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Drug Delivery

The importance of drug delivery to chemists, medicinal and otherwise, has increased since the advent of integrated drug discovery processes. Physicochemical and biological barriers, pathways for drug delivery, formulation, pharmacokinetic and pharmacodynamic issues, metabolism, and cell culture models used in studying drug delivery are just some of the topics that make drug delivery an exciting field for researchers.

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Controlling Toxicity of Peptide–Drug Conjugates by Different Chemical Linker Structures

Linked up: The human Y1 receptor preferring peptide [F7,P34]NPY is coupled to methotrexate through different cleavable linker structures for prospective breast cancer therapy. The toxicity of these novel peptide–drug conjugates is clearly dependent on the linkage type and a new linker is identified.

ChemMedChem, April 9, 2015, DOI: 10.1002/cmdc.201402514

Lina Weinschenk, Tristan Gollnest, Dominique Schols, Jan Balzarini, Chris Meier
Bis(benzoyloxybenzyl)-DiPPro Nucleoside Diphosphates of Anti-HIV Active Nucleoside Analogues [Full Paper]

Bis(benzoyloxybenzyl)-DiPPro Nucleoside Diphosphates of Anti-HIV Active Nucleoside Analogues

Fine-tuning stability: Bis(benzoyloxybenzyl) groups were used to mask two of the negative charges of nucleoside diphosphates to form DiPPro compounds. Modification by different substituents in the 4-positions had a strong impact on the chemical and enzymatic stability. With strong acceptor substituents, the NDPs were released almost exclusively in PBS or in cell extracts.

ChemMedChem, April 2, 2015, DOI: 10.1002/cmdc.201500063

Orit Redy-Keisar, Shiran Ferber, Ronit Satchi-Fainaro, Doron Shabat
NIR Fluorogenic Dye as a Modular Platform for Prodrug Assembly: Real-Time in vivo Monitoring of Drug Release [Full Paper]

NIR Fluorogenic Dye as a Modular Platform for Prodrug Assembly: Real-Time in vivo Monitoring of Drug Release

Drug release quantified: We have developed a new modular approach for the preparation of theranostic prodrugs with a turn-ON near-infrared (NIR) fluorescence mode of action. The prodrugs release their chemotherapeutic cargo and an active cyanine fluorophore upon reaction with a specific analyte. The release of the drug can be monitored through the produced NIR fluorescence.

ChemMedChem, April 2, 2015, DOI: 10.1002/cmdc.201500060

Shuo Fang, Yuge Niu, Wenjun Zhu, Yemin Zhang, Liangli Yu, Xinsong Li
Liposomes Assembled from a Dual Drug-tailed Phospholipid for Cancer Therapy [Full Paper]

Liposomes Assembled from a Dual Drug-tailed Phospholipid for Cancer Therapy

A novel dual drug-tailed phospholipid that can form liposomes as a combination of prodrug and drug carrier is reported. The dual chlorambucil-tailed phospholipid (DCTP), a phospholipid prodrug, undergoes assembly to form a liposome without any additives by the thin lipid film technique. The liposomes had higher cytotoxic effects to cancer cell lines than free DCTP and chlorambucil.

Chem. Asian J., March 12, 2015, DOI: 10.1002/asia.201500067

Stefania R. Cicco, Danilo Vona, Elvira De Giglio, Stefania Cometa, Monica Mattioli-Belmonte, Fabio Palumbo, Roberta Ragni, Gianluca M. Farinola
Chemically Modified Diatoms Biosilica for Bone Cell Growth with Combined Drug-Delivery and Antioxidant Properties [Full Paper]

Chemically Modified Diatoms Biosilica for Bone Cell Growth with Combined Drug-Delivery and Antioxidant Properties

Them bones gonna rise again: Covalent functionalization of nanostructured silica shells from diatoms with TEMPO radical endows biosilica with both drug-delivery properties and antioxidant activity. The resulting functional biosilica is demonstrated to be a suitable substrate for bone cell growth.

