Loco-regional radiosensitizing nanoparticles-in-gel augments head and neck cancer chemoradiotherapy

• Published in: Journal of controlled release 2022-03, Vol.343, p.288-302
• Main Authors: Bhardwaj, Prateek, Gota, Vikram, Vishwakarma, Komal, Pai, Venkatesh, Chaudhari, Pradip, Mohanty, Bhabani, Thorat, Rahul, Yadav, Subhash, Gurjar, Murari, Goda, Jayant Sastri, Banerjee, Rinti
• Format: Article
• Language: English
• Subjects: Apoptosis; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Chemoradiotherapy; Chemoradiotherapy - methods; Cisplatin; Head and Neck Neoplasms - drug therapy; Head and neck squamous cell carcinoma; Humans; Loco-regional; Nanoparticle-in-hydrogel; Nanoparticles; Positron Emission Tomography Computed Tomography; Squamous Cell Carcinoma of Head and Neck - drug therapy; Synergistic radiosensitizers
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2022.01.040

The therapeutic gain in loco-regionally advanced unresectable head and neck squamous cell carcinoma (HNSCC) is limited with the traditional use of concurrent chemoradiotherapy (CRT) owing to dose-limiting toxicities of systemic clinical radiosensitizers. Delivery through regional platforms is challenging due to limited drug permeation but allows spatio-temporal control of combinatorial regimens locally to overcome drug resistance. We address these challenges by developing biodegradable gellan- and lipid-based dual nanocarriers-in-ion-triggered porous mucoadhesive hydrogels for enhanced site-specific delivery of clinically relevant radiosensitizers i.e. cisplatin and paclitaxel. Interestingly, the nanoparticle-in-gel prolonged the tumor bioaccumulation of both the chemotherapeutic drugs with reduced systemic absorption, thereby improving in vivo efficacy which was confirmed by PET-CT imaging and safety as compared to systemic commercial formulations approved for HNSCC chemoradiotherapy. The nanoparticles facilitated intracellular radiosensitizer uptake and cell arrest to synergistically enhance radiation-induced DNA nicks and apoptosis. Our findings suggest the clinical potential of the present platform in the loco-regional management of HNSCC requiring curative CRT. [Display omitted] •For regional delivery, particle-in-gel offers advantage over free drugs and nanoparticles.•Gellan gum hydrogel contains cisplatin loaded high acyl gellan gum nanoparticles.•As second nanoparticle, the gel contains paclitaxel loaded soya lecithin liposome.•Synergistic radiosensitizers induces cell cycle arrest, DNA damage, and apoptosis.•Sustained drug releasing depot enhances tumor levels and reduces systemic absorption.