Intranasal bFGF‑Els alleviate doxorubicin‑induced cognitive deficits in mice by modulating the PI3K/AKT pathway and suppressing oxidative stress, neuroinflammation, and apoptosis

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Chemotherapy-induced cognitive impairment (CICI), a frequent consequence of doxorubicin (DOX) treatment in patients with breast cancer, currently lacks effective preventive measures. This work explored whether administering basic fibroblast growth factor (bFGF)-encapsulated elastic nanoliposomes (bFGF-Els) administered intranasally could mitigate DOX-induced cognitive impairment in a mouse model of triple-negative breast cancer. The optimized bFGF-Els were spherical and uniform, with a mean size of 110.8 nm, a polydispersity index of 0.079, a zeta potential of -32.6 mV, an encapsulation efficiency of 87.5%, and favorable deformability. Compared with those receiving DOX alone, mice receiving intranasal bFGF-Els showed markedly better cognitive performance, as evidenced by reduced escape latency and increased platform crossing and target quadrant time (all P < 0.01). Histological and biochemical analyses revealed that bFGF-Els attenuated hippocampal CA1 neuronal damage, decreased reactive oxygen species and malondialdehyde levels, restored superoxide dismutase and glutathione peroxidase activity, and reduced pro‑inflammatory cytokines (interleukin‑1β, interleukin‑6, and tumor necrosis factor‑α) (all P < 0.01). At the mechanistic level, bFGF-Els increased the ratios of phosphorylated PI3K to total PI3K and phosphorylated AKT to total AKT and increased the levels of nuclear Nrf2 (nuclear factor erythroid 2‑related factor 2), heme oxygenase‑1(HO-1), NAD(P)H:quinone oxidoreductase‑1(NQO1), and B‑cell lymphoma 2 (Bcl-2), while reducing nuclear factor‑κB (NF-κB), Bcl‑2‑associated X protein (Bax), and cleaved caspase‑3 (all P < 0.01). bFGF-Els did not affect the anti-tumor efficacy of DOX, as the tumor volume and weight were similar among all the groups treated with DOX (P > 0.05). In conclusion, intranasal bFGF-Els enable efficient bFGF transport to the brain and relieves DOX-triggered CICI by curbing oxidative stress, neuroinflammation, and apoptosis through the PI3K/AKT axis, all while preserving the antitumor activity of chemotherapy.

Intranasal bFGF-Els alleviate doxorubicin-induced cognitive impairment in a breast cancer mouse model by modulating the PI3K/AKT pathway and reducing oxidative stress, neuroinflammation, and apoptosis, without compromising chemotherapy efficacy.