PROTACs using microneedle patches to the diseased tissues.In this study, we use an estrogen receptor alpha (ER alpha)-degradingPROTAC, ERD308, to treat ER-positive breast cancer. A pH-sensitivemicelle, MPEG-poly(beta-amino ester) (MPEG-PAE), is used to encapsulateERD308 along with an FDA-approved CDK4/6 inhibitor, Palbociclib (Pal),before loading into biodegradable microneedle patches. These patchesenable prolonged drug release into deep tumors, maintaining therapeuticlevels for at least 4 days, with an excellent drug retention rateof over 87% in tumors. ERD308 released from the microneedle patchescan sufficiently degrade ER alpha in MCF7 cells. Co-administrationof ERD308 and Palbociclib exhibits excellent efficacy by over 80%tumor reduction as well as a good safety profile. Our work demonstratesthe feasibility and proof-of-concept therapeutic potential of usingmicroneedle patches to directly deliver PROTACs into tumors.

Automated summary

Proteolysis-targeting chimera (PROTAC) is an emerging technique for degrading disease-related proteins. This study demonstrates the feasibility of using microneedle patches to directly deliver PROTACs into tumors, overcoming the challenges of solubility and lack of organ targeting. The microneedle patches enable prolonged drug release and exhibit excellent efficacy in degrading disease-related proteins and reducing tumor size.