Drug Delivery and Targeting (Track)




Drug-loaded multilayered films featuring uni-/dual-directional, highly adjustable, long-term sustained drug release behaviors for single-/dual-drug delivery stent application to treat malignant bodily tubular structures or cavities

Shengrong Guo
Department: School of Pharmacy, Institution: Shanghai Jiao Tong University 800 Dongchuan Road, Shanghai, People’s Republic of China

Abstract:

Stents have been widely used for treatment of stenosis/stricture and occlusion of bodily tubular structures or cavities, such as blood vessel, esophagus, biliary, pancreatic, prostate and urethral ducts, thanks to its desirable ability in providing support or expanding the lumen. More recently, drug-delivery stents emerged and have received increasingly attention, by virtue of its dual functions of providing mechanic support and releasing drug to treat malignancy positively or prevent restenosis. Therefore, drug-delivery stent can function simultaneously as both a mechanical device and a drug delivery system for locoregional treatment.

In the light of recent advances in bioresorbable film-based stents and drug delivery systems, we developed a series of new antitumor drug-incorporated PCL/PLA films featuring complex structures, which endowed the films with uni-/dual-directional, highly adjustable, long-term sustained drug release behaviors for treatment of complex local tubular or cavity diseases. Two most widely used bioresorbable polymers (poly(ε-caprolactone) (PCL) and poly(l-lactic acid) (PLLA)), three drugs (antitumor 5-fluorouracil and paclitaxel as well as antibacterial ofloxacin), and two methods (hot-molding method and solution casting method) were used in the preparation of drug-loaded films. Three types of multilayered films were prepared: (I) Film_{type I}: bilayered film with a drug-free PCL layer (backing layer) and a 5-fluorouracil-loaded PCL layer; (II) Film_{type II}: trilayered film with a backing layer, a 5-fluorouracil-loaded layer and a drug-free/PEG-added PCL layer as coating layer; (III) Film_{type III}: trilayered film with a drug-free PLA layer (isolating layer), an ofloxacin-loaded PLA layer and a paclitaxel-loaded PLA layer. A variety of properties, including mechanic properties, in vitro drug release, evolution of microstructures and ex vivo permeation performances, of these films were investigated to simulate and predict the properties of this film-based polymeric biodegradable stent. Characterization of the films by scanning electron microscopy (SEM) revealed that the 5-fluorouracil/paclitaxel particles were homogeneously dispersed in the drug-loaded layer, and there emerged many pores on surface and in bulk of film after drug and PEG release, and the porous structure gradually evolved with drug and PEG release during the incubation in PBS. Drug release and Franz’s cells investigation results revealed that: (a) all the three types of films, Film_{type I}, Film_{type II} and Film_{type III}, could sustain their drug releases for more than 90 days; (b) the backing layers of Film_{type I} and Film_{type II} successfully blocked the drug permeation through them so that drug release was in a unidirectional manner—95% of drug was released from the 5-fluorouracil-loaded layer side, which was designed to touch the malignant tissue wall; (c) the in vitro release behavior for Film_{type I} was found to be dependent on the drug loading dose and enviromental pH, and could also be effctively regulated by adding hydrophilic PEG as pore forming agent in the drug-loaded layer; (d) with a coating layer, Film_{type II} could better control the release of drug from 5-fluorouracil-loaded layer than Film_{type I}, and zero-order release patterns were observed for a range of coating formulations; (e) the addition of PEG as porogen in the coating layer of Film_{type II} accelerated the drug release due to the elevation of coating permeability to drug, and the pore-forming mechanism of PEG was found to be leaving voids after its fast leaching out, revealed by the test monitoring PEG release and by SEM observation of dynamic microstructures. (f) Loading of drug in the coating layer could lead to a characterized two-phased release profile, thanks to the dynamic drug release contributed initially by the outer coating layer and then by the inner drug-loaded layer. (g) For Film_{type III}, the anti-bacterial ofloxacin and anti-cancer paclitaxel were released respectively from the two sides of films, with the design concept that ofloxacin side facing the lumen of stent and the paclitaxel side touching the malignant tissue wall; the isolating layer blocked the permeations of both ofloxacin and paclitaxel through it, thus avoiding the release of drugs from their reverse directions and ensuring the efficient delivery of drugs to the target sites. Porcine esophageal mucosa was employed to investigate the drug release from films and then ex vivo permeation through mucosa, and it was demonstrated that drug permeation behavior determined by the drug release pattern from the film. Therefore, the drug delivery into tissue wall could also be regulated by changing the film formulation. These results demonstrate that the strategy of applying complex multilayered structures to the films can endow the films with high flexibility in releasing drug. With the virtue of delivering drug in a uni-/dual-directional, controlled and long-term manner, the multilayered films offer an attractive mode to produce film-based drug delivery stents for local treatment of stenosis/stricture or occlusion.

Keywords: Stent; Drug delivery system; multilayered films; Poly(epsilon-caprolactone) (PCL); Poly(lactic acid) (PLA); Scanning electron microscopy (SEM).