Novel drug-conjugated amphiphilic A(14)B(7) miktoarm star copolymers composed of 14 poly(epsilon-caprolactone) (PCL) arms and 7 poly(ethylene glycol) (PEG) arms with beta-cyclodextrin (beta-CD) as core moiety were synthesized by the combination of controlled ring-opening polymerization (CROP) and "click" chemistry. (1)H NMR, FT-IR, and SEC-MALLS analyses confirmed the well-defined A(14)B(7) miktoarm star architecture. These amphiphilic miktoarm star copolymers could self-assemble into multimorphological aggregates in aqueous solution, which were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Moreover, the drug-loading efficiency and drug-encapsulation efficiency of the drug-conjugated miktoarm star copolymers were higher than those of the corresponding non-drug-conjugated miktoarm star copolymers.

The clinical utility of doxorubicin (DOX) is restricted by its severe side effects. Continuous efforts are aimed at developing efficacious DOX-delivery systems that may overcome the drawbacks of existing ones. Herein, we report a self-assembling prodrug forming high drug loading nanoparticles for DOX delivery. A low molecular weight polyethylene glycol (PEG) chain as the hydrophilic part was anchored to hydrophobic DOX via an acid-cleavable hydrazone bond to form the amphiphilic prodrug PEG-DOX. In aqueous solution, PEG-DOX formed nanoparticles with a diameter of $125 nm and extremely high drug loading ($46 wt%). These nanoparticles were stable in PBS but released DOX in an acidic pH-triggered manner.Interestingly, taken up by cells via endocytosis, PEG-DOX bypassed the P-glycoprotein (P-gp)-mediated efflux of DOX, leading to drug accumulation in DOX-resistant human breast cancer cells (MCF-7/ADR).More importantly, PEG-DOX exhibited potent antitumor activity in vitro and in vivo, and showed significantly increased in vivo safety than free DOX. These encouraging data merit further preclinical and clinical development on PEG-DOX.

Per‐2,3‐acetyl‐β‐cyclodextrin with seven primary hydroxyl groups was synthesized by selective modification and used as multifunctional initiator for the ring‐opening polymerization of ε‐caprolactone (CL). Well‐defined β‐cyclodextrin‐centered seven‐arm star poly(ε‐caprolactone)s (CDSPCLs) with narrow molecular weight distributions (≤1.15) have been successfully prepared in the presence of Sn(Oct)2 at 120 °C. The molecular weight of CDSPCLs was characterized by end group 1H NMR analyses and size‐exclusion chromatography (SEC), which could be well controlled by the molar ratio of the monomer to the initiator. Furthermore, amphiphilic seven‐arm star poly(ε‐caprolactone‐b‐ethylene glycol)s (CDSPCL‐b‐PEGs) were synthesized by the coupling reaction of CDSPCLs with carboxyl‐terminated mPEGs. 1H NMR and SEC analyses confirmed the expected star block structures. Differential scanning calorimetry analyses suggested that the melting temperature (Tm), the crystallization temperature (Tc), and the crystallinity degree (Xc) of CDSPCLs all increased with the increasing of the molecular weight, and were lower than that of the linear poly(ε‐caprolactone). As for CDSPCL‐b‐PEGs, the Tc and Tm of the PCL blocks were significantly influenced by the PEG segments in the copolymers. Moreover, these amphiphilic star block copolymers could self‐assemble into spherical micelles with the particle size ranging from 10 to 40 nm. Their micellization behaviors were characterized by dynamic light scattering and transmission electron microscopy. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6455–6465, 2008

Novel amphiphilic eight‐arm star triblock copolymers, star poly(ε‐caprolactone)‐block‐poly(acrylic acid)‐block‐poly(ε‐caprolactone)s (SPCL‐PAA‐PCL) with resorcinarene as core moiety were prepared by combination of ROP, ATRP, and “click” reaction strategy. First, the hydroxyl end groups of the predefined eight‐arm SPCLs synthesized by ROP were converted to 2‐bromoesters which permitted ATRP of tert‐butyl acrylate (tBA) to form star diblock copolymers: SPCL‐PtBA. Next, the bromide end groups of SPCL‐PtBA were quantitatively converted to terminal azides by NaN3, which were combined with presynthesized alkyne‐terminated poly(ε‐caprolactone) (A‐PCL) in the presence of Cu(I)/N,N,N′,N″,N″‐pentamethyldiethylenetriamine in DMF to give the star triblock copolymers: SPCL‐PtBA‐PCL. 1H NMR, FTIR, and SEC analyses confirmed the expected star triblock architecture. The hydrolysis of tert‐butyl ester groups of the poly(tert‐butyl acrylate) blocks gave the amphiphilic star triblock copolymers: SPCL‐PAA‐PCL. These amphiphilic star triblock copolymers could self‐assemble into spherical micelles in aqueous solution with the particle size ranging from 20 to 60 nm. Their micellization behaviors were characterized by dynamic light scattering and transmission electron microscopy. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2905–2916, 2009

