Sequentially Activatable Polypeptide Nanoparticles for Combinatory Photodynamic Chemotherapy of Breast Cancer

Stimuli-activatable nanomaterials hold significant promise for tumor-specific drug delivery by recognizing the internal or external stimulus. Herein, we reported a dual-responsive and biodegradable polypeptide nanoparticle (PPTP@PTX₂ NP) for combinatory chemotherapy and photodynamic therapy (PDT) of breast cancer. The NPs were engineered by encapsulating diselenide bond linked dimeric prodrug of paclitaxel (PTX₂) in an intracellular acidity-activatable polypeptide micelle. Specifically, the acid-responsive polypeptide was synthesized by grafting a tetraphenyl porphyrin (TPP) photosensitizer and N,N-diisopropylethylenediamine (DPA) onto the poly(ethylene glycol)-block-poly(glutamic acid) diblock copolymer by the amidation reaction, which self-assembled into micellar NPs and was activated inside the acidic endocytic vesicles to perform PDT. The paclitaxel dimer can be stably loaded into the polypeptide NPs and be restored by PDT inside the tumor cells. The formed PPTP@PTX₂ NPs remained inert during blood circulation and passively accumulated in the tumor foci, which could be activated within the endocytic vesicles via acid-triggered protonation of DPA groups to generate fluorescence signal and release PTX₂ in 4T1 murine breast tumor cells. Upon 660 nm laser irradiation, the activated NPs carried out PDT via TPP and chemotherapy via PTX to induce apoptosis of 4T1 cells and thereby efficiently inhibited 4T1 tumor growth and prevented metastasis of tumor cells.