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Abstract: This research is aimed to develop a kind of poly(ethylene glycol) shell-sheddable magnetic nanomicelle as the carrier of doxorubicin (Dox) in order to enhance its cellular uptake ability, and achieve synchronous magnetic resonance imaging (MRI)-visible function. Firstly, the five-member rings in poly (l-succinimide) (PSI) were successively opened by the amino terminated disulfide-linked poly(ethylene glycol) monomethyl ether (mPEG-SS-NH2) and dopamine (DA) to produce the graft copolymer of mPEG-SS-NH-graft-PAsp-DA. And then, drug-loaded magnetic nanomicelles of mPEG-SS-NH-graft-PAsp-DA@Fe3O4.Dox were obtained by the Fe3O4 nanoparticle-induced self-assembly of mPEG-SS-NH-graft-PAsp-DA. These magnetic nanomicelles showed spherical shapes with average particle size of about 120nm measured by dynamic light scattering (DLS). Due to the detachment of PEG shell in the presence of dithiothreitol (DTT), the magnetic nanomicelles showed accelerated in vitro release of Dox, and enhanced cellular uptake ability. Compared with free Dox, the Dox-loaded magnetic nanomicelles showed essential decreased cytotoxicity against Bel-7402 cell line. If its high r 2 relaxation rate (221mM−1 s−1) and good negative contrast effect for magnetic resonance imaging (MRI) were taken into account, mPEG-SS-NH-graft-PAsp-DA@Fe3O4.Dox could be used as MRI-detectable drug carrier of Dox with enhanced cellular uptake ability. [Copyright &y& Elsevier]

Highlights: [•] A reduction-sensitive drug carrier has been fabricated for the delivery of anti-cancer paclitaxel. [•] The polyion complexation of hydrophilic chains contributed to higher stability of assemblies in aqueous media. [•] The assembled micelle showed the advantages of potential passive targeting to tumor, reduction-sensitive controlled release, and so on. [Copyright &y& Elsevier]

To achieve passive targeting and controlled drug release at tumor sites trigged by low pH value and high level of glutathione (GSH), optimized delivery system for doxorubicin (DOX) based on core cross-linked nanomicelles was developed in this research. Particularly, methoxypoly(ethylene glycol)-nitrophenyl carbonate (mPEG-NPC) and 3,4-dihydroxyphenylaceticacid were grafted onto synthesized poly( N,N′ -cystamine bisacrylamide- N -Boc-1,2-diaminoethane) (poly(CBA-DAE)) to give methoxypoly(ethylene glycol)- g -poly( N,N′ -cystamine bisacrylamide- N -Boc-1, 2-diaminoethane)- g -3, 4-dihydroxyphenylaceticacid (mPEG- g -SS-PCD-DA). Core cross-linked micelles (CCLMs/SS) with a decreased average particle size of 121 nm were prepared by adding Fe 3+ into uncross-linked micelles (UCLMs/SS) self-assembled from mPEG- g -SS-PCD-DA. DOX-loaded CCLMs/SS exhibited minimal drug leakage (17.3%) under simulated blood conditions compared to DOX-loaded UCLMs/SS (31.3%). Fast drug release (52.4%) of DOX-loaded CCLMs/SS was achieved compared to DOX-loaded CCLMs/CC (32.9%) without disulfide bonds under simulated lysosomes condition over 42 h. The cytotoxicity of DOX-loaded CCLMs/SS against A549 cells pretreated with 40 mM NH 4 Cl was decreased significantly compared to that without NH 4 Cl treatment, and it is higher than that of DOX-loaded CCLMs/CC, further confirmed DOX release was triggered by the low pH value and high level of reductive agents of lysosomes. Compared with free DOX, DOX-loaded CCLMs/SS showed enhanced cellular uptake ability during 24 h of incubation through endocytosis. Besides, charge conversion of micelles happened when pH varied from 7.4 to 6.5, which facilitates the cellular uptake against A549 cells. In summary, all these results indicated that CCLMs/SS as a new type of intelligent nanocarriers exhibited excellent potential for drug delivery. [ABSTRACT FROM AUTHOR]