ChemPlusChem, March 4, 2015, DOI: 10.1002/cplu.201402398

Alberto Dal Corso, Michele Caruso, Laura Belvisi, Daniela Arosio, Umberto Piarulli, Clara Albanese, Fabio Gasparri, Aurelio Marsiglio, Francesco Sola, Sonia Troiani, Barbara Valsasina, Luca Pignataro, Daniele Donati, Cesare Gennari
Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers [Full Paper]

Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers

It's all about selectivity: Two RGD peptidomimetic–paclitaxel (PTX) conjugates endowed with peptide linkers were prepared, and their activities as tumor-homing devices were tested in vitro against two cancer cell lines expressing different levels of αvβ3 integrin. One of these conjugates (see scheme; AA: amino acid) was able to kill the αvβ3-expressing tumor cells with remarkably increased selectivity relative to that of the free PTX.

Chem. Eur. J. 2015, 21, No. 18, 6921-6929

Yan Zhang, Chunyue Deng, Sha Liu, Jin Wu, Zhangbao Chen, Chong Li, Weiyue Lu
Active Targeting of Tumors through Conformational Epitope Imprinting [Communication]

Active Targeting of Tumors through Conformational Epitope Imprinting

Magic bullet: A peptide served as an “indirect” targeting ligand to mediate active tumor-targeted drug delivery. A disulfide-linked α-helix containing peptide, apamin, was used to mimic the extracellular, structured N-terminal part of the protein p32. The combination with surface molecular imprinting produced a nanocarrier that recognizes p32-positive tumors in vivo.

Angew. Chem. Int. Ed. 2015, 54, No. 17, 5157-5160

Theodossis A. Theodossiou, A. Ricardo Gonçalves, Konstantina Yannakopoulou, Ellen Skarpen, Kristian Berg
Photochemical Internalization of Tamoxifens Transported by a “Trojan-Horse” Nanoconjugate into Breast-Cancer Cell Lines [Communication]

Photochemical Internalization of Tamoxifens Transported by a “Trojan-Horse” Nanoconjugate into Breast-Cancer Cell Lines

Smuggled within enemy walls: A porphyrin–β-cyclodextrin (mTHPP–βCD) conjugate was used to “smuggle” small tamoxifen (TAM) molecules into cells by endocytosis on the command of light (see picture; FITC=fluorescein isothiocyanate). Upon irradiation with red light, the porphyrin ruptured the endosomal membranes, and the large tamoxifen payload that was released caused substantial and permanent cytotoxicity to tamoxifen-sensitive MCF7 cells.

Angew. Chem. Int. Ed. 2015, 54, No. 16, 4885-4889

Si Yu Tan, Chung Yen Ang, Zhong Luo, Peizhou Li, Kim Truc Nguyen, Yanli Zhao
An iGlu Receptor Antagonist and Its Simultaneous Use with an Anticancer Drug for Cancer Therapy [Full Paper]

An iGlu Receptor Antagonist and Its Simultaneous Use with an Anticancer Drug for Cancer Therapy

Double agent: The simultaneous use of a neuroprotective drug and an anticancer drug delivered by mesoporous silica nanoparticles was investigated for the treatment of metastatic melanoma cancer, resulting in improved targeting and anticancer properties.

Chem. Eur. J. 2015, 21, No. 16, 6123-6131

Giulia Tuci, Lapo Luconi, Andrea Rossin, Francesco Baldini, Stefano Cicchi, Sara Tombelli, Cosimo Trono, Ambra Giannetti, Ilse Manet, Stefano Fedeli, Alberto Brandi, Giuliano Giambastiani
A Hetero-Bifunctional Spacer for the Smart Engineering of Carbon-Based Nanostructures [Full Paper]

A Hetero-Bifunctional Spacer for the Smart Engineering of Carbon-Based Nanostructures

Building on solid foundations: A hetero-bifunctional linker joining a “cleavable” disulfide moiety and a “clickable” terminal acetylene group was synthesized and used to decorate carbon nanotubes (CNTs). When used in combination with other selected terminal acetylene molecules, the linker can impart multimodality through a controlled click reaction to give carbon nanohybrids (see figure).

ChemPlusChem 2015, 80, No. 04, 704-714

Yevgeny Brudno, Rajiv M. Desai, Brian J. Kwee, Neel S. Joshi, Michael Aizenberg, David J. Mooney
In Vivo Targeting through Click Chemistry [Communication]

In Vivo Targeting through Click Chemistry

Clicks degrees of separation: Selective targeting of small molecules to intramuscular and intradermal sites was achieved by click chemistry. Click-mediated targeting gave a high degree of specificity for the target sites, and this targeting could be repeated over at least one month through nine administrations. Spatial resolution of two different molecules can be achieved by targeting them to two distinct sites in the same animal by use of orthogonal click chemistries, establishing the possibility of combining incompatible therapies in patients.

