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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 Fe 3+ 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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A biodegradable brush-type copolymer PHF- g-(PCL-PEG) based on a cleavable polyacetal backbone and biodegradable side chain modified with polyethylene glycol (PEG) was synthesized in this paper. This particular structure was directional to facilitate the formation of spherical or rod-shaped micelles. Flow cytometry showed that rod-shaped micelles displayed enhanced cellular uptake compared to spherical micelles. Rod-shaped micelles were selected to investigate their drug delivery abilities in detail. In vitro experiments verified the pH-triggered drug release of DOX-loaded micelles, and the release rate of doxorubicin (DOX) was 77% at pH 5.0 and 26% at pH 7.4. In drug-release kinetic analysis, a double-exponential model achieved the best fit. The copolymer appeared to be almost nontoxic, while the DOX-loaded micelles showed equivalent cytotoxicity compared to DOX at high concentration. The endocytosis of DOX-loaded micelles was two times that of DOX. Our findings suggest that the pH-sensitive brush type copolymer could be a possible carrier in drug delivery.

Rod-like nanomedicines facilitate cellular uptake. This research is aimed to develop fluorescence-visible rod-like nanomedicines with enhanced cellular uptake and intracellular drug controlled release based on cis-aconityl-doxorubicin (CAD) labeled cellulose nanocrystal rods (CNR). Particularly, CAD was synthesized by the ring-opening reaction between cis-aconitic anhydride (CAA) and the amino group of Doxorubicin (DOX). Amidation reaction occurred between the 6-carboxylic groups of CAD and the amino groups of aminated CNR to give CAD labeled CNR (CAD@CNR). Compared with CNR, CAD@CNR showed similar morphology and crystal structure. The mean length of CAD@CNR was ca. 118 nm with aspect ratio ranging from 12 to 15, facilitating their endocytosis. CAD@CNR prodrug was rather stable in pH 7.4 phosphate buffer solution but tended to be hydrolyzed to release DOX under acidic condition, due to the rapid degradation of amide bonds between DOX and cis-aconitic acid via an intramolecular acid-catalyzed mechanism. CAD@CNR prodrug showed sustained drug release profiles over 40 h, and the cumulative drug release showed a tendency to increase from 36 to 80% with the pH value decreasing from 7.4 to 5.0. The half maximal inhibitory concentration (IC 50 ) of CAD@CNR prodrug against NCI H 460 cells without NH 4 Cl (lysosomotropic weak bases) pretreatment was 1.75 times higher than that with 40 mM NH 4 Cl pretreatment, further confirmed that the DOX release from the CAD@CNR prodrug was triggered by the low pH value of lysosome (pH 5.0). Compared with DOX·HCl, CAD@CNR prodrug showed enhanced cellular uptake ability during 12 or 24 h of incubation due to the endocytosis mechanism of CAD@CNR prodrug. After incubation with cells, CAD@CNR prodrug could be observed by using fluorescence microscope due to the red fluorescence of DOX. In a word, CAD@CNR showed great potential as fluorescence-visible drug delivery system with enhanced cellular uptake and intracellular drug release due to its rod-like morphology, suitable aspect ratio, and acid-triggered drug release., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In order to achieve the passive tumor targeting and acid-triggered drugs release in lysosomes, optimized delivery system for doxorubicin based on pH-sensitive complex nanomicelles with suitable particle size was developed in this research. Particularly, poly(L-succinimide) was thoroughly ring-opened by ethylenediamine to give the poly(N-(2-aminoethyl)-L-aspartamide). Then, graft copolymer mPEG-graft-poly(N-(2-aminoethyl)-L-aspartamide)-hexahydrophthalic acid (mPEG-g-P(ae-Asp)-Hap) was synthesized by grafting mPEG-2000 and hexahydrophthalic anhydride onto poly(N-(2-aminoethyl)-L-aspartamide). In vitro studies revealed that mPEG-g-P(ae-Asp)-Hap copolymer was stable in neutral solutions but tend to be hydrolyzed under acidic condition, which was attributed to the acid-sensitive properties of hexahydrophthalic amides (β-carboxylic amides). MPEG-g-P(ae-Asp)-Hap copolymer with critical aggregation concentration of 0.166 mg·mL -1 could self-assemble into stable blank nanomicelles with an average particle hydrodynamic diameter of 98.1 nm, but the hydrodynamic diameter of doxorubicin-loaded nanomicelles (mPEG-g-P(ae-Asp)-Hap·Dox) was smaller and approximately 77.5 nm. MPEG-g-P(ae-Asp)-Hap·Dox nanomicelles showed sustained drug release profiles over 34 h, and the cumulative drug release showed a tendency to increase from 25% to 62% with the pH value decreasing from 7.4 to 5.0 due to the acid-triggered disassembly of nanomicelles. The cytotoxicity of mPEG-g-P(ae-Asp)-Hap·Dox nanomicelles against A549 treated with 40 mM NH 4 Cl (lysosomotropic weak bases) was decreased significantly than that without NH 4 Cl treatment, further confirmed the drug release from the nanomicelles was triggered by the low pH value of lysosome (pH 5.0). Compared with doxorubicin HCl, mPEG-g-P(ae-Asp)-Hap·Dox nanomicelle drug showed enhanced cellular uptake ability during 2 or 4 h of incubation due to the endocytosis mechanism of nanomicelle drug. In summary, the cleavage of pH-sensitive β-carboxylic amides bonds on the hydrophobic branch of mPEG-g-P(ae-Asp)-Hap copolymer triggered the disassembly of the nanomicelles and release of doxorubicin in the acidic lysosomal compartments of cancer cells. These nanomicelles exhibited excellent potential for drug delivery due to their smart properties-PEGylation, suitable size, and acid-triggered drug release.

