Multifunctional pH-disintegrable micellar nanoparticles of asymmetrically functionalized β-cyclodextrin-based star copolymer covalently conjugated with doxorubicin and DOTA-Gd moieties.

We report on a novel type of multifunctional pH-disintegrable micellar nanoparticles fabricated from asymmetrically functionalized β-cyclodextrin (β-CD) based star copolymers covalently conjugated with doxorubicin (DOX), folic acid (FA), and DOTA-Gd moieties for integrated cancer cell-targeted drug delivery and magnetic resonance (MR) imaging contrast enhancement. Asymmetrically functionalized β-CD, (N(3))(7)-CD-(Br)(14), which possesses 7 azide functionalities and 14 α-bromopropionate moieties in the upper and lower rim of rigid toroidal β-CD core, respectively, was synthesized at first. The subsequent atom transfer radical polymerization (ATRP) of N-(2-hydroxypropyl) methacrylamide (HPMA), conjugation with DOX and FA, and click reaction with alkynyl-(DOTA-Gd) complex afforded (DOTA-Gd)(7)-CD-(PHPMA-FA-DOX)(14) star copolymer comprising of 7 DOTA-Gd complex moieties and 14 PHPMA arms covalently anchored with DOX and FA via acid-labile carbamate linkages and ester bonds, respectively. The covalent conjugation with ∼13 DOX molecules onto PHPMA arms per star copolymer (∼14 wt% loading content) endows the initially hydrophilic one with amphiphilicity, leading to the self-assembly into micellar nanoparticles of several tens of nanometers in aqueous solution at pH 7.4. In vitro DOX release profile from micellar nanoparticles is highly pH-dependent, and over a time period of 42 h, cumulative releases of ∼10%, 53%, and 89% conjugated DOX at pH 7.4, 5.0, and 4.0, respectively, were observed. Most importantly, the pH-modulated release of conjugated DOX from micellar nanoparticles is accompanied with the micelle disintegration due to the loss of amphiphilicity of the star copolymer scaffold. In vitro cell viability assays revealed that (DOTA-Gd)(7)-CD-(PHPMA(15))(14) star copolymer is almost non-cytotoxic up to a concentration of 0.5 g/L, whereas DOX-conjugated micellar nanoparticles of (DOTA-Gd)(7)-CD-(PHPMA-FA-DOX)(14) can effectively enter and kill HeLa cells at a concentration higher than ∼80 mg/L. In vitro MR imaging experiments indicated a considerably enhanced T(1) relaxivity (r(1) = 11.4 s(-1) mM(-1)) for micellar nanoparticles compared to that for the small molecule counterpart, alkynyl-DOTA-Gd (r(1) = 3.1 s(-1) mM(-1)). In vivo MR imaging assay in rats revealed considerable accumulation of micellar nanoparticles within rat liver and kidney and prominent positive contrast enhancement. The integrated design of diagnostic and therapeutic functions of multifunctional pH-disintegrable micellar nanoparticles augurs well for their practical applications in the field of image-guided cancer chemotherapy.

Liu T ，Li X ，Qian Y ，Hu X ，Liu S ... -  《-》

Amphiphilic multiarm star block copolymer-based multifunctional unimolecular micelles for cancer targeted drug delivery and MR imaging.