This study sought to develop a new type nanomicelle based on boronate ester-linked poly(ethylene glycol)- b -poly(benzyl glutamate) (PEG-BC-PBLG) diblock copolymer as the carrier of doxorubicin (Dox) to achieve acid-induced detachment of PEG shells and subsequent boronic acid-mediated enhanced endocytosis. In vitro studies revealed that the PEG-BC-PBLG copolymer was stable in neutral solutions but tend to hydrolysed under acidic conditions, which was attributed to the acid-sensitive properties of boronate ester bonds. The formation of PEG-BC@PBLG micelles was confirmed based on critical micelle concentration (CMC), particle size, and morphology observations. It was observed that these micelles were spherical with an average particle size of approximately 80 nm, as measured by dynamic laser scattering (DLS), suggesting their passive targeting to tumour tissue and endocytosis potential. Dox-loaded PEG-BC@PBLG micelles (PEG-BC@PBLG·Dox) showed sustained drug release profiles over 9 h, and their cumulative drug release was dependent on the pH value of the environment. Remarkably, cellular uptake ability of PEG-BC@PBLG micelles was found to be higher than that of non-boronate ester-linked PEG@PBLG micelles due to boronic acid-mediated endocytosis, as revealed by confocal laser scanning microscopy (CLSM) imaging of fluorescein isothiocyanate (FITC) green-conjugated micelles, thereby providing higher cytotoxicity against HepG2 cells. The antitumour activity and toxicity of PEG-BC@PBLG·Dox micelles in vivo were evaluated in BLAB/c mice against HepG2 cell-derived tumours. Compared with Dox, PEG-BC@PBLG·Dox showed reduced toxicity, whereas its tumour growth inhibition rate was 17% higher than that of free Dox. These results indicate the great potential of PEG-BC@PBLG micelles as the carrier of various lipophilic anticancer drugs with improved anti-tumour efficacy. [ABSTRACT FROM AUTHOR]

In this study, a novel micellar drug carrier was fabricated from an amphiphilic diblock copolymer containing poly (ethylene glycol) monomethyl ether (mPEG) and stearic moiety (C 18 ) with a linkage of valine-citrulline (VC), which can be cleaved by cathepsin B (C B ) enriched in lysosome of tumor cell. Moreover, the self-assembled micelles were observed as ellipsoid shape with major and minor axis of ca. 169 and 103 nm, respectively. Such drug carrier was used to encapsulate anti-cancer drug doxorubicin (DOX), and hence showed a faster drug release behavior in a mimic lysosome condition containing cathepsin B. It was ascribed to the lysosome-sensitivity of the valine-citrulline linkage, which was verified by the size distribution curve shifted to greater size under the same mimic lysosome condition. Furthermore, in comparison with pristine doxorubicin, the encapsulation strategy of as-fabricated micellar carrier resulted in a predominant decrease of cytotoxicity. On the whole, a micellar drug carrier, which can be disassembled by cathepsin B, has been emerging as a potential of specific drug release in lysosome. Additionally, the controlled nanoscale together with elongated structure of such assembled ellipsoid micelles might contribute passive targeting function to tumor tissue and faster cellular uptake behavior (Zhou et al. [33] ). [ABSTRACT FROM AUTHOR]

Gd(III) chelate is currently used as positive magnetic resonance imaging (MRI) contrast agent in clinical diagnosis, but generally induces the risk of nephrogenic systemic fibrosis (NSF) due to the dissociated Gd 3+ from Gd(III) chelates. To develop a novel positive MRI contrast agent with low toxicity and high sensitivity, ultrasmall MnO nanoparticles were PEGylated via catechol-Mn chelation and conjugated with cRGD as active targeting function to tumor. Particularly, the MnO nanoparticles with a size of ca. 5 nm were modified by α,β-poly(aspartic acid)-based graft polymer containing PEG and DOPA moieties and, meanwhile, conjugated with cRGD to produce the contrast agent with a size of ca. 100 nm and a longitudinal relaxivity ( r 1 ) of 10.2 mM −1 S −1 . Such nanoscaled contrast agent integrated passive- and active-targeting function to tumor, and its efficient accumulation behavior in tumor was verified by in vivo distribution study. At the same time, the PEG moiety played a role of hydrophilic coating to improve the biocompatibility and stability under storing and physiological conditions, and especially might guarantee enough circulation time in blood. Moreover, in vivo MRI revealed a good and long-term effect of enhancing MRI signal for as-fabricated contrast agent while cell viability assay proved its acceptable cytotoxicity for MRI application. On the whole, the as-fabricated PEGylated and cRGD-functionalized contrast agent based on ultrasmall MnO nanoparticles showed a great potential to the T 1 -weighted MRI diagnosis of tumor. [ABSTRACT FROM AUTHOR]

