Pulmonary delivery of cisplatin–hyaluronan conjugates via endotracheal instillation for the treatment of lung cancer

Cisplatin (CDDP) intravenous treatments suffer several dose-limiting toxicity issues. Hyaluronan (HA), a naturally occurring biopolymer in the interstitium, is primarily cleared by the lymphatic system. An alteration in input rate and administration route through pulmonary delivery of hyaluronan–cisplatin (HA–Pt) conjugate may increase local lung CDDP concentrations and decrease systemic toxicity.Sprague–Dawley rats were split into four groups: i.v. CDDP (3.5 mg/kg), i.v. HA–Pt conjugate (3.5 mg/kg equivalent CDDP), lung instillation CDDP and lung instillation HA–Pt conjugate. Total platinum level in the lungs of the HA–Pt lung instillation group was 5.7-fold and 1.2-fold higher than the CDDP intravenous group at 24 and 96 h, respectively. A 1.1-fold increase of Pt accumulation in lung draining nodes for the HA–Pt lung instillation group was achieved at 24 h relative to the CDDP i.v. group. In the brain and kidneys, the CDDP i.v. group had higher tissue/plasma ratios compared to the HA–Pt lung instillation group. Augmented tissue distribution from CDDP i.v. could translate into enhanced tissue toxicity compared to the altered input rate and distribution of the intrapulmonary nanoformulation.In conclusion, a local pulmonary CDDP delivery system was developed with increased platinum concentration in the lungs and draining nodes compared to i.v. therapy.