Doxorubicin‐Loaded Polymeric Micelle Overcomes Multidrug Resistance of Cancer by Double‐Targeting Folate Receptor and Early Endosomal pH

Abstract

An optimized, pH-sensitive mixed micelle system conjugated with folic acid was prepared to challenge multidrug resistance (MDR) in cancers. The micelles were composed of poly(histidine (His)-co-phenylalanine (Phe))-b-poly(ethylene glycol) (PEG) and poly(L-lactic acid) (PLLA)-b-PEG-folate. Core-forming, pH-sensitive hydrophobic blocks of poly(His-co-Phe) of varying composition were synthesized. The composition-dependent pK values of poly(His-co-Phe) (Mn=5,000−5,500 Da) were examined. The size and critical micelle concentration were evaluated as a function of pH. The pH sensitivity of the micelles was roughly controlled by the copolymer composition, and its fine tuning to early endosomal pH was achieved by blending PLLA(3K)-b-PEG (2K)-folate, especially in the presence of a basic anticancer drug, doxorubicin (DOX).To prove the efficacy of the micellar system, in vitro tests including cell viability, folate receptormediated endocytosis, and endosomolytic acitivity were conducted against both wild-type (A2780) and DOX-resistant ovarian carcinoma cell lines (A2780/DOX R ). From the physicochemical properties and in vitro results, a mixed micelle system composed of poly(His-co-Phe (16 mole%))-b-PEG (80 wt%) and PLLA-b-PEG-folate (20 wt%) was selected to target early endosomal pH. DOXloaded (ca. 20 wt%) micelles effectively killed both wild-type sensitive and MDR cancer cell lines through an instantaneous high dose of DOX in the cytosol, resulting from active internalization, accelerated DOX release triggered by endosomal pH, and a disruption of endosomal pH.

Maghemite Functionalization for Antitumor Drug Vehiculization

“…Polymer vehicles for doxorubicin may have the form of liposomes (Niu et al, 2010;Pakunlu et al, 2006;Rifkin et al, 2006) and polymeric micelles (Cuong et al, 2011;Gao et al, 2005;Kim et al, 2008;You et al, 2008). Nowadays there has been an enormous amount of research on the doxorubicin union with nanoparticulate carriers (Nawara et al, 2012;Du et al, 2011;Nowicka et al, 2009).…”

“…7.10), cuya excelente utilidad terapéutica en muy diversos tumores está bien demostrada (Minotti et al, 2004). Debe mencionarse sin embargo que, como ocurre con otras antriciclinas, su uso presenta toxicidad cardíaca crónica, acumulativa y dependiente de la dosis, por lo que se han diseñado diversos tipos de métodos para su transporte y liberación, particularmente liposomas (Niu et al, 2010;Pakunlu et al, 2006;Rifkin et al, 2006), micelas poliméricas (Cuong et al, 2011;Gao et al, 2005;Kim et al, 2008;You et al, 2008) y nanopartículas portadoras (Nawara et al, 2012;Du et al, 2011;Nowicka et al, 2009). …”

A pH-sensitive multifunctional gene carrier assembled via layer-by-layer technique for efficient gene delivery

“…21 It was expected that the outermost layer of CMCS would fall off from the surface of CMCS-CLDPD in the acidic environment of tumors. Therefore, in order to evaluate the pH sensitivity of CMCS-CLDPD, the in vitro release of DNA from CMCS-CLDPD in 50 mM phosphate buffer solution (PBS) with different pH values (pH 5.5, 6.0, 6.5, 7.0, 7.4) was determined.…”

Folate-conjugated methoxy poly (ethylene glycol)/poly (L-Alanine) amphiphilic block copolymeric micelles for targeted delivery of paclitaxel

“…Thus, folic acid has been used as a targeting ligand to deliver therapeutic agents to cancer cells due to its high binding affinity to folate receptors, low immunogenicity, ease of modification, small size and functional stability (Park et al, 2005). Several folate-drug conjugates have been reported in the literatures, such as folate-low molecular weight drugs , Aronov et al, 2003, Satyam, 2008, folate-liposomes (Gabizon et al, 2004, Shi et al, 2002, Wu et al, 2006, Xiang et al, 2008, folate-gene vectors (Kim et al, 2007, Liang et al, 2008, Yoshida et al, 2006, folate-nanoparticles (Pan andFeng, 2008, Chen et al, 2008), folate-micelles (Park et al, 2005, Alemdaroglu et al, 2008, Kim et al, 2008, Yang et al, 2008, Chu et al, 2009, folate-prodrugs (Henne et al, 2006, Suzuki et al, 2007, Cavallaro et al, 2006, folate-imaging agents (KE et al, 2004.…”