Gemcitabine, 2′,2′-difluoro-2′-deoxycytidine (dFdC), is the first-line antitumor agent in the treatment of pancreatic tumors. However, it possesses certain drawbacks, such as poor biological half-life resulted from rapid metabolism and the induction of resistance, leading to its restricted therapeutic potential. With the purpose of overcoming the above drawbacks, we developed a novel VESylated gemcitabine (VES-dFdC) prodrug by coupling the N 4 -amino group of the pyrimidine ring of dFdC to the carboxylic group of vitamin E succinate (VES). The resulting amphiphilic compound could protect the N 4 -amino group of the pyrimidine ring of dFdC from being degraded by cytidine deaminase. What is more, the prodrug was able to form nanocapsules in aqueous media (similar to the structure of cytomembrane), confirmed by transmission electron microscope (TEM). Their average particle size is about 107 nm with zeta potential of −33.4 mV measured by dynamic light scattering (DLS). VES-dFdC nanocapsules showed accelerated accumulative drug release profile in simulated lysosome environment (sodium acetate buffer pH 5 + cathepsin B, an enzyme in lysosome), due to the easily hydrolyzed property of amide bond by cathepsin B, while rather stable in PBS (pH 7.4) or sodium acetate buffer (pH 5.0) without cathepsin B, indicating their enhanced intracellular drug controlled release manner. Besides, VES-dFdC prodrug nanocapsules showed enhanced cellular uptake ability, and the amount of cellular uptake of the nanocapsules by the pancreatic cancer cell line BxPC-3 is seventy times higher than that of native gemcitabine in the first 1.5 h. Compared with free gemcitabine, VES-dFdC nanocapsules showed essentially increased growth inhibition activity against BxPC-3 cells, indicating its great potential as prodrug for pancreatic tumor therapy with improved antitumor activity. [ABSTRACT FROM AUTHOR]

Identifying an efficient tumor-targeted drug delivery system is an urgent task for the treatment of metastatic breast cancer. Herein, we report for the first time that a pH and redox dual-responsive polymer prodrug displays prominent inhibition of breast cancer metastasis to the lung. The polymer molecule was synthesized from hyaluronic acid (HA) and hydroxychloroquine (HCQ) through disulfide bonds as redox-sensitive linkers that self-assemble into nanocapsules (HA-ss-HCQ nanocapsules) at pH 7.4. Due to the pKa value of HCQ and built-in disulfide bonds, the nanocapsules were endowed with pH and redox dual-responsive properties. The in vitro drug release curve revealed that HA-ss-HCQ nanocapsules release drugs more quickly under low pH and high redox conditions. Moreover, the nanocapsules displayed active targeting and selectivity to metastatic breast cancer cells. Cellular uptake of Nile red-loaded nanocapsules observed by fluorescence microscopy showed that the nanocapsules exerted significantly enhanced cellular internalization capacity, which was greatly diminished by free HA. The IC 50 of HA-ss-HCQ nanocapsules in 4T1 cells was 2.23-fold lower than that of free HCQ. Importantly, wound healing assays and Transwell experiments demonstrated that HA-ss-HCQ nanocapsules greatly inhibited the migration and invasion of 4T1 cells. In particular, the metastasis of 4T1 cells to the lung was also remarkably suppressed by HA-ss-HCQ nanocapsules with minimal toxicity in an in vitro lung metastasis model, which was verified by the detection of macroscopic metastatic nodules and histological examination. In summary, this study provides a promising strategy for active-targeting therapy in metastatic breast cancer. [Display omitted] • Hyaluronic acid serves as both a carrier and an active targeting ligand. • HA-ss-HCQ has both lysosomal acidic environment and reducing environment sensitivity. • HA-ss-HCQ can significantly inhibit 4T1 cell migration and invasion. • HA-ss-HCQ may be used as carriers for the combined delivery of HCQ and other drugs. [ABSTRACT FROM AUTHOR]

Highlights: [•] mPEGylated artesunate amphiphilic conjugate was prepared through esterification. [•] The mPEG–ART conjugate was inclined to form nanocapsules in aqueous media. [•] The nanocapsules was biodegradation due to the easily hydrolyzed property of ester bond by esterase, which is abundant in cells. [•] The nanocapsules showed decreased cytotoxicity against L1210 and MCF7 cell line compared with free ART. [ABSTRACT FROM AUTHOR]

Highlights: [•] mPEG-PLG(CPT@CD) nanoparticles induced by host–guest interaction was fabricated. [•] The active lactone ring of CPT showed remarkably enhanced stability against hydrolysis under physiological condition, due to the protection effect from a dual lock system (the environment of micelle and the exterior surface of β-CD). [•] The nanoparticles displayed sustained and chemically stimulated release behavior. [•] The nanoparticles showed decreased cytotoxicity against MCF-7 cell line compared with free CPT. [Copyright &y& Elsevier]

Highlights: [•] CPT supramolecular micelles of mPEG-Ad@BAC-CDen/CPT were obtained by incorporation of CPT into mPEG-Ad@ BAC-CDen via dialysis method. [•] Owing to the reduction degradability of disulfide linker in main chain of BAC-CDen, the CPT sustainably release from micelles together with the gradual cleavage of polymer. [•] MPEG-Ad@BAC-CDen supramolecular micelles effectively protected the active lactone ring of CPT from hydrolysis under physiological condition. [•] Compared with free CPT, the CPT-loaded supramolecular micelles showed essential decreased cytotoxicity against L929 cell line. [Copyright &y& Elsevier]

