Regulating tumor innervation by nanodrugs potentiates cancer immunochemotherapy and relieve chemotherapy-induced neuropathic pain

Sympathetic nerves play a pivotal role in promoting tumor growth through crosstalk with tumor and stromal cells. Chemotherapy exacerbates the infiltration of sympathetic nerves into tumors, thereby providing a rationale for inhibiting sympathetic innervation to enhance chemotherapy. Here, we discove...

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Bibliographic Details
Published in:Biomaterials 2024-09, Vol.309, p.122603, Article 122603
Main Authors: Zuo, Shuting, Wang, Zhenyu, Jiang, Xiaoman, Zhao, Yuewu, Wen, Panyue, Wang, Jine, Li, Junjie, Tanaka, Masaru, Dan, Shao, Zhang, Yan, Wang, Zheng
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Breast Neoplasms - drug therapy
Breast Neoplasms - pathology
Cell Line, Tumor
Chemotherapy-induced peripheral neuropathic pain
Doxorubicin - pharmacology
Female
Humans
Immunochemotherapy
Immunotherapy - methods
Mice
Mice, Inbred BALB C
Nanodrug
Nanoparticles - chemistry
Nerve growth factor
Nerve Growth Factor - metabolism
Neuralgia - chemically induced
Polylactic Acid-Polyglycolic Acid Copolymer - chemistry
RNA, Small Interfering
Sympathetic nerves
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Summary:Sympathetic nerves play a pivotal role in promoting tumor growth through crosstalk with tumor and stromal cells. Chemotherapy exacerbates the infiltration of sympathetic nerves into tumors, thereby providing a rationale for inhibiting sympathetic innervation to enhance chemotherapy. Here, we discovered that doxorubicin increases the density and activity of sympathetic nerves in breast cancer mainly by upregulating the expression of nerve growth factors (NGFs) in cancer cells. To address this, we developed a combination therapy by co-encapsulating small interfering RNA (siRNA) and doxorubicin within breast cancer-targeted poly (lactic-co-glycolic acid) (PLGA) nanoparticles, aiming to suppress NGF expression post-chemotherapy. Incorporating NGF blockade into the nanoplatform for chemotherapy effectively mitigated the chemotherapy-induced proliferation of sympathetic nerves. This not only bolstered the tumoricidal activity of chemotherapy, but also amplified its stimulatory impact on the antitumor immune response by increasing the infiltration of immunostimulatory cells into tumors while concurrently reducing the frequency of immunosuppressive cells. Consequently, the combined nanodrug approach, when coupled with anti-PD-L1 treatment, exhibited a remarkable suppression of primary and deeply metastatic tumors with minimal systematic toxicity. Importantly, the nanoplatform relieved chemotherapy-induced peripheral neuropathic pain (CIPNP) by diminishing the expression of pain mediator NGFs. In summary, this research underscores the significant potential of NGF knockdown in enhancing immunochemotherapy outcomes and presents a nanoplatform for the highly efficient and low-toxicity treatment of breast cancer.
ISSN:0142-9612
1878-5905
1878-5905
DOI:10.1016/j.biomaterials.2024.122603