ChemMedChem 2015, 10, No. 04, 617-620

Maria V. Babak, Damian Plażuk, Samuel M. Meier, Homayon John Arabshahi, Jóhannes Reynisson, Błażej Rychlik, Andrzej Błauż, Katarzyna Szulc, Muhammad Hanif, Sebastian Strobl, Alexander Roller, Bernhard K. Keppler, Christian G. Hartinger
Half-Sandwich Ruthenium(II) Biotin Conjugates as Biological Vectors to Cancer Cells [Full Paper]

Half-Sandwich Ruthenium(II) Biotin Conjugates as Biological Vectors to Cancer Cells

On target: Ruthenium(II) arene complexes with biotin-containing ligands were prepared so that drug delivery through tumor-specific vitamin-receptor mediated endocytosis could be exploited (see figure). Complex formation with a {Ru(η6-p-cymene)} fragment resulted in significantly enhanced cytotoxicity in comparison with free ligands. These novel half-sandwich ruthenium(II) biotin conjugates may act as biological vectors to cancer cells.

Chem. Eur. J. 2015, 21, No. 13, 5110-5117

Lu Zhang, Qiang Feng, Jiuling Wang, Jiashu Sun, Xinghua Shi, Xingyu Jiang
Microfluidic Synthesis of Rigid Nanovesicles for Hydrophilic Reagents Delivery [Communication]

Microfluidic Synthesis of Rigid Nanovesicles for Hydrophilic Reagents Delivery

Nanocarriers made easy: A multistage microfluidic chip is adopted for the one-step synthesis of water core/PLGA shell/lipid layer rigid nanovesicles (RNVs) and effective entrapment of various kinds of hydrophilic reagents. An enhanced anti-tumor effect is observed by co-delivering siMDR1 and Dox using RNVs in both in vitro and in vivo experiments.

Angew. Chem. Int. Ed. 2015, 54, No. 13, 3952-3956

Joab O. Onyango, Michael S. Chung, Chee-Huat Eng, Lukas M. Klees, Rachel Langenbacher, Lan Yao, Ming An
Noncanonical Amino Acids to Improve the pH Response of pHLIP Insertion at Tumor Acidity [Communication]

Noncanonical Amino Acids to Improve the pH Response of pHLIP Insertion at Tumor Acidity

The pH low insertion peptide (pHLIP) allows drugs to be delivered selectively to the cytoplasm of cancer cells based on tumor extracellular acidity (pHe). Incorporation of noncanonical amino acids into pHLIP can increase the pH at which it inserts into membranes, thus better matching tumor pHe, without compromising the sharpness of transition.

Angew. Chem. Int. Ed. 2015, 54, No. 12, 3658-3663

Photoreversible Prodrugs and Protags: Switching the Release of Maleimides by Using Light under Physiological Conditions

Light release: The use of a photoswitch to control the release of a reactive chemical entity (drug or tag) with light under physiological conditions has been demonstrated. A water-soluble furyl-substituted diarylethene derivative was used in the reversible Diels–Alder reactions with maleimides to yield photoswitchable Diels–Alder adducts. Employing bioorthogonal visible light, the release of therapeutically effective concentrations of maleimide-based reactive inhibitors or labels from these “prodrugs” or “protags” could be photoreversibly triggered (see figure). A thorough investigation of the release dynamics is also presented.

Chem. Eur. J. 2015, 21, No. 11, 4422-4427

Size, Charge, and Stability of Fully Serine-Based Catanionic Vesicles: Towards Versatile Biocompatible Nanocarriers

Biocompatible vesicles: Cationic and anionic surfactants derived from serine are mixed in water to yield robust vesicles of varying size, charge, and pH (see figure). The structures show long-term stability and thus offer high potential as biocompatible nanocarriers.

Chem. Eur. J. 2015, 21, No. 10, 4092-4101

Weishuo Li, Liwen Huang, Xiaoying Ying, You Jian, Yuan Hong, Fuqiang Hu, Yongzhong Du
Antitumor Drug Delivery Modulated by A Polymeric Micelle with an Upper Critical Solution Temperature [Communication]

Antitumor Drug Delivery Modulated by A Polymeric Micelle with an Upper Critical Solution Temperature

Smart device: Poly(AAm-co-AN)-g-PEG micelles were used as a temperature-triggered drug delivery system based on their upper critical solution temperature. The polymeric micelles displayed a good drug release profile both in vitro and in vivo. Additionally, an excellent antitumor efficiency was achieved. DOX=doxorubicin.