Abstract: Surface modification of nanoparticles with poly (ethylene glycol) (PEG) shows poor cellular uptake, although it affords long circulation time and passive targeting potential to the tumor tissue. In this research, poly(ethylene glycol) shell-sheddable nanomicelle prodrug of camptothecin (CPT) was developed, in order to enhance the cellular uptake ability, achieve the passive targeting potential to tumor tissue and long circulation time, and to improve the stability of CPT in aqueous media. Firstly, the five-member rings in poly (l-succinimide) (PSI) were successively opened by the amino terminated disulfide-linked poly (ethylene glycol) monomethyl ether (mPEG-SS-NH2) and 6-aminocaproic acid to produce the graft copolymer of mPEG-SS-NH-g-PHAsp. And then, the resultant prodrug of mPEG-SS-NH-g-PHAsp-CPT was obtained by the esterification between carboxylic groups of mPEG-SS-NH-g-PHAsp and 20-OH of CPT. The prodrug was able to form spherical micelles in aqueous media because of its amphiphilic nature with average particle size of about 100nm measured by dynamic light scattering (DLS), suggesting its passive targeting potential to tumor tissue. Due to the detachment of PEG shell in the presence of dithiothreitol (DTT), the nanomicelle showed a tendency to aggregation, intense release of CPT, and enhanced cellular uptake ability. Also, the mPEG-SS-NH-g-PHAsp-CPT nanomicelle effectively protected the active lactone ring of CPT from hydrolysis under physiological condition. Compared with free CPT, mPEG-SS-NH-g-PHAsp-CPT nanomicelle showed essentially decreased cytotoxicity against L929 cell line in 24h, especially at high dosage, indicating its great potential as tumor tissue targeted prodrug. [Copyright &y& Elsevier]

Abstract: This research is aimed to develop a kind of hollow nanosphere based on β-cyclodextrin-grafted α, β-poly(aspartic acid) (β-CD-graft-PAsp) as drug carrier to enhance the stability of camptothecin (CPT) in aqueous media. Firstly, mono(6-(2-aminoethyl) amino-6-deoxy)-β-cyclodextrin (β-CDen) was synthesized by a substitution reaction between mono-6-deoxy-6-(p-tolylsulfonyl)-β-cyclodextrin (6-OTs-β-CD) and ethylenediamine; and then, the five-member rings in poly(l-succinimide) (PSI) were successively opened by β-CDen to obtain β-CD-graft-PAsp. The synthesized β-CD-graft-PAsp was found to form the unique hollow nanosphere with the internal hole of about 17nm and many β-CD cavities of 0.7nm interspersed on the shell. The drug-loading behavior of the hollow nanosphere was also evaluated by using CPT as guest molecule of β-CD. It was worth of note that the β-CD-graft-PAsp hollow nanosphere as carrier enhanced the stability of CPT in aqueous media, and the CPT from the β-CD-graft-PAsp hollow nanosphere displayed a sustained release profile and hence resulted in the essential decrease of cytotoxicity to L929 cell line. Furthermore, almost no cytotoxicity of the β-CD-graft-PAsp is desirable for the application of drug carrier. As a result, the β-CD-graft-PAsp hollow nanosphere showed a great potential as the carrier of CPT. [Copyright &y& Elsevier]

Abstract: This research is aimed to develop a nano-sized supramolecular micelle delivery system of cis-dichlorodiammine platinum (II) (CDDP) in order to achieve the passive tumor targeting. Firstly, star-shaped poly (γ-benzyl-l-glutamate) was synthesized by the ring-opening polymerization of γ-benzyl-l-glutamate-N-carboxyanhydride initiated with per-6-amino-β-cyclodextrin. After removal of benzyl groups, β-cyclodextrin based seven-armed poly (l-glutamic acid) (β-CD-7PLGA) was obtained. β-CD-7PLGA/CDDP complexes were prepared by the complex reaction between the carboxylic groups of β-CD-7PLGA and CDDP. Further inclusion of β-CD-7PLGA/CDDP complexes with adamantine terminated mPEG (mPEG-Ad) gave CDDP supramolecular micelles (mPEG-Ad@β-CD-7PLGA/CDDP). The formation of mPEG-Ad@β-CD-7PLGA/CDDP supramolecular micelles was confirmed by fluorescence spectrophotoscopy and particle size measurements. All the micelles showed spherical shape, and their sizes increased from 100 to 135nm with the increase of PLGA arm molecular weight. mPEG-Ad@CD-7PLGA/CDDP micelles showed sustained drug release profiles over 50h in PBS. Compared with CDDP, mPEG-Ad@β-CD-7PLGA/CDDP supramolecular micelles showed essential decreased cytotoxicity to KB cells, suggesting their great potential as the delivery carriers of CDDP. [Copyright &y& Elsevier]