We report on the fabrication of multifunctional polymeric unimolecular micelles as an integrated platform for cancer targeted drug delivery and magnetic resonance imaging (MRI) contrast enhancement under in vitro and in vivo conditions. Starting from a fractionated fourth-generation hyperbranched polyester (Boltorn H40), the ring-opening polymerization of ɛ-caprolactone (CL) from the periphery of H40 and subsequent terminal group esterification with 2-bromoisobutyryl bromide afforded star copolymer-based atom transfer radical polymerization (ATRP) macroinitiator, H40-PCL-Br. Well-defined multiarm star block copolymers, H40-PCL-b-P(OEGMA-co-AzPMA), were then synthesized by the ATRP of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and 3-azidopropyl methacrylate (AzPMA). This was followed by the click reaction of H40-PCL-b-P(OEGMA-co-AzPMA) with alkynyl-functionalized cancer cell-targeting moieties, alkynyl-folate, and T(1)-type MRI contrast agents, alkynyl-DOTA-Gd (DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakisacetic acid), affording H40-PCL-b-P(OEGMA-Gd-FA). In aqueous solution, the amphiphilic multiarm star block copolymer exists as structurally stable unimolecular micelles possessing a hyperbranched polyester core, a hydrophobic PCL inner layer, and a hydrophilic P(OEGMA-Gd-FA) outer corona. H40-PCL-b-P(OEGMA-Gd-FA) unimolecular micelles are capable of encapsulating paclitaxel, a well-known hydrophobic anticancer drug, with a loading content of 6.67 w/w% and exhibiting controlled release of up to 80% loaded drug over a time period of ∼120 h. In vitro MRI experiments demonstrated considerably enhanced T(1) relaxivity (18.14 s(-1) mM(-1)) for unimolecular micelles compared to 3.12 s(-1) mM(-1) for that of the small molecule counterpart, alkynyl-DOTA-Gd. Further experiments of in vivo MR imaging in rats revealed good accumulation of unimolecular micelles within rat liver and kidney, prominent positive contrast enhancement, and relatively long duration of blood circulation. The reported unimolecular micelles-based structurally stable nanocarriers synergistically integrated with cancer targeted drug delivery and controlled release and MR imaging functions augur well for their potential applications as theranostic systems.

Li X ，Qian Y ，Liu T ，Hu X ，Zhang G ，You Y ，Liu S ... -  《-》

Light-triggered concomitant enhancement of magnetic resonance imaging contrast performance and drug release rate of functionalized amphiphilic diblock copolymer micelles.

Li Y ，Qian Y ，Liu T ，Zhang G ，Liu S ... -  《-》

Doxorubicin-conjugated β-NaYF4:Gd(3+)/Tb(3+) multifunctional, phosphor nanorods: a multi-modal, luminescent, magnetic probe for simultaneous optical and magnetic resonance imaging and an excellent pH-triggered anti-cancer drug delivery nanovehicle.

Padhye P ，Alam A ，Ghorai S ，Chattopadhyay S ，Poddar P ... -  《-》

Codelivery of doxorubicin and camptothecin by dual-responsive unimolecular micelle-based β-cyclodextrin for enhanced chemotherapy.

Tumor microenvironment (TME)-induced drug delivery technology is a promising strategy for improving low drug accumulation efficiency, short blood circulation and weak therapeutic effect. In this work, a dual-responsive (reduction- and pH-responsive) polyprodrug nanoreactor based on β-cyclodextrin (β-CD) was constructed for combinational chemotherapy. Specifically, the dual-responsive star polymeric prodrug was synthesized by atom transfer radical polymerization (ATRP) based on a starburst initiator of β-CD-Br. The obtained polyprodrug contained a hydrophilic chain of poly-(ethylene glycol) methyl ether methacrylate (POEGMA) and a hydrophobic part of camptothecin (CPT) prodrug and poly[2-(diisopropylamino)ethyl methacrylate] (PDPA), denoted as β-CD-PDPA-POEGMA-PCPT (CCDO for short). The obtained CCDO could form stable unimolecular micelles, which could be efficiently internalized by cancer cells. To enhance the curative effect, the anticancer agent doxorubicin (DOX) could be encapsulated into the hydrophobic cavity of the CCDO by hydrophobic-hydrophobic interaction. In vitro drug release studies showed that the obtained CCDO/DOX micelles controlled the release of active CPT and DOX occurring in a reductive environment and at low pH. In vitro cytotoxicity results suggested that the anticancer efficacy of dual-responsive CCDO/DOX micelles was superior to that of CCDO micelles. In addition, in vivo results verified good blood compatibility of the unimolecular micelles. This integrated dual-responsive drug delivery system may solve the low drug loading and poor controlled release problems found in traditional polymer-based drug carriers, providing an innovative and promising route for cancer therapy.

Gao YE ，Bai S ，Ma X ，Zhang X ，Hou M ，Shi X ，Huang X ，Chen J ，Wen F ，Xue P ，Kang Y ，Xu Z ... -  《-》