Angew. Chem. Int. Ed. 2015, 54, No. 10, 3126-3131

Seung Beom Kim, Tae Heon Lee, Il Yoon, Young Key Shim, Woo Kyoung Lee
Gold Nanorod–Photosensitizer Complex Obtained by Layer-by-Layer Method for Photodynamic/Photothermal Therapy In Vitro [Communication]

Gold Nanorod–Photosensitizer Complex Obtained by Layer-by-Layer Method for Photodynamic/Photothermal Therapy In Vitro

Double up: A gold nanorod (GNR)–photosensitizer (PS) complex, which was prepared by using the LbL method, exhibits high anticancer activity in vitro using a synergistic therapy of photothermal therapy (PTT) followed by photodynamic therapy (PDT). In this system, PTT controls the PS release to maximize 1O2 photogeneration for PDT.

Chem. Asian J. 2015, 10, No. 03, 563-567

Juan Yan, Chongya Hu, Ping Wang, Bin Zhao, Xiangyuan Ouyang, Juan Zhou, Rui Liu, Dannong He, Chunhai Fan, Shiping Song
Growth and Origami Folding of DNA on Nanoparticles for High-Efficiency Molecular Transport in Cellular Imaging and Drug Delivery [Communication]

Growth and Origami Folding of DNA on Nanoparticles for High-Efficiency Molecular Transport in Cellular Imaging and Drug Delivery

A novel 3D gold-DNA superstructure based on DNA growing and origami folding on gold nanoparticles had been fabricated. The new 3D superstructures exhibit great potential for high-efficiency molecule transport for use in cellular imaging and drug delivery.

Angew. Chem. Int. Ed. 2015, 54, No. 08, 2431-2435

Ying-Jie Zhu, Feng Chen
pH-Responsive Drug-Delivery Systems [Focus Review]

pH-Responsive Drug-Delivery Systems

Get a response! pH-Responsive drug-delivery systems have promising applications because they are “smart” or “intelligent” in overcoming the shortcomings of conventional drug formulations and are able to deliver drugs in a controlled manner at specific sites and times, which results in high therapeutic efficacy. Recent progress obtained for pH-responsive drug-delivery systems and future perspectives is presented.

Chem. Asian J. 2015, 10, No. 02, 284-305

Huijie Zhu, Jin Li, Xiao-Bing Zhang, Mao Ye, Weihong Tan
Nucleic Acid Aptamer-Mediated Drug Delivery for Targeted Cancer Therapy [Minireview]

Nucleic Acid Aptamer-Mediated Drug Delivery for Targeted Cancer Therapy

Targeted & Specific: The applications of nucleic acid aptamers in cancer are reviewed. Single-stranded (ss) oligonucleotide (DNA or RNA)-based aptamers conjugated with drugs and nanomaterials are covered in detail, highlighting their therapeutic potential while acknowledging the challenges that remain to be overcome.

ChemMedChem 2015, 10, No. 01, 39-45

Stimuli-Responsive Polymeric Nanoparticles for Nanomedicine

Bringing life from cell death: Stimuli-responsive polymeric nanoparticles can respond to the microenvironment of a particular disease and its cells. Internal triggers as well as external devices permit temporally and spatially controlled drug delivery. The development of well-defined nanomedicines is critical for their behavior in vivo.

ChemMedChem 2015, 10, No. 01, 24-38

Targeted Treatment of Cancer with Nanotherapeutics Based on Mesoporous Silica Nanoparticles

Nanotherapeutics are designed and constructed from mesoporous silica nanoparticles for the targeted treatment of cancer based on characteristics of tumor tissues. The picture shows drug delivery triggered by the acidic extracellular environment of cancer, endocytosis of the drug carrier, and intracellular release of cargo drugs.

ChemPlusChem 2015, 80, No. 01, 26-36

Tianmeng Sun, Yu Shrike Zhang, Bo Pang, Dong Choon Hyun, Miaoxin Yang, Younan Xia
Engineered Nanoparticles for Drug Delivery in Cancer Therapy [Review]

Engineered Nanoparticles for Drug Delivery in Cancer Therapy

On the way to nanomedicine: Considerable advances in the development of nanoparticles for cancer therapy have been made in recent years. Nanoparticle-based drug-delivery systems offer advantages with regard to multidrug resistance, systemic delivery, and clearance, and enable for example specific tumor targeting and controlled release of therapeutic agents.

