Poly(anhydride) nanoparticles for the oral administration of camptothecin

Resumo

The oral route is preferred by patients receiving chronic treatments (i.e. cancer) since it provides better quality of life. However, few oral chemotherapeutic agents are currently available. So, there is a need to develop strategies to increase these treatments¿ oral bioavailability. Camptothecin, a molecule that shows powerful anticancer activity, is still not used in clinic due to its difficult physicochemical characteristics and poor active form¿s stability. Thus, this molecule is a suitable candidate to encapsulate into carriers for its oral delivery. This work is based on the formulation of camptothecin in poly(anhydride) nanoparticles by two different strategies. The first one consisting in the preparation of poly(anhydride) containing different β-cyclodextrins or poly(ethyleneglycols). These nanoparticles were able to encapsulate the anticancer agent and exhibited different in vitro release profiles, but none of them released the loaded drug until they were incubated under simulated intestinal conditions. Pharmacokinetic studies performed in Wistar rats revealed that the relative oral bioavailability of camptothecin increased up to nearly 7 times when administered encapsulated compared to the oral bioavailability of the bare drug, being the carriers able to protect the molecule¿s active and less toxic form. The second strategy consisted on the synthesis of new cyclodextrin- or poly(ethylene glycol)-Gantrez® AN conjugates. These polymers were characterized, and used to prepare CPT-loaded nanoparticles, presenting suitable characteristics for their oral administration. The in vitro studies showed no release of the drug under simulated gastric conditions by the carriers while ex vivo imaging demonstrated their remarkable mucopenetrating abilities in the proximal ileum of rats. Finally, a pharmacokinetic study after the oral administration of the CPT-loaded nanoparticles to Wistar rats revealed that both formulations were able to enhance the drug¿s bioavailability, being the ones manufactured with the poly(ethylene glycol)-Gantrez® AN more effective than the ones fabricated with cyclodextrin-Gantrez® AN (Fr 7.6 versus 2.9). Overall, the encapsulation of camptothecin in poly(anhydride) nanoparticles enhanced the oral uptake of the drug both by increasing its stability and enhancing its intestinal permeability.