Abstract: This research is aimed to develop a biodegradable micelle delivery system with sheddable poly (ethylene glycol) shell to achieve the reduction-triggered intracellular sustained release of 6-mercaptopurine (6-MP) and decreased toxicity. Firstly, the amino-disulfide linked poly (ethylene glycol) monomethyl ether (mPEG-SS-NH2) was synthesized by the amidation reaction between cystamine and active ester of mPEG and p-nitrophenyl chloroformate (p-NPC) (mPEG–NPC). And then, the five-member rings in poly (l-succinimide) (PSI) were successively opened by mPEG-SS-NH2 and 2-(pyridyldithio)-ethylamine (PDA) to produce the graft copolymer of mPEG-SS-NH-graft-PAsp-PDA. To avoid the drug initial burst, 6-MP was covalently conjugated with mPEG-SS-NH-graft-PAsp-PDA by thoil–disulfide exchange reaction to give the resultant product mPEG-SS-NH-graft-PAsp-MP. The product was found to form spherical micelles in aqueous media because of its amphiphilic nature with average particle size of 160nm measured by dynamic light scattering (DLS). It was found that the mPEG-SS-NH-graft-PAsp-MP micelles, though stable in phosphate buffer solution (PBS), were prone to aggregation in the presence of dithiothreitol (DTT). The in vitro drug release studies revealed the release of 6-MP were distinct from the conventional micelles whose drugs loaded by physical encapsulation. Sustained release profile of 6-MP over 85h was found in the presence of DTT (40mM) simulating the intracellular condition while minimal drug release was observed within 24h at the level of DTT corresponding to extracellular environment. Remarkably, the cell viability results showed there was essential decrease of cytotoxicity to HL-60 cell line compared to free 6-MP. [Copyright &y& Elsevier]

Abstract: Biodegradable micelles with sheddable poly(ethylene glycol) shells were fabricated based on poly(ethylene glycol)-block-poly(γ-benzyl l-glutamate) (mPEG-SS-PBLG) diblock copolymer and applied as the carrier of 7-ethyl-10-hydroxy-camptothecin (SN-38) in order to enhance its solubility and stability in aqueous media. The diblock polymer was designed to have the hydrophilic PEG moiety and hydrophobic PBLG moiety linked by biodegradable disulfide bond, so in reducing environment the PEG shells can be detached. The polymer was able to form the micelles of nano-scale in aqueous media, suggesting their passive targeting potential to tumor tissue. Water-insoluble antitumor drug, SN-38, was easily encapsulated into mPEG-SS-PBLG nanomicelles by lyophilization method. When setting theoretical drug loading content at 10wt%, the drug encapsulation efficiency (EE) was assayed as 73.5%. Owing to the disulfide bond in mPEG-SS-PBLG, intense release of SN-38 occurred in the presence of dithiothreitol (DTT) at the concentration of simulating the intracellular condition, however, micelles showed gradual release of SN-38 in the absence of DTT. Also, the mPEG-SS-PBLG micelles effectively protected the active lactone ring of SN-38 from hydrolysis under physiological condition. Compared with free SN-38, SN-38-loaded nanomicelles showed essentially decreased cytotoxicity against L929 cell line in 24h, bare mPEG-SS-PBLG nanomicelles showed almost non-toxicity. [Copyright &y& Elsevier]

Abstract: To develop a tumor-targeting nano-sized delivery system of cis-dichlorodiammine platinum(II) (CDDP), polymer-metal complex micelles were fabricated from folate-conjugated PEG-graft-α,β-poly [(N-amino acidyl)-aspartamide] (FA-PEG-g-PAAsp) and CDDP. The formation of polymer-metal complex micelles was confirmed by the measurements of critical aggregation concentration (CAC) and particle size, and the morphological observation. It was found that all the micelles showed spherical shapes with clear core–shell structures in narrow size distributions. The typical particle size measured by dynamic laser scattering (DLS) was ca. 105nm, suggesting their passive targeting to tumor tissue and endocytosis potential. FA-PEG-g-PAAsp-CDDP micelles showed sustained drug release profiles over 40h, and their accumulative drug release was ranked in the order of FA-PEG-g-PAsp-Ami-CDDPFA-PEG-g-PAAsp-CDDP>mPEG-g-PAAsp-CDDP, the severe toxicity of CDDP in vivo limited its use as ideal anti-tumor drug. Furthermore, FA-PEG-g-PAAsp-CDDP and mPEG-g-PAAsp-CDDP showed rather low toxicity against mice, just similar to that of PBS. It indicated the great potential utilization of the FA-PEG-g-PAAsp-CDDP micelles as the tumor-targeted drug carriers of CDDP with improved anti-tumor efficacy. [Copyright &y& Elsevier]

