The preparation and evaluation of dual-tumor microenvironment-responsive transformable nanoscale drug delivery system for breast cancer combination therapy

Ranked second and fourth respectively in incidence rate and mortality rate among various cancers, breast cancer is characterized by strong invasion, high recurrence, poor prognosis and a lack of effective treatment, rendering the quality of life and the survival time of patients unsatisfactory. Herein, we designed a dual-response shape-transformable nanomicelle consisted of two amphipathy chains of different length, within which the chemotherapeutic agent paclitaxel (PTX) is encapsulated in the hydrophobic cavity. Based on it a combined therapy of photodynamic therapy, immunotherapy and chemotherapy was developed to augment the accumulation of therapeutic drugs in breast cancer tissues and treating efficacy. Entered in tumour microenvironment (TME), the shape transformation of micelles would be triggered by reactive oxygen species (ROS) and matrix metalloproteinase-2 (MMP-2), so as to increase the retention of the photosensitizer pyropheophorbide-a (Ppa) in tumours and release PTX and D-type programmed cell death ligand 1 (PD-L1) peptide antagonist (dPPA) concurrently, thus addressing the incompatibility of long blood circulation time, tumor penetration and retention. Under the irradiation of near infrared light, ROS produced by Ppa brought about stronger killing of cancer cells, activation of host immunity and promotion of ROS response. The dual-responsive group PTX@DTPD-PPP, along with two single-responsive groups PTX@DTPD-PRP and PTX@DPD-PPP and non-responsive group PTX@DPD-PRP were initially synthesized and characterized. Through cellular uptake experiment, light-responsive ROS generation experiment, cytotoxicity test, migration and invasion test and so forth, we proved the enhancement in both drug delivery and treating effect of dual-responsive formation. These findings demonstrate that PTX@DTPD-PPP is fulfilled with an uniform particle size (144 ± 1.3 nm) and a negative surface (-6.8 ± 0.9 mV), as well as the transformation responsiveness in 4 h within in vitro experiments. Both the drug accumulation and cellular toxicity of dual-responsive group are prominently increased in contrast with free Ppa, free PTX as well as other formations, laying a foundation for the sequent in-vivo studies.