title: UPEC biomimickry at the urothelial barrier: lectin-functionalized PLGA microparticles for improved intravesical chemotherapy.
abstract: The urgent demand for more potent treatment schedules in bladder cancer (BCa) therapy calls for a refinement of the intravesical administration modalities. However, progress on drug delivery systems tailored to the penetration-hostile urothelial barrier lags behind the advancements in comparable fields. This study reports on a multimodal, carrier-based delivery concept that combines biorecognitive targeting with modified release strategies for improved intravesical chemotherapy. The plant lectin wheat germ agglutinin (WGA) was immobilized on poly(lactide-co-glycolide) (PLGA) microparticles (MP) to induce stable cytoadhesion via cellular carbohydrate chains, similar to the specific attachment mechanism utilized by uropathogenic bacteria. A panel of DNA-selective chemotherapeutics with established track record in uro-oncology was screened for physicochemical compatibility with the polymeric carrier formulation. Critical limitations in encapsulation efficiency were found for mitomycin C (MMC), doxorubicin (DOX), and gemcitabine hydrochloride (GEM), despite multiparametric optimization of the preparation conditions. In contrast, the amphiphilic 4-(N)-stearoyl prodrug of gemcitabine (GEM-C18) exhibited excellent processability with PLGA. In vitro bioassays on 5637 human BCa cells showed that the enhanced cytoadhesion of WGA-GEM-C18-PGLA-MP traces back to the specific lectin/carbohydrate interaction, and is not easily disrupted by adverse environmental factors. Owing to several synergistic effects, the combined prodrug/targeting approach resulted in strong cytostatic response even when adjusting the exposure scheme to the confined temporal conditions of instillative treatment. Our results highlight the importance of fine-tuning both pharmacokinetic and pharmacologic parameters to gain adequate impact on urothelial cancer cells, and assign promising potential to glycan-targeted delivery concepts for the intravesical route.
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstrasse 14, Vienna A 1090, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Neutsch
authors.forename: Michael
authors.initials: M
authors.lastname: Wambacher
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Wirth
authors.forename: Sylvia
authors.initials: S
authors.lastname: Spijker
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Kählig
authors.forename: Michael
authors.initials: M
authors.lastname: Wirth
authors.forename: Franz
authors.initials: F
authors.lastname: Gabor
mesh_terms: D000283:Administration, Intravesical; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D040761:Biomimetic Materials; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D016685:Mitomycin / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry*; D013229:Stearic Acids / Q000737:chemistry; D001749:Urinary Bladder Neoplasms; D019459:Urothelium / Q000378:metabolism; D014909:Wheat Germ Agglutinins / Q000737:chemistry*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D010713:Phosphatidylcholines; D011355:Prodrugs; D013229:Stearic Acids; D014909:Wheat Germ Agglutinins; D003841:Deoxycytidine; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C031183:stearic acid; D016685:Mitomycin; D004317:Doxorubicin; D000093542:Gemcitabine