Abstract: Polysaccharide nanocrystals, such as rod-like cellulose nanocrystals and chitin whiskers and platelet-like starch nanocrystals, were incorporated into alginate-based nanocomposite microspheres with the aim of enhancing mechanical strength and regulating drug release behavior. The structures and properties of the sols and the resultant nanocomposite microspheres were characterized by rheological testing, Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and scanning electron microscopy (SEM). The presence of polysaccharide nanocrystals increased the stability of the crosslinked network structure, and the nanocomposite microspheres consequently exhibited prominent sustained release profiles, as demonstrated by inhibited diffusion of theophylline. Furthermore, based on the drug release results, the release kinetics and transport mechanisms were analyzed and discussed. [Copyright &y& Elsevier]

Abstract: To enhance the stability and long-term circulation of camptothecin (CPT), mPEGylated α,β-poly (l-aspartic acid)-CPT conjugates were synthesized, and used to fabricate nanomicelle. Firstly, α,β-poly (l-aspartic acid) derivative (PAA-der) containing alkyne groups was synthesized via the ring-opening of PSI with propargyl amine. And then, azide-functionalized CPT derivatives (CPT-N3) and azide-terminated poly (ethylene glycol) methyl ether (mPEG-N3) were conjugated with PAA-der by click cycloaddition to give mPEG-graft-PAA-CPT conjugates. The formation of mPEG-graft-PAA-CPT nanomicelles was confirmed by fluorescence spectrophotoscopy and particle size measurements. It was found that all the nanomicelles showed spherical shapes with size about 178nm. MPEG-graft-PAA-CPT nanomicelles showed good storage stability, even incubation at 37°C for 60 days, and improved the stability of CPT lactone form in aqueous media. A steady release rate of CPT was kept for 72h, suggested the great potential of mPEG-graft-PAA-CPT nanomicelles as polymer prodrug of CPT. [ABSTRACT FROM AUTHOR]

Abstract: In this research, amphiphilic brush-like polycations were synthesized, and used to fabricate cationic nanomicelle as the carrier of 7-ethyl-10-hydroxy-camptothecin (SN-38), in order to enhance its cellular uptake, solubility and stability in aqueous media. In particular, cationic chitosan-graft-polycaprolactone (CS-g-PCL) copolymers were synthesized with a facile one-pot manner via ring-opening polymerization of ɛ-CL onto the hydroxyl groups of CS by using methanesulfonic acid as solvent and catalyst. The formation of CS-g-PCL nanomicelles was confirmed by fluorescence spectrophotoscopy and particle size measurements. It was found that all the nanomicelles showed spherical shapes with narrow size distributions. Their sizes ranged from 47 to 113nm, and the zeta potentials ranged from 26.7 to 50.8mV, depending on the grafting content of PCL in CS-g-PCL, suggesting their passive targeting to tumor tissue and endocytosis potential. Water-insoluble antitumor drug, SN-38, was easily encapsulated into CS-g-PCL nanomicelles by lyophilization method. In comparison with bare CS-g-PCL nanomicelles, the corresponding SN-38-loaded nanomicelles showed increased particle sizes and a little reduced zeta potentials. With an increase of grafting PCL content, the drug encapsulation efficiency (EE) and drug loading (DL) of the nanomicelles increased from 64.3 to 84.6% and 6.43 to 8.66%, respectively, whereas their accumulative drug release showed a tendency to decrease due to the enhanced hydrophobic interaction between hydrophobic drug and hydrophobic PCL segments in CS-g-PCL. Also, the CS-g-PCL nanomicelles effectively protected the active lactone ring of SN-38 from hydrolysis under physiological condition, due to the encapsulation of SN-38 into the hydrophobic cores in the nanomicelles. Compared with free SN-38, the SN-38-loaded nanomicelles showed essential decreased cytotoxicity against L929 cell line, and bare CS-g-PCL nanomicelles almost showed non-toxicity. These results suggested the potential utilization of the CS-g-PCL nanomicelles as the carriers of hydrophobic drugs with improving the delivery and release properties. [Copyright &y& Elsevier]

