title: Synthesis and self-assembly of amphiphilic poly(acrylicacid)-poly(ɛ-caprolactone)-poly(acrylicacid) block copolymer as novel carrier for 7-ethyl-10-hydroxy camptothecin.
abstract: The process of molecular self-assembly plays a crucial role in formulation of polymeric nanoparticulated drug delivery carriers as it creates the possibility for enhanced drug encapsulation and carrier surface engineering. This study aimed to develop a novel self-assembled polymeric micelles for targeted delivery in tumor cells in order to overcome not only various drawbacks of 7-ethyl-10-hydroxy camptothecin (SN-38) but also various reported limitations of other drug delivery systems, especially low drug loading and premature release. Custom synthesized amphiphilic triblock copolymer poly(acrylic acid)-poly(ɛ-caprolactone)-poly(acrylic acid) (PAA(13)-PCL(35)-PAA(13)) was used to prepare kinetically stable micelles by nanoprecipitation and modified nanoprecipitation procedure. Core-shell micelles with diameter of 120-140 nm, negative zeta potential and satisfactory drug loading were produced. The prepared formulations were stable in pH range of 3-12 and in media with NaCl concentration <1 mol/l. Screening mixed level factorial 3 × 2(2) design identified that the process temperature as well as the type of organic solvent has influence upon the efficacy of encapsulation, particle size, dissolution rate and burst release. Fourier transform infrared and differential scanning calorimetry analyses confirmed the entrapment of the active substance into the micelles. The kinetic analysis of dissolution studies revealed that the main mechanism of drug release from the prepared formulations is Fickian diffusion. Growth inhibition studies as well as DNA fragmentation assay performed on SW-480 cell lines clearly demonstrated increased growth inhibition effect and presence of fragmented DNA in cells treated with loaded micelles compared to SN-38 solution. Altogether, these results point out to potential biomedical and clinical application of PAA-PCL-PAA systems in the future.
authors.affiliation: Institute of Pharmaceutical Technology, Faculty of Pharmacy, University Ss. Cyril and Methodius, Skopje, Republic of Macedonia.
authors.forename: Beti
authors.initials: B
authors.lastname: Djurdjic
authors.affiliation: Institute of Pharmaceutical Technology, Faculty of Pharmacy, University Ss. Cyril and Methodius, Skopje, Republic of Macedonia.
authors.forename: Simona
authors.initials: S
authors.lastname: Dimchevska
authors.affiliation: Institute of Pharmaceutical Technology, Faculty of Pharmacy, University Ss. Cyril and Methodius, Skopje, Republic of Macedonia.
authors.forename: Nikola
authors.initials: N
authors.lastname: Geskovski
authors.affiliation: Institute of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, University Ss. Cyril and Methodius, Skopje, Republic of Macedonia.
authors.forename: Marija
authors.initials: M
authors.lastname: Petrusevska
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Valerya
authors.initials: V
authors.lastname: Gancheva
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Georgi
authors.initials: G
authors.lastname: Georgiev
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Petar
authors.initials: P
authors.lastname: Petrov
authors.affiliation: Institute of Pharmaceutical Technology, Faculty of Pharmacy, University Ss. Cyril and Methodius, Skopje, Republic of Macedonia kago@ff.ukim.edu.mk.
authors.forename: Katerina
authors.initials: K
authors.lastname: Goracinova
mesh_terms: D065966:Absorption, Physicochemical; D000180:Acrylic Resins / Q000009:adverse effects / Q000737:chemistry*; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000009:adverse effects / Q000737:chemistry*; D004058:Diffusion; D006801:Humans; D000077146:Irinotecan; D008422:Materials Testing; D053769:Nanocapsules / Q000009:adverse effects / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D011091:Polyesters / Q000009:adverse effects / Q000737:chemistry*; D016896:Treatment Outcome
chemical_list: D000180:Acrylic Resins; D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D053769:Nanocapsules; D011091:Polyesters; C538905:poly(epsilon-caprolactone)-b-poly(acrylic acid); D000077146:Irinotecan; D002166:Camptothecin
keywords: Poly(acrylic acid)–poly(ɛ-caprolactone)–poly(acrylic acid) block copolymer; SN-38; cell culture efficacy studies; polymeric micelles; targeted delivery