Angew. Chem. Int. Ed. 2014, 53, No. 46, 12320-12364

Pedro M. S. D. Cal, Gonçalo J. L. Bernardes, Pedro M. P. Gois
Cysteine-Selective Reactions for Antibody Conjugation [Highlight]

Cysteine-Selective Reactions for Antibody Conjugation

Moving tracks from maleimide: New site-selective protein modification reactions at cysteine have been developed. Unlike conventional maleimide conjugation, which results in a labile thioether succinimide, the new bioconjugation reactions result in stable conjugates and provide opportunities to develop a new generation of homogeneous, stable, and therapeutically useful conjugates.

Angew. Chem. Int. Ed. 2014, 53, No. 40, 10585-10587

Sandra García-Gallego, Gonçalo J. L. Bernardes
Carbon-Monoxide-Releasing Molecules for the Delivery of Therapeutic CO In Vivo [Minireview]

Carbon-Monoxide-Releasing Molecules for the Delivery of Therapeutic CO In Vivo

On target: Carbon-monoxide-releasing molecules (CORMs) are promising agents for the treatment of several diseases. CORMs are particularly good for enabling CO delivery in a controlled manner without affecting oxygen transport by hemoglobin. Significant progress in the methods for CO detection in live cells and the understanding of the reactivity of CORMs in vivo provides insights into CO biology and the design of safer, and more selective and efficient CORMs for clinical use.

Angew. Chem. Int. Ed. 2014, 53, No. 37, 9712-9721

Sven Kruspe, Florian Mittelberger, Kristina Szameit, Ulrich Hahn
Aptamers as Drug Delivery Vehicles [Review]

Aptamers as Drug Delivery Vehicles

Selective delivery: Active drug targeting enhances the efficacy and specificity of systemic therapeutics. Aptamers, artificial nucleic acid ligands, represent powerful targeting tools that can act as cell-specific drug carriers. The advancements from the past decade have provided various approaches that open new gateways for drug administration in cancer therapy.

ChemMedChem 2014, 9, No. 09, 1998-2011

Dong Choon Hyun, Nathanael S. Levinson, Unyong Jeong, Younan Xia
Emerging Applications of Phase-Change Materials (PCMs): Teaching an Old Dog New Tricks [Review]

Emerging Applications of Phase-Change Materials (PCMs): Teaching an Old Dog New Tricks

PCMs on the rise: As a result of their sharp melting points and large heats of fusion during phase transition, phase-change materials (PCMs) have already found commercial use in thermal management. The vast potential of this class of fascinating materials has recently been tapped in a diverse array of high-tech applications such as controlled release, information storage, sensing/detection, and barcoding.

Angew. Chem. Int. Ed. 2014, 53, No. 15, 3780-3795

Sabrina Nowag, Rainer Haag
pH-Responsive Micro- and Nanocarrier Systems [Highlight]

pH-Responsive Micro- and Nanocarrier Systems

Release on demand: The pH gradients between extra- and intracellular regions can be utilized for the controlled release of drugs and biological cargos from delivery systems. Biocompatible carrier systems with pH-cleavable units must fulfill many other criteria as well, for example, a long blood circulation time. This can be achieved by tailored micro- and nanocarriers based on macromolecular architectures or stable self-assembled systems.

Angew. Chem. Int. Ed. 2014, 53, No. 01, 49-51

Wei Cao, Yuwei Gu, Myriam Meineck, Huaping Xu
The Combination of Chemotherapy and Radiotherapy towards More Efficient Drug Delivery [Focus Review]

The Combination of Chemotherapy and Radiotherapy towards More Efficient Drug Delivery

Missing a piece? We propose the idea of combining regular chemotherapy with radiation therapy to minimize side effects and to increase drug-delivery efficiency. The unfinished puzzle in the picture shows the Aesculapian snake—the symbol of pharmacy and cure—to remind us that there is still a gap between potent chemotherapeutics and radiotherapy. We hope the emerging research area summarized in this Focus Review can function as the connecting pieces to solve the puzzle of an effective and comprehensive treatment.

Chem. Asian J. 2014, 9, No. 01, 48-57

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