Spatiotemporally‐Programmed Dual‐Acid‐Sensitive Nanoworms of Albumin‐Poly(tertiary amine)‐Doxorubicin Conjugates for Enhanced Cancer Chemotherapy

Abstract Nanomedicines are potentially useful for targeted cancer chemotherapy; however, it is difficult to design nanomedicines with controllable structures and functions to overcome a series of biological and pathological barriers to efficiently kill cancer cells in vivo. Here, this work reports in situ growth of dual‐acid‐sensitive poly(tertiary amine)‐doxorubicin conjugates from albumin to form dual‐acid‐sensitive albumin‐poly(tertiary amine)‐doxorubicin conjugates that self‐assemble into nanospheres and nanoworms in a controlled manner. Both nanospheres and nanoworms rapidly dissociate into positively‐charged unimers at pH < 6.9 and quickly releases the conjugated drug of doxorubicin at pH < 5.6, leading to enhanced penetration in tumor cell spheroids as well as improved uptake and cytotoxicity to tumor cells at pH < 6.9. Notably, nanoworms are less taken up by endothelial cells than nanospheres and doxorubicin, leading to improved pharmacokinetics. In a mouse model of triple negative breast cancer, nanoworms accumulate and penetrate into tumors more efficiently than nanospheres and doxorubicin, leading to enhanced tumor accumulation and penetration. As a result, nanoworms outperform nanospheres and doxorubicin in suppressing tumor growth and elongating the animal survival time, without observed side effects. These findings demonstrate that intelligent nanoworms with spatiotemporally programmed dual‐acid‐sensitive properties are promising as next‐generation nanomedicines for targeted cancer chemotherapy.