| Common chemotherapy for cancer treatment is through intravenous injection,which always accompanied with acute toxicity and side effect,unavoidable pain and inconvenience.Whereas,oral administration is more desirable due to its flexible and controlled dosing schedule,reduced cost,as well as relatively prolonged systemic exposure profile with less fluctuation,which potentially leads to lower toxicity and improved efficacy and patients’ life quality.However,most chemotherapeutics have low solubility and poor permeability across gastrointestinal(GI)barrier as well as instability in gastric environment with extreme acidity,which limits their application in oral administration.Therefore,constructing novel oral delivery systems might solve up-mentioned problems and provide a new trend for cancer chemotherapyNovel polymersome self-assembled by amphiphilic β-cyclodextrin(β-CD)-centered tri-arm star polymer was developped as the carrier for Biopharmaceutics Classification System(BCS)Class Ⅲ drug,doxorubicin hydrochloride(DOX·HCl).This novel drug delivery system was assumed to improve DOX·HCl permeability by taking advantage of β-CD’s ability of forming inclusion complexation with biomembranes,which could further improve oral bioavailability.It is also conjectured that the inclusion complexation with DOX-HCl could extend drug loading area in the polymersomes,which would lead to substantially improved loading capacity for DOX-HClThe main content and conclusions are summarized belowFirstly,methoxy poly(ethylene glycol)-b-polylactide(mPEG-b-PLA)copolymers were synthesized by ring-opening polymerization,which were further conjugated to the hydroxyl groups of β-CD with the mPEG-b-PLA/β-CD conjugation ratio of 3/1(mol/mol).The molecular weight(MW)ratio between mPEG and PLA block was determined according to the volume fractions of the mPEG block(fEO)in amphiphilic polymers that could self-assemble into polymersomes.Therefore,the final three kinds of β-CD-centered tri-arm polymers were(mPEG2k-PLA2.5k)3-CD,(mPEG2k-PLA3k)3-CD and(mPEG2k-PLA3.5k)3-CD,with over 90%yield for mPEG-b-PLA synthesis and 75%yield for the recation between mPEG-b-PLA and β-CD.Secondly,blank and drug-loaded(mPEG2k-PLA2.5k)3-CD,(mPEG2k-PLA3k)3-CD and(mPEG2k-PLA3.5k)3-CD nanoparticles were made by the oil/water emulsion method.(mPEG2k-PLA3k)3-CD nanoparticles were preliminarily identified with typical vesicle-like structures with an aqueous inner core surrounded by a hydrophobic periphery after observing morphology of three kinds of blank nanoparticles using a transmission electron microscope.Dual drug loading areas in(mPEG2k-PLA3k)3-CD nanoparticles were further verified by observing water-soluble and lipophilic fluorescent dyes co-loaded nanoparticles under confocal microscopy.Meanwhile,(mPEG2k-PLA3k)3-CD nanopartilces exhibited higher DOX·HCl loading capacity(8.78%)than that of(mPEG2k-PLA2.5k)3-CD and(mPEG2k-PLA3.5k)3-CD nanoparticles,which was below 1%.Hence,the(mPEG2k-PLA3k)3-CD copolymer was confirmed to have the potential to form polymersome structure.Greatly improved loading capacity of(mPEG2k-PLA3k)3-CD polymersomes(about 8-fold enhanced)compared with classic mPEG5k-b-PLA12k polymersomes was contributed by the inclusion complexation between β-CD cavity and hydrophobic part of DOX-HCl,leading to extended loading area,which was verified by phase solubility analysis and observing increased absorption intensity on UV-vis spectra of drug-loaded polymersome solution.The drug release pattern of drug-loaded(mPEG2k-PLA3k)3-CD polymersomes was also investigated to determine the stability and sustained release property of the polymersomes in GI tract and during the systemic circulation.The release of the drug from was less than 35%in 24 hours under simulated intestinal fluid and physiological conditions(pH 6.8 and pH 7.4)and less than 50%in 2 hours under simulated gastric fluid(pH 1.2).Thirdly,the ability of(mPEG2k-PLA3k)3-CD polymersomes in improving oral absorption in vitro was investigated using DOX-HCl and rhodamine123(R123),both of which have poor permeability,as model drugs,MDCK cell monolayer as in vitro GI tract model,cellular uptake and transport study as evaluation criterions.It was found that cellular uptake and its rate was improved after DOX·HCl and R123 were encapsulated into polymersomes according to flow cytometry and confocal images Papp,AB values of DOX-HCl-loaded polymersomes(Ps-DOX-HCl)and R123-loaded polymersomes(Ps-R123)were approximately 1.63 and 2.01-fold higher than that of free drugs,while the Papp,BA values of Ps-DOX-HCl and Ps-R123 were only 37.74%and 36.90%of that for free ones at 37℃,which illustrated that the carrier could increase absorptive transport and attenuate the drug efflux.This phenomenon was further illustrated by transport studies under a lower temperature(4℃)and endocytosis inhibitors,revealing that membrane transport pathways for drug-loaded polymersomes were changed to active transcellular transport including caveolae-mediated endocytosis and macropinocytosis from passive paracellular route as free drugs.Moreover,fusion with the degradative lysosomes could be avoided during the transport process for drug-loaded polymersomes,which guaranteed its structure integralityLastly,in vivo pharmacokinetic studies in mice demonstrated a significant increase in the oral bioavailability of Ps-DOX-HCl compared with free DOX-HCl(7.32-fold),as well as extended half-life(8.22-fold).This resulted in a substantial anti-cancer efficacy against S180 tumor in vivo.The tumor inhibitory rates of intravenous injected free DOX-HCl at a dose of 2 mg/kg and oral administration of Ps-DOX-HCl at doses of 10 mg/kg and 20 mg/kg were 32.76%,26.58%and 49.34%,respectively.Furthermore,it was testified that the cardiotoxicity,which is intrinsically induced by DOX·HCl,and toxicity toward gastrointestinal tissues could be avoided using the β-CD-based polymersome carrier according to histological studiesIn summary,this study constructed a novel drug delivery system for oral administration of BCS Class III drugs based on β-CD-centered amphiphilic copolymers with improved loading capacity and transmembrane ability,leading to dramatically enhanced oral bioavailability.Moreover,its application in oral chemotherapy could not only lead to similar or even better antitumor effects than intravenous administration of free drugs,but also avoid unnecessary acute toxicity towards normal tissues as well as injury to gastrointestinal tissues.Therefore,this drug delivery system could provide cancer patients a more efficient and safer method to receive chemotherapy. |
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