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 121nm 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 42h. The cytotoxicity of DOX-loaded CCLMs/SS against A549 cells pretreated with 40mM 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 24h 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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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 80nm, 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 9h, 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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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 (C18) with a linkage of valine-citrulline (VC), which can be cleaved by cathepsin B (CB) 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 103nm, 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.)., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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 120 nm 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 r2 relaxation rate (221 mM(-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 © 2013 Elsevier B.V. All rights reserved.)

Rod‐like‐shape nanomedicines with the ability of lysosomal pH‐controlled drug release can precisely deliver doxorubicin (DOX) into its target, nucleus, and can fully exert its anticancer effect. Taking advantage of their large specific surface area, cellulose nanocrystals (CNCs) were used to fabricate pH‐responsive DOX‐loaded rod‐like shaped hybrids nanomedicines: cis‐aconityl‐doxorubicin (CAD)@polyethylenimine (PEI)@CNCs (CAD@PEI@CNCs) via layer‐by‐layer (LbL) assembly. In vitro, CAD@PEI@CNCs hybrids displayed rod‐like shape, high drug loading content, lysosomal pH‐controlled drug release, efficient and precise doxorubicin (DOX) delivering into the nucleus. Moreover, the cellular uptake of CAD@PEI@CNCs hybrids was 20.9 folds higher than that of DOX·HCl against A549 cells. The cytotoxicity of CAD@PEI@CNCs hybrids was much higher than that of DOX·HCl and the pH‐irresponsive hybrids against A549 cell. In vivo, CAD@PEI@CNCs hybrids exhibited good antitumor effect: (42.0 ± 6)% inhibition rate and few harms to the nude mice. Altogether, rod‐like shaped pH‐responsive CAD@PEI@CNCs hybrids nanomedicines could efficiently overcome the vascular and tumor barriers, and precisely deliver DOX to nucleus to convert DOX antitumor effects. These results indicate that CAD@PEI@CNCs have great potential to act as advanced nanomedicines with enhanced delivery efficiency and therapeutic efficiency. [ABSTRACT FROM AUTHOR]

A novel pH-sensitive polymeric prodrug of camptothecin (CPT) by polymerizing γ-camptothecin-glutamate N-carboxyanhydride (Glu (CPT)-NCA) on boronate ester-linked poly (ethyleneglycol) (PEG) directly via the amine-initiated ring open polymerization (ROP) has been developed. The resulting amphiphilic prodrug (mPEG-BC-PGluCPT) could self-assemble into nanoparticles and encapsulate doxorubicin (Dox) simultaneously in aqueous solution for dual-drug delivery. The formation of polymeric prodrug micelles (mPEG-BC@PGluCPT) was confirmed by the measurements of critical aggregation concentration (CAC), particle size, and morphology observations. The mPEG-BC@PGluCPT micelles were colloidally stable in solutions for two weeks. Polymeric prodrug micelles mPEG-BC@PGluCPT and Dox-loaded micelles mPEG-BC@PGluCPT⋅Dox showed sustained drug release profiles over 48 h. As expected, drug release was accelerated by the decreasement of pH value from 7.4 to 6.0, which demonstrated pH-dependent manner of drug release. Additionally, it was found that cellular uptake of mPEG-BC@PGluCPT⋅Dox micelles on HepG2 cells was higher than that on HL-7702 cells, especially in culture medium at pH 6.0. The enhanced cellular uptake of mPEG-BC@PGluCPT⋅Dox micelles under acidic condition on HepG2 cells resulted in the higher cytotoxicity of mPEG-BC@PGluCPT⋅Dox micelles at acidic pH than that at pH 7.4. [ABSTRACT FROM PUBLISHER]