Abstract
Multidrug resistance (MDR) remains an unmet challenge in chemotherapy. Stimuli-responsive nanocarriers emerge as a promising tool to overcome MDR. Herein, pH-sensitive poly(β-amino ester)s polymers (PHP)-based micellar nanoparticles were synthesized for enhanced doxorubicin (DOX) delivery in drug resistant breast cancer MCF-7/ADR cells. DOX-loaded PHP micelles showed rapid cell-internalization and lysosomal escape in MCF-7/ADR cells. The cytotoxicity assays showed relatively higher cell inhibition of DOX-loaded PHP micelles than that of free DOX against MCF-7/ADR cells. Further mechanistic studies showed that PHP micelles were able to inhibit P-glycoprotein (P-gp) activity by lowering mitochondrial membrane potentials and ATP levels. These results suggested that the enhanced antitumor effect might be attributed to PHP-mediated lysosomal escape and drug efflux inhibition. Therefore, PHP would be a promising pH-responsive nanocarrier for enhanced intracellular drug delivery and overcoming MDR in cancer cells.
Highlights
Multidrug resistance (MDR) is a common issue in chemotherapy, resulting in the poor prognosis
It has been reported that several mechanisms are associated with MDR and one of them is P-glycoprotein (P-gp)-mediated efflux of intracellular drugs and compromised therapeutic efficacy [4]
DiDscOuXs-sliooanded PHP micelles were more cytotoxic to MCF-7/ADR cells than free DOX (Figure 9D), TsuPgGgSeIsnatnitndhgiPsPHsHtPuP/dcTyoP, uGaldSpoHwv-aessercneossmtitimieveaMtemDdiRcteoellfbaferecn7t .ai8nn9oMμsygCs/tFme-m7L/,Aw1D2as.R6 dμceegvl/lesml.oLpTehadendtIoC55d30 eoμlifgv/DermODLX,O-lroXeasdpineetdcotiPdvHerulPyg
Summary
Multidrug resistance (MDR) is a common issue in chemotherapy, resulting in the poor prognosis. It has been reported that several mechanisms are associated with MDR and one of them is P-glycoprotein (P-gp)-mediated efflux of intracellular drugs and compromised therapeutic efficacy [4] To address this issue, an increasing number of studies have exploited stimuli-responsive nanoparticle-based drug delivery systems to reverse P-gp-mediated MDR [5,6,7]. When the nanopar2tiocfle1s6 are taken up by cells through the endocytosis pathway, rapid acidification is initiated in endo/lysosomes, where the pH values can reach as low as 4.5–6.0 Such pH changes can be exploited wtohienrietiathtee tphHe cvhaalnugees coafnnarenaocpharatsiclleosw, sausch4.5a–s6t.h0.e sSiuzcehrepdHuccthioann,gdesisacsasnembebleyxporloaitgegdretgoaitnioitniattoe cthoentcrhoal nthgeedoeflinvaenryopoafrdtirculgess,tsoutcuhmaosrsth[1e3s–i1z5e].reTdouocbtitoanin, sduiscahspseHm-rbelsypoornsaigvgerpegroaptieorntyt,ooncoensttrroaltetghye idsetlhiveeuryseooffdpruolgysmtoertsucmoonrtasi[n1i3n–g15io].nTizoaoblbetagirnosuupcshthpaHt -urnesdpeorgnosivheydprrooppheirltiyc,itoynaensdtrhatyedgryopishtohbeicuistye sowf pitochlyems evrsiacopnrtoationninagtioionniozarbldeegprrooutopnsatthioant u[n1d6e].rgAo shyadrtoyppheiliociftycalansdsihcayldrioopnhizoabbilceitypsowlyimtcehress, pvioalyp(rβo-taomnaintioonesotrerd)sephraovtoenbaeteionne[x1t6e]n.sAivsealytyepxpe loofrecdlasassicbailoidoengizraadblaebpleoalynmdebriso, cpoomlyp(βat-iabmleinmoaetestreiar)lss fhoarvaenbteiceannecexrtednrsuivgeldyeelixvpelroyre[1d7a–s19b]i.oIdteggernaedraablllye ahnads baiopcKobmvpaaltuibeleofm~a6t.e5rifarlosmfoirtsantetirctaianrcyeramdriunge gdreoliuvpesr,yw[h17ic–h19is].tuInt agbelneebryalmlyohdauslaatinpgKtbhevaaldujeacoenf t~f6u.n5cftrioomnalitgsroteurptisa[r2y0]a.mOinnethgerootuhpesr, hwanhdic,hthies rtuapniadblperboytomnaotdiounlaotifnpgotlhye(βa-dajmaciennot efustnecrt)iso-nbaalsegdronuapnso[p2a0r].tiOclnesthuepoonthaercihdaicndp,Hthcearnapiniddupcreot“opnraottioonn sopf opnogley”(βe-fafemctisn,owehsitcehr)fsa-cbialisteadtesnathneopesacratipceleosfuepnocanpasucildaitcedpdHrucgasnfirnodmulcyeso“psormoteosn. The mixture was precipitated in diethyl ether twice, followed by being dried in vacuum. 1H NMR studies were carried out by using a Bruker AMX 500 NMR spectrophotometer (500 MHz) with CDCl3 as the solvent. 1H NMR (ppm): δ 1.20–1.40 (10H, –(HCH)2CH(CH2)3CH(HCH)2–), 1.40 (4H, –(HCH)2CH(CH2)3CH(HCH)2–), 1.65–1.70 (6H, –OCH2CH2(CH2)2CH2CH2O– and –(CH2)2CH (CH2)3CH(CH2)2–), 1.90–2.10 (4H, –COOCH2CH2(CH2)2CH2CH2COO–), 2.50 (4H, –CH2COO–), 2.65 (4H, –(HCH)2N–), 2.80 (4H, –(HCH)2N–), 3.3–3.4 (3H, CH3O–), 3.5–3.7 (4XH, CH2 in PEG repeat unit), 4.0–4.1 (4H, –COOCH2–), 4.20 (2H, –COOCH2–)
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