<p>Hypoxia-Targeting Multifunctional Nanoparticles for Sensitized Chemotherapy and Phototherapy in Head and Neck Squamous Cell Carcinoma</p>

Abstract

Chemotherapy in head and neck squamous cell carcinoma (HNSCC) has many systemic side effects, as well as hypoxia-induced chemoresistance. To reduce side effects and enhance chemosensitivity are urgently needed. Methods: We synthesized a drug delivery system (named CECMa NPs) based on cisplatin (CDDP) and metformin (chemotherapeutic sensitizer), of which chlorin e6 (Ce6) and polyethylene glycol diamine (PEG) were synthesized as the shell, an anti-LDLR antibody (which can target to hypoxic tumor cells) was modified on the surface to achieve tumor targeting. Results: The NPs possessed a great synergistic effect of chemotherapy and phototherapy. After laser stimulation, both CDDP and metformin can be released in situ to achieve antitumor effects. Meanwhile, PDT and PTT triggered by a laser have anticancer effects. Furthermore, compared with free cisplatin, CECMa exhibits less systemic toxicity with laser irradiation in the xenograft mouse tumor model. Conclusion: CECMa effectively destroyed the tumors via hypoxia targeting multimodal therapy both in vitro and in vivo, thereby providing a novel strategy for targeting head and neck squamous cell carcinoma.

Hypoxia-induced therapy resistance: Available hypoxia-targeting strategies and current advances in head and neck cancer

“…One of these experiments managed to co-deliver an antineoplastic agent (doxorubicin) and a HIF-1 inhibitor drug (triptolide) and the results pointed out that triptolide enhanced the uptake of doxorubicin, improving efficacy in oral squamous cell carcinoma cells [103] . A similar experiment, which synthesized nanoparticles containing cisplatin and metformin, also proved to increase drug efficiency and decrease toxicity in HNSCC models [99] .…”

“…One of the most recent and revolutionary strategies that have been suggested to improve treatment response is nanoparticles containing combination of HIF-targeted drugs [ 98 , 99 ], anti-angiogenic agents [100] and/or hypoxia-activated prodrugs [ 2 , 101 , 102 ]. Considering most hypoxia-activated prodrugs have failed clinical trials, likely due to insufficient drug delivery, a recent in silico analysis attempted to evaluate the outcomes of lipidic nanoparticles containing both anti-angiogenic agents (AAs) and hypoxia-activated prodrugs (HAPs), in an attempt to improve HAPs delivery and efficiency.…”

“…An additional advantage of using nanoparticles, apart from time-controlled release and synergistic effect, is the optional addition of external tumor-specific antibodies to further increase tumor selectivity [99] . Other studies using similar nanoparticle strategies include one that attempted to combine two HIF-α inhibitors, called YC-1 and irinotecan, and observed as a result a 5.7-fold increase in efficiency in lung cancer cells [98] .…”

Stimuli-responsive drug delivery systems for head and neck cancer therapy

“…Other therapy modalities like chemotherapy and gene therapy were also combined to the phototherapy (Agostinis et al, 2011). For instance, Song et al (2020) designed chlorin e6 (Ce6) linked DDS co-loaded with cisplatin (CDDP) and metformin for Head and Neck Squamous Cell Carcinoma. The PS Ce6 showed laser-triggered PTT and PDT effect while CDDP and metformin served as the chemotherapeutic core.…”

Immune/Hypoxic Tumor Microenvironment Regulation-Enhanced Photodynamic Treatment Realized by pH-Responsive Phase Transition-Targeting Nanobubbles

“…However, the hypoxic tumor microenvironment cannot provide an adequate amount of oxygen for PDT, greatly reducing the efficacy of PDT. In addition to adopting hemoglobin and perfluorocarbon vesicles as direct oxygen donators to modify the hypoxic tumor microenvironment, an alternative strategy that increases the oxygen concentration by reducing its consumption is gaining attention. − Metformin (MET) is a safe and inexpensive drug for the treatment of type 2 diabetes . Interesting findings have recently described that that MET was an effective respiratory depressant. , Therefore, the combination of metformin and photosensitizer Ce6 for tumor treatment could adjust the intratumor oxygen consumption and facilitate the efficacy of PDT. , Unfortunately, the treatment of PDT alone often results in poor tumor treatment effects due to some limitations, such as tumor hypoxic conditions, low specificity, and reactive oxygen species (ROS) production efficiency .…”