Abstract: This research is aimed to develop a nanomicelle delivery system in order to enhance the solubility and stability of camptothecin (CPT) in aqueous media. In this case, α,β-poly[(N-carboxybutyl)-l-aspartamide] (PBAsp)–CPT was conjugated by the esterification between PBAsp and 20-OH of CPT, and hence used to fabricate nanomicelles with a particle size between the pore size of blood capillary in normal tissue and that in tumor tissue. It was worthy of note that the drug-loaded system of PBAsp–CPT nanomicelle improved the solubility and stability of CPT in aqueous media. However, with an increase of the CPT loading in PBAsp–CPT, the solubility sharply decreased. Meanwhile, the sizes of PBAsp–CPT nanomicelles showed a tendency of increase. Moreover, the drug release of PBAsp–CPT nanomicelles displayed a linear sustaining profile, and hence resulted in the essential decrease of cytotoxicity to L929 cell line. The assembled nanomicelles based on the PBAsp–CPT conjugates showed a great potential as polymer prodrug of tumor therapy, and the controlled nano-scale might achieve the passive tumor targeting. [Copyright &y& Elsevier]

Abstract: To design peptide-targeted iron oxide as magnetic resonance imaging (MRI) contrast agents, amino-functionalized magnetic nanogels were prepared by using N-(2-aminoethyl) methacrylamide hydrochloride (AEM·HCl) as monomer via new photochemical approach. Their chemical structure and composition were characterized by Fourier transform infrared spectra (FTIR) and thermogravimetric analyses (TGA). The core–shell structure of magnetic nanogels was confirmed by high-resolution transmission electron microscopy (HRTEM). The good storage stability, high magnetic content (88.7%), high saturation magnetizations and superparamagnetic behavior suggested their great potentials as MRI contrast agents, which were confirmed by their measurements of r 2 and coronal image of the crossing of mouse kidney. [Copyright &y& Elsevier]

Abstract: The aim of research is to develop and optimize delivery system for cis-dichlorodiammine platinum(II) (CDDP) based on polymer–metal complex nanomicelles with controllable particle size in order to achieve the passive tumor targeting. In particular, graft copolymers, mPEG–g-α,β-poly [(N-amino acidyl)-dl-aspartamide] (mPEG–g-PAAsp) were synthesized by the ring-opening reaction of polysuccinimide with mPEG-NH2 (M w: 2000 and 5000Da), and then with l-aspartic acid and l-glutamic acid, respectively. mPEG–g-PAAsp–CDDP complex nanomicelles were fabricated from mPEG–g-PAAsp and CDDP. The formation of mPEG–g-PAAsp–CDDP nanomicelles was confirmed by fluorescence spectrophotoscopy, electrical conductivity and particle size measurements. It was found that all the nanomicelles showed spherical shapes with clear core-shell structures and narrow size distributions. Their sizes ranged from 80 to 160nm, suggesting of their passive targeting potential to tumor tissue. With the increase of the molecular weight of mPEG, the sizes of mPEG–g-PAAsp–CDDP micelles showed a tendency to increase. mPEG–g-PAAsp–CDDP nanomicelles showed linear gradual drug release profiles in 40h, suggestion of their sustained drug release behaviors. Compared with CDDP, mPEG–g-PAAsp–CDDP micelles showed essential decreased cytotoxicity to Bel-7402 cell line. [Copyright &y& Elsevier]

[Display omitted] • Hyaluronic acid-decorated carborane-TAT conjugation nanomicelles was fabricated by layer-by-layer self-assembly approach. • The core-shell structure Carborane-TAT@HA nanomicelle showed enhanced selectivity of tumor cellular uptake. • Carborane-TAT@HA nanomicelle has great potential to be used as a boron drug for BNCT. Boron neutron capture therapy (BNCT) has received widespread attention as a new type of radiation therapy. The main problem encountered in BNCT is insufficient tumor cellular uptake of boron agents. In this study, cell-penetrating peptide TAT-conjugated o-carborane was synthesized. The conjugation can self-assemble to form positively charged carborane-TAT micelles, and then adsorb negatively charged hyaluronic acid (HA) to give core-shell structured carborane-TAT@HA micelles. Carborane-TAT@HA micelles exhibits a large amount of boron uptake at the tumor tissue through the enhanced permeability and retention (EPR) effect and the ability of HA to bind to CD44 receptors. Carborane-TAT@HA was wrapped by the HA shell during systemic circulation to avoid non-specific uptake of TAT with normal cells, while tumor microenvironment-responsive shedding of HA shell could expose Carborane-TAT to penetrate the cell membrane into tumor cells. Experiments have proved the enhanced selectivity of tumor cellular uptake of the boron drug, displayed excellent drug delivery potential, and can meet the basic requirements of BNCT. [ABSTRACT FROM AUTHOR]

