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In vivo antitumor activity of PHT-427 inhibitor-loaded polymeric nanoparticles in head and neck squamous cell
Joaquín Yanes-Díaz1, Raquel Palao-Suay2,3, Francisca Inmaculada Camacho-Castañeda4,5
1Otolaryngology Department, Hospital Universitario de Getafe, Madrid, Spain.
Abstract:
Recent studies on head and neck squamous cell carcinoma (HNSCC) tumorigenesis have revealed several dysregulated molecular pathways. The phosphatidylinositol-3-kinase (PI3K) signaling pathway is frequently activated in HNSCC, making it an attractive target for therapies. PHT-427 is a dual inhibitor of PI3K and the mammalian target of AKT/PDK1. This study evaluates the anticancer efficacy of the inhibitor PHT-427 loaded into polymeric nanoparticles (NP) based on α-TOS (NP-427) administered by intratumoral injection into a hypopharyngeal squamous cell carcinoma (FaDu cells) heterotopic xenograft mouse model. The nanocarrier system, based on block copolymers of N-vinylpyrrolidone (VP) and a methacrylic derivative of α-TOS (MTOS), was synthesized, and PHT-427 was loaded into the delivery system. First, we evaluated the effect of NP-427 on tumor growth by measuring tumor volume, mouse weight, survival, and the development of tumor ulceration and necrosis. In addition, we measured PI3KCA/AKT/PDK1 gene expression, PI3KCA/AKT/PDK1 protein levels, Epidermal Growth Factor Receptor (EGFR), and angiogenesis in the tumor tissue. PHT-427 encapsulation increased drug efficacy and safety, as demonstrated by decreased tumor volume, reduced PI3K/AKT/PDK1 pathway expression, and improved antitumor activity and necrosis induction in the mouse xenograft model. EGFR and angiogenesis marker (Factor VIII) expression were significantly lower in the NP-427 group compared to other experimental groups. Administration of encapsulated PHT-427 at the tumor sites proves promising for HNSCC therapy.
Insights
Encapsulating PHT-427 into α-TOS nanoparticles (NP-427) effectively treats head and neck squamous cell carcinoma (HNSCC) in mice. This novel nanoparticle delivery system reduces tumor growth and enhances drug safety for HNSCC therapy.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- Head and neck squamous cell carcinoma (HNSCC) exhibits dysregulated molecular pathways, notably the phosphatidylinositol-3-kinase (PI3K) signaling pathway.
- The PI3K pathway's frequent activation in HNSCC makes it a key therapeutic target.
- PHT-427, a dual PI3K and AKT/PDK1 inhibitor, shows potential for HNSCC treatment.
Purpose of the Study:
- To evaluate the anticancer efficacy and safety of PHT-427 loaded into α-TOS-based polymeric nanoparticles (NP-427).
- To assess NP-427's impact on tumor growth, molecular markers, and survival in a hypopharyngeal HNSCC xenograft model.
Main Methods:
- Synthesis of α-TOS-based polymeric nanoparticles (N-vinylpyrrolidone and α-TOS derivative) for PHT-427 encapsulation.
- Intratumoral administration of NP-427 in a FaDu cell xenograft mouse model.
- Assessment of tumor volume, mouse weight, survival, ulceration, necrosis, and molecular markers (PI3K/AKT/PDK1 pathway, EGFR, Factor VIII).
Main Results:
- NP-427 significantly reduced tumor volume and improved survival compared to controls.
- Encapsulation enhanced PHT-427's efficacy, decreasing PI3K/AKT/PDK1 pathway expression and inducing tumor necrosis.
- NP-427 treatment led to significantly lower expression of Epidermal Growth Factor Receptor (EGFR) and angiogenesis marker Factor VIII.
Conclusions:
- PHT-427 encapsulated in α-TOS nanoparticles demonstrates enhanced anticancer efficacy and safety for HNSCC.
- Intratumoral administration of NP-427 is a promising strategy for head and neck squamous cell carcinoma therapy.
- Targeting the PI3K/AKT/PDK1 pathway with NP-427 offers a potential new avenue for HNSCC treatment.
