Poly(amino acid) nanoformulation of cyclin-dependent kinase 4 and 6 inhibitor for molecularly targeted immunotherapy in triple-negative breast cancer

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) selectively arrest malignant cells in the G1 phase of cell cycle by inhibiting CDK4/6-mediated phosphorylation of retinoblastoma protein. However, CDK4/6i therapy is often ineffective against triple-negative breast cancer (TNBC) due to the high lysosomal content in TNBC cells, which sequesters the drugs and prevents them from reaching their nuclear target. To address this challenge, three pH- and glutathione-responsive poly(amino acid) nanogels composed of methoxy poly(ethylene glycol) of various lengths and poly(L-glutamic acid-co-L-cystine) (mPEG−P(Glu₁₀-co-Cys²₅)) were developed to efficiently deliver the CDK4/6i abemaciclib (ABE) to TNBC cells. These nanogels bypassed lysosomal sequestration, thereby enhancing the efficacy of molecularly targeted immunotherapy. Among the nanogels, the formulation with mPEG2000 (NG2000) exhibited the highest efficiency in delivering ABE, resulting in increased cell apoptosis, activation of an anti-cancer immune response, reduction of immunosuppression, and improved therapeutic outcomes against TNBC. Furthermore, NG2000/ABE enhanced immune checkpoint therapy for TNBC, achieving a tumor inhibition rate of 89.66%. These findings demonstrate the potential of poly(amino acid) nanoformulations for delivering CDK4/6 inhibitors as molecularly targeted immunotherapy for TNBC in clinical applications.