Well-defined drug-conjugated amphiphilic A 2 B 2 miktoarm star copolymers [(PCL) 2 -(PEG) 2 -D] were prepared by the combination of controlled ring-opening polymerization (CROP) and ''click'' reaction strategy. First, bromide functionalized poly(e-caprolactone) (PCL-Br) with double hydroxyl end groups was synthesized by the CROP of e-caprolactone using 2,2-bis(bromomethyl)propane-1,3-diol as a difunctional initiator in the presence of Sn(Oct) 2 at 110 C. Next, the bromide groups of PCL-Br were quantitatively converted to azide form by NaN 3 to give PCL-N 3 . Subsequently, the end hydroxyl groups of PCL-N 3 were capped with ibuprofen as a model drug at room temperature. Finally, copper(I)-catalyzed cycloaddition reaction between ibuprofen-conjugated PCL-N 3 and slightly excess alkyne-terminated poly-(ethylene glycol) (A-PEG) led to ibuprofen-conjugated A 2 B 2 miktoarm star copolymer [(PCL) 2 -(PEG) 2 -D]. The excess A-PEG was removed by dialysis. 1 H NMR, FTIR and SEC analyzes confirmed the expected miktoarm star architecture. These amphiphilic miktoarm star copolymers could self-assemble into multimorphological aggregates in aqueous solution, which were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In addition, the drug-loading capacity of these drug-conjugated miktoarm star copolymers as well as their nondrug-conjugated analogs were also investigated in detail. V V C 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 6962-6976, 2009 a (PCL13) 2 -(PEG25) 2 -D, 13 and 25 represent the polymerization degree of PCL and PEG, respectively. D represents the drug-conjugated sample. b Number-average mean diameters measured by dynamic light scattering (DLS). c PDI denotes the polydispersities of nanoparticles in aqueous solution.6972 GOU ET AL.

Novel amphiphilic A14B7 multimiktoarm star copolymers composed of 14 poly(ε‐caprolactone) (PCL) arms and 7 poly(acrylic acid) (PAA) arms with β‐cyclodextrin (β‐CD) as core moiety were synthesized by the combination of controlled ring‐opening polymerization (CROP) and atom transfer radical polymerization (ATRP). 14‐Arm star PCL homopolymers (CDSi‐SPCL) were first synthesized by the CROP of CL using per‐6‐(tert‐butyldimethylsilyl)‐β‐CD as the multifunctional initiator in the presence of Sn(Oct)2 at 125 °C. Subsequently, the hydroxyl end groups of CDSi‐SPCL were blocked by acetyl chloride. After desilylation of the tert‐butyldimethylsilyl ether groups from the β‐CD core, 7 ATRP initiating sites were introduced by treating with 2‐bromoisobutyryl bromide, which further initiated ATRP of tert‐butyl acrylate (tBA) to prepare well‐defined A14B7 multimiktoarm star copolymers [CDS(PCL‐PtBA)]. Their molecular structures and physical properties were in detail characterized by 1H NMR, SEC‐MALLS, and DSC. The selective hydrolysis of tert‐butyl ester groups of the PtBA block gave the amphiphilic A14B7 multimiktoarm star copolymers [CDS(PCL‐PAA)]. These amphiphilic copolymers could self‐assemble into multimorphological aggregates in aqueous solution, which were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM) and atomic force microscopy (AFM). © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2961–2974, 2010

Two novel multifunctional precursors with eight alcoholic hydroxyls were synthesized by derivatization of resorcinarene. Well‐defined eight‐arm star‐shaped poly(ε‐caprolactone)s (SPCLs) with reasonably narrow molecular weight distributions have been successfully prepared using the precursors as macro‐initiators and yttrium tris(2,6‐di‐tert‐butyl‐4‐methylphenolate) [Y(DBMP)3] as catalyst at 40 °C. The molecular weight of SPCLs was characterized by end group 1H NMR analyses and size‐exclusion chromatography, which could be well controlled by the molar ratio of the monomer to the precursor. The polymerization is more controllable with the precursor holding longer hydrocarbon chains as R groups. Differential scanning calorimetry analyses suggested that the maximal melting point, the crystallization temperature, and the degree of crystallinities of SPCLs increased with the increasing of the molecular weight, and were significantly lower than that of the counterpart linear poly(ε‐caprolactone) (LPCL). Furthermore, polarized optical microscopy indicated that LPCL showed fast crystallization rate with apparent Maltese cross pattern, whereas SPCL exhibited irregular spherulite and apparently slower crystallization rate. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2108–2118, 2008

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