Advanced Drug Delivery Systems for Therapeutic Applications


This special issue of Advanced Healthcare Materials highlights some of the excellent research that has been featured at the International Advanced Drug Delivery Symposium (IADDS) in Taiwan over the last few years, supplemented by other outstanding contributions on drug delivery systems. Since 2007, National Tsing Hua University and the Industrial Technology Research Institute have held the IADDS annually, with the objective of bridging the knowledge gap between academic research and industrial need. This special issue is guest-edited by Professor Hsing-Wen Sung of National Tsing Hua University and Professor Zhuang Liu of Soochow University. The topics include stimuli-responsive carrier systems, targeting and imaging technologies, and drug, gene, and cell delivery applications for the treatment of pathological conditions, including cancers, heart, and eye diseases, as well as inflammatory injuries.

Stimuli-responsive carrier systems that undergo significant changes in their physicochemical properties in response to various physical or chemical stimuli for controllable drug delivery have attracted much attention in recent years. Physical stimuli include temperature, light, and magnetic, ultrasonic, and electrical fields, while chemical stimuli include pH, enzyme, and specific molecular recognition events. These carrier systems can differentially increase drug accumulation at targeted lesions, significantly reducing systemic toxicity.

Servant et al. prepared graphene-based electroresponsive scaffolds as an on-demand drug delivery system. The authors elucidated how the heat-dissipating properties of graphene provide significant advantages in the design of electroresponsive hydrogels and can maintain their optimal functionality by mitigating the adverse effects of unwanted heating. Feng et al. designed a graphene-based pH-responsive nanocarrier system for combined chemo- and photothermal therapy. Such combination therapy, which works particularly well at tumor microenvironmental pH, can overcome the multidrug resistance of cancer cells, which is a major problem in current chemotherapy in the treatment of cancers.

Ma's group used a prodrug strategy to obtain lyophilizable, high-drug-loading micelle formulations using diester derivatives of β-lapachone. In the presence of esterase, β-lap prodrugs were efficiently converted into a parent drug (β-lap), resulting in the NQO1-dependent lethality of NSCLC cells. Zhang et al. fabricated peptide dendrimer–doxorubicin conjugate-based nanoparticles (NPs) as an enzyme-responsive drug delivery system for cancer therapy; their in vitro and in vivo results obtained in healthy and tumor-bearing mice demonstrated significant increased therapeutic indices and reduced side effects.

Molecularly targeted delivery improves the cytotoxic effect of chemotherapeutic agents. Sun et al. developed a new platform for targeting breast cancer stem cells by functionalizing the surface of Au nanocages with SV119. The interiors of the nanocages could be loaded with an anticancer drug to eradicate cancer stem cells synergistically by a combination of photothermal and chemo therapies. Kim's group published interesting, targeting-related work: they formulated particle-stabilized emulsion droplets with a high-density core and used them to deliver particles as large as 200 nm to particular sites within the posterior segment of the eye by gravity-mediated targeting.

Intact porphysome NPs are inactive for photodynamic therapy (PDT). Jin and co-workers prepared activatable nanosized beacons for PDT. Receptor-mediated endocytosis via the incorporation of a targeting ligand such as folate in the porphysome facilitated the disruption of its nanostructure inside the cells, switching on the photodynamic activity of the densely packed porphyrins for effective PDT. In nanotherapeutics, exiting form cells is just as important as entering. Exocytosis rates determine residency time in a cell, which is an important determinant of therapeutic efficacy and of eventual clearance from the cell. Kim et al. demonstrated that surface functionality determines the efficiency of exocytosis, providing a strategy for optimizing nanocarriers.

