The use of biotinylated-EGF-modified gelatin nanoparticle carrier to enhance cisplatin accumulation in cancerous lungs via inhalation
To develop a polymer-anticancer drug conjugate, we employed gelatin nanoparticles (GPs) as carriers of cisplatin (CDDP) with anticipated improved therapeutic effect and reduced side effects. The anticancer activities of CDDP-incorporated in GPs (GP–Pt) with biotinylated-EGF (bEGF) modification (GP–Pt–bEGF) were studied. GP–Pt–bEGF with EGFR affinity produced much higher Pt concentrations in A549 cells (high EGFR expression) than in HFL1 cells (low EGFR expression). An in vitro anticancer study showed that GP–Pt–bEGF was more potent than free CDDP or GP–Pt because of its rapid effect on the cell cycle as well as a lower IC50 (1.2 μg/ml) that inhibits A549 cell growth. PI staining showed that cells treated with GP–Pt-bEGF for only 4 h had the highest sub-G1 population.The CDDP formulations – free CDDP, GP–Pt, and GP–Pt–bEGF – were given by intratumorous injections to SCID mice in a subcutaneous model. This treatment showed that GP–Pt–bEGF had stronger anti-tumor activity and was less toxic than free CDDP in vivo. Mice treated with GP–Pt–bEGF showed slight body weight loss, whereas free CDDP treatment at the same dose caused a body weight loss of 20–30%. Furthermore, these formulations were given to mice with lung cancer via aerosol delivery. This treatment showed that inhaled GP–Pt–bEGF could target EGFR-overexpressing cells to achieve high cisplatin dosage in cancerous lungs.To summarize, gelatin nanoparticles loaded with CDDP and decorated with EGF tumor-specific ligand were successfully developed. Their in vitro and in vivo targeting ability and anticancer effect were confirmed. The aerosol delivery of the nanodrug carrier was demonstrated. Simple aerosol delivery of targeted drug carriers may prove useful for the clinical treatment of lung cancer patients.
Journal: Biomaterials - Volume 30, Issue 20, July 2009, Pages 3476–3485