Abstract

Immunogenic cell death (ICD) can activate the anticancer immune response and is highly attractive to improve cancer treatment efficacy.[1] ICD is closely related with endoplasmic reticulum (ER) stress and a series of ICD inducers were recently reported based on ER-targeted photodynamic/photothermal agents or metal complexes.[2] However, these ER-targeted ICD inducers suffer from complicated synthesis and heavy metal cytotoxicity. Inspired by the promising clinical potential of small organic molecules, herein, we develop an ER-targeted fluorescent self-reporting ICD inducer SA-Cbl by simple conjugation of chemotherapeutic drug chlorambucil (Cbl) with salicylaldehyde (SA). SA-Cbl can selectively accumulate in ER to induce rapid ROS generation and unfolded protein response process, which led to a fast release of damage-associated molecular patterns (DAMPs) and efficient dendritic cells maturation. Meanwhile, the ER-targeted accumulation and ER-stress inducing process can be in situ monitored based on the turn-on fluorescence of SA-Cbl, which is highly pH and polarity-sensitive and can selectively interact with ER proteins. Compared with traditional chemotherapy drug doxorubicin, the superior anticancer immunity effect of SA-Cbl was verified via an in vivo tumor model. This study thus provides a new strategy for developing fluorescent self-reporting ICD inducers by decoration of chemotherapeutic drugs with pH and polarity sensitive organic fluorophores.

Scheme 1. Design principle of SA-Cbl as a type II ICD inducer for cancer therapy.

Reference:

1. Garg, A. D.; Peric, A. M.; Romano, E.; Agostinis, P. Int. J. Dev. Biol. 2015, 59, 131 – 140. 
2. Asadzadeh, Z.; Safarzadeh, E.; Safaei, S.; Baradaran, A.; Mohammadi, A.; Hajiasgharzadeh, K.; Derakhshani, A.; Argentiero, A.; Silvestris, N.; Baradaran, B. Cancers 2020, 12, 1047 – 1094.