Efficacy and Toxicity of Peritumoral Delivery of Nanoconjugated Cisplatin in an In Vivo Murine Model of Head and Neck Squamous Cell Carcinoma

Abstract

Importance Treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) uses a multi-disciplinary approach often limited by the toxicity and drug resistance of platinum agents. Objectives To test whether a nanocarrier-conjugated cisplatin boosting locoregional drug delivery improves tumor efficacy while decreasing systemic toxicity over systemic cisplatin in a murine model of locally advanced HNSCC. Design A randomized, controlled, in vivo study compared standard cisplatin with nanocarrier (hyaluronan [HA])–conjugated cisplatin (HA-cisplatin) each at 50% of the maximum tolerated doses in a murine model of locally advanced HNSCC (10 mice/arm, each injected with 1 × 106 MDA-1986 HNSCC cells, with phosphate-buffered saline and HA-only control arms). Mice were treated for 3 weeks and observed for 3 additional weeks. Setting Academic medical center. Participants Forty female Nu/Nu mice. Randomization and treatment arms were initiated once tumor volumes reached 30 mm3. Intervention Injection with MDA-1986 HNSCC cells followed by 3 weeks of treatment with cisplatin, HA-cisplatin, phosphate-buffered saline, or HA only. Main Outcomes and Measures Animal weights and tumor volumes were measured 3 times each week (modified RECIST [Response Evaluation Criteria in Solid Tumors]). At necropsy, animal kidneys were examined for nephrotoxic effects and cochleae were examined for ototoxic effects. Results The mice treated with HA-cisplatin showed superior tumor efficacy (1 with complete clinical response, 3 with partial response, 1 with stable disease, and 5 with progressive disease) compared with standard cisplatin (no animals with complete clinical response, 1 with partial response, 1 with stable disease, and 8 with progressive disease), which was statistically significant (P=.003). All control animals developed progressive disease. Weight loss and body score were surrogate measures of treatment toxicity. The HA-cisplatin group had the least weight loss (mean [SD], 10.8% [4.7%]) compared with the cisplatin group (13.6% [5.6%]; P=.25). Body score dropped to 2 or less in all cisplatin-treated mice but not in any HA-cisplatin–treated mice, which also lacked any histologic signs of nephrotoxic or ototoxic effects. Conclusions and Relevance Nanoconjugated HA-cisplatin significantly improves tumor efficacy with lower toxicity compared with standard cisplatin in locally advanced HNSCC in vivo, justifying additional translational studies.

Phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate in dogs with naturally occurring malignant tumors

“…In mouse xenografts of squamous cell carcinoma (SCC) of the head and neck and breast cancer, the formulation has shown improved tumor control over conventionally administered cisplatin. 1,2 Complementing this enhanced local efficacy, the pharmacokinetic profile of this formulation is superior to intravenously administered cisplatin with a reduced C max but greater area-under-the-curve (AUC), resulting in reduced nephrotoxicity, enhanced local efficacy, and extended systemic tumor cell exposure. 3,4 In a pilot trial of HA-Pt in dogs with spontaneous soft tissue sarcomas, the formulation resulted in similarly favorable tumor and plasma distributions.…”

“…Compared to cisplatin, HA-Pt significantly decreased tumor burden, prolonged survival rate, and reduced systemic toxicity as indicated by weight loss and pathological analysis in mice. 1,2,8 …”

Intratracheal Administration of Hyaluronan-Cisplatin Conjugate Nanoparticles Significantly Attenuates Lung Cancer Growth in Mice

“…Recently, a hyaluronan-cisplatin nanoconjugate (HA-Pt) has been developed and demonstrated to be useful in pre-clinical studies for loco-regional therapy of multiple cancers, including head and neck squamous cell carcinoma (16-18), breast cancer (19), melanoma (20), and soft tissue sarcoma (21). Hyaluronan (HA) is an inert, naturally-occurring glycosaminoglycan polysaccharide found in the extracellular matrix of most mammalian connective tissues (22).…”

Effects of peritumoral nanoconjugated cisplatin on laryngeal cancer stem cells

“…In previously published work, there were significantly increased lymphatic tissue concentrations of cisplatin and reduced organ toxicities with peritumoral injections of cisplatin conjugated to nanoscopic (25–100 nM) particles of HA (HA‐cisplatin) compared to systemically delivered standard cisplatin therapy. In related studies investigating this drug in orthotopic murine models, HA‐cisplatin was found to have significantly higher anticancer efficacy in vivo relative to conventional IV cisplatin therapy in HNSCC xenografts implanted in the buccal mucosa of the subject mice …”

“…In related studies investigating this drug in orthotopic murine models, HA-cisplatin was found to have significantly higher anticancer efficacy in vivo relative to conventional IV cisplatin therapy in HNSCC xenografts implanted in the buccal mucosa of the subject mice. 3,9 Moreover, HA is also a highly specific ligand for the CD44 surface receptors, 10 and CD44 is described as a cell surface marker specific for CSCs in HNSCC. In fact, CSCs were first successfully isolated from HNSCC cell lines utilizing CD44 expression.…”