title: Nanoencapsulation of ABT-737 and camptothecin enhances their clinical potential through synergistic antitumor effects and reduction of systemic toxicity.
abstract: The simultaneous delivery of multiple cancer drugs in combination therapies to achieve optimal therapeutic effects in patients can be challenging. This study investigated whether co-encapsulation of the BH3-mimetic ABT-737 and the topoisomerase I inhibitor camptothecin (CPT) in PEGylated polymeric nanoparticles (NPs) was a viable strategy for overcoming their clinical limitations and to deliver both compounds at optimal ratios. We found that thrombocytopenia induced by exposure to ABT-737 was diminished through its encapsulation in NPs. Similarly, CPT-associated leukopenia and gastrointestinal toxicity were reduced compared with the administration of free CPT. In addition to the reduction of dose-limiting side effects, the co-encapsulation of both anticancer compounds in a single NP produced synergistic induction of apoptosis in both in vitro and in vivo colorectal cancer models. This strategy may widen the therapeutic window of these and other drugs and may enhance the clinical efficacy of synergistic drug combinations.
authors.affiliation: 1] School of Pharmacy, Queen's University Belfast, Belfast, UK [2] Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: D
authors.initials: D
authors.lastname: Schmid
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: G E
authors.initials: GE
authors.lastname: Jarvis
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, UK.
authors.forename: F
authors.initials: F
authors.lastname: Fay
authors.affiliation: Centre for Infection and Immunity, Queen's University Belfast, Belfast, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Small
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, UK.
authors.forename: M K
authors.initials: MK
authors.lastname: Greene
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: J
authors.initials: J
authors.lastname: Majkut
authors.affiliation: Centre for Infection and Immunity, Queen's University Belfast, Belfast, UK.
authors.forename: S
authors.initials: S
authors.lastname: Spence
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: K M
authors.initials: KM
authors.lastname: McLaughlin
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: K D
authors.initials: KD
authors.lastname: McCloskey
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: P G
authors.initials: PG
authors.lastname: Johnston
authors.affiliation: Centre for Infection and Immunity, Queen's University Belfast, Belfast, UK.
authors.forename: A
authors.initials: A
authors.lastname: Kissenpfennig
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: D B
authors.initials: DB
authors.lastname: Longley
authors.affiliation: 1] School of Pharmacy, Queen's University Belfast, Belfast, UK [2] Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Scott
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D002166:Camptothecin / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D004339:Drug Compounding / Q000379:methods*; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D009596:Nitrophenols / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D013449:Sulfonamides / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D013921:Thrombocytopenia / Q000209:etiology
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D002166:Camptothecin