• TAT was shielded by the PEG corona during circulation while exposed at tumor site. • The nanomicelles enhanced the cellular uptake and reduced the drug efflux. • IC 50 value of DOX·HCl was lowered 4 times against MCF-7/ADR cells by this carrier. • The nanomicelles demonstrated highest accumulation in tumor tissues. • The nanomicelles exhibited superior tumor growth suppression. This study aimed to develop sheddable polyethylene glycol (PEG) shells with TAT-modified core cross-linked nanomicelles as drug-delivery carriers of doxorubicin (DOX) to establish a programmed response against the tumor microenvironment, enhanced endocytosis, and lysosomal pH-triggered DOX release. First, poly(L-succinimide) (PSI) underwent a ring-opening reaction with ethylenediamine to generate poly(N-(2-aminoethyl)- l -aspartamide) (P(ae-Asp)). Next, the thiolytic cleavable PEG, 3,4-dihydroxyphenylacetic acid, and TAT were grafted onto P(ae-Asp) to synthesize the amphiphilic graft copolymer of mPEG-SS-g-P(ae-Asp)-MCA-DA-TAT. In aqueous solution, the amphiphilic polymer self-assembled into nanomicelles, encapsulating DOX into the hydrophobic core of micelles. TAT was shielded by the PEG corona during circulation to avoid non-specific transmembrane interaction with normal cells, while the tumor redox environment-responsive shedding of PEG could expose TAT to promote internalization of tumor cells. In order to improve the stability of nanomicelles and achieve pH-triggered drug release, a core cross-linking strategy based on the coordination of catechol and Fe3+ was adopted. In vitro studies demonstrated that core cross-linked nanomicelles maintained the nanostructure in 100 times dilution in pH 7.4 phosphate-buffered saline (PBS). Moreover, DOX release from DOX-loaded core cross-linked nanomicelles (DOX-TAT-CCLMs) was favored at simulated lysosomal conditions over simulated plasma conditions, indicating that these nanomicelles demonstrate characteristics of pH-triggered DOX release. The TAT modification considerably enhanced the mean fluorescence intensity of the nanomicelles endocytosed by MCF-7/ADR cells by 8 times, compared with DOX·HCl after 8 h of incubation. Notably, the IC 50 value of nanomicelles (11.61 ± 0.95 μg/mL) was nearly 4 times lower than that of DOX·HCl against MCF-7/ADR cells, implying that the nanomicelles could overcome drug resistance observed in MCF-7/ADR cells. Furthermore, the DOX-TAT-CCLMs reported superior tumor growth suppression in a 4T1 tumor-bearing mouse model. Thus, the redox- and pH- stimuli stepwise-responsive novel nanomicelles fabricated from the mPEG-SS-g-P(ae-Asp)-MCA-DA-TAT graft copolymer exhibited multifunctionality and displayed great potential for drug delivery. [ABSTRACT FROM AUTHOR]

• This nanoplatform facilitated drug loading with high drug loading efficiency. • The nanoplatform adopted pH-dependent crosslinking strategy. • The nanoplatform exhibited enhanced and fast endocytosis against HepG2 cells. • The nanoplatform exhibited outstanding antiproliferative effect. • The nanoplatform exhibited significantly low drug efflux. A novel bioinspired nanoplatform capable of fast endocytosis, lysosomal pH-triggered drug release, and reduced drug efflux based on PBA-PEG- b -P(Glu- co -GluDA) copolymer was developed in this study. The synthesized copolymer could facilitate doxorubicin encapsulation with relatively high drug-loading content and efficiency. Inspired by mussel byssal threads, a core crosslinking strategy based on the coordination between catechol and ferric ions was introduced to improve the stability of nanomicelles and realize lysosomal pH-controlled drug release. This nanoplatform could maintain integrity even after being dissolved in a good solvent, demonstrating its the potential to withstand infinite dilution of plasma after intravenous injection. Moreover, this nanoplatform demonstrated lysosomal pH-triggered drug release, and the cumulative release amount of doxorubicin under a simulated lysosomal condition was 13 times higher than that under a simulated plasma condition. Moreover, as a result of the high binding capacity between phenylboronic acid (PBA) and sialic acid on the surface of human hepatoma cell line (HepG2), the fast and enhanced endocytosis in addition to lysosomal pH-triggered release property and significantly low efflux, this nanoplatform exhibits improved delivery efficiency of doxorubicin into the nucleus and notably outstanding antiproliferative effects compared with doxorubicin. Furthermore, the PBA modification remarkably increased the mean fluorescence intensity of this nanoplatform endocytosed by HepG2 cells to twice that of doxorubicin after one hour of incubation. The nanoplatform exhibited an inhibition rate of 70% against tumor growth. Thus, this novel nanoplatform based on PBA-PEG- b -P(Glu- co -GluDA) copolymer displayed multifunctionality and exhibited great potential as an intelligent nanoplatform for antitumor drug delivery. [ABSTRACT FROM AUTHOR]