Imaging-guided therapy has recently been receiving considerable attention. Li et al. studied imaging-guided drug delivery. In their work, a set of mesoporous silica (mSiO2)-coated quantum dot (QD) NPs that were functionalized with an enzyme-responsive cell-penetrating peptide sequence were fabricated. Using these NPs, they performed the nucleus-targeted delivery of an antitumor drug, demonstrating simultaneous targeting and delivery through QD fluorescence in real time. In their imaging work, Pu et al. developed phosphorylcholine-coated near-infrared semiconducting polymer NPs to enable rapid internalization in cells, high tolerance to reactive oxygen species (ROS), and sufficiently deep optical penetration of tissues. These NPs can be utilized as universal fluorescent labeling agents in the long-term tracking of primary cancer cells in living animals. In another study, Wang and co-workers formulated a bimodal nanoprobe that incorporated a single symmetrical fluorous dendron-cyanine dye molecule to overcome the shortcomings of conventional contrast agents for quantitative 19F MRI and fluorescent imaging. This nanoprobe has great potential for quantitative and sensitive multimodal bioimaging.

Fang et al. developed magnetic core–shell NPs with dual-targeting modalities of lactoferrin and magnetic guidance, to overcome multidrug resistance and co-deliver doxorubicin and curcumin intracellularly to inhibit the growth of brain glioma. In another study, Topete et al. prepared polymeric–Au nanohybrids that were co-loaded with doxorubicin and SPIONs and functionalized with folic acid for use in combined imaging and cancer therapy; they demonstrated that these nanohybrids were highly selective and had a synergistic cytotoxic effect. Also, Kuang's group formulated supramolecular nanofibrils that self-assembled from small peptide derivatives with the characteristic feature of amyloid oligomers; they showed that the nanofibrils effectively inhibited tumor progression both in vitro and in vivo, supporting a new anticancer method.

The development of vaccines that are based on nanomaterials has recently been a hot topic. Ahn et al. elucidated a novel cancer vaccine that was based on Au NPs; they demonstrated that Au NPs enabled efficient antigen delivery to dendritic cells and then activated the cells to facilitate cross-presentation, eventually inducing antigen-specific cytotoxic T-lymphocyte responses. These results have great potential for cancer immunotherapy. One of the signature characteristics of inflamed tissues is the presence of a variety of ROS. Yoshitomi and Nagasaki prepared nitroxide radical-containing NPs with ROS-scavenging capabilities for the treatment of oxidative stress injuries, such as ischemia–reperfusion injuries, colitis, and small intestinal inflammation.

Nanotechnology offers promising means to develop efficient siRNA and DNA delivery systems for therapeutic applications. Carbon dots have been extensively explored as a type of nanocarbon material for biomedical uses. In work by Wang et al., fluorescence carbon dots were coated with cationic polymers and used as carriers for delivering siRNA and DNA, which simultaneously served as an imaging probe under a two-photon microscope. In a review article, Ku et al. reported on recent advances in tumor-targeting strategies that are based on NP technologies, including passive targeting and active targeting, for cancer therapy. Recent advances in siRNA nanocarriers that contain multifunctionalities for cancer treatment were also highlighted. Ukawa and co-workers described a neutralized NP system of ss-cleavable and pH-activated lipid-like materials as a long-lasting and liver-specific gene delivery system. These neutralized NPs had a circulation half-life of more than 2 weeks, causing neither immunological responses nor hepatotoxicity following intravenous administration, when carrying pDNA that is free of CpG-motifs.

Finally, using a thermoresponsive methylcellulose hydrogel system, Huang's group fabricated various injectable cell constructs, including cell sheet fragments, cell bodies, core–shell cell bodies, and hypoxic-mixed cell bodies, for treating ischemic heart diseases. The researchers discussed their in vitro observations and the in vivo therapeutic efficacy of each cell construct.

In summary, the topics of the articles that are published in this special issue concern a diverse range of materials and methods for targeting, imaging, and the controlled release of drugs and genes, and provide a comprehensive overview of concepts that have evolved over the last few years and the current trends that are emerging on the horizon. These articles reveal that significant progress has been made in developing advanced drug delivery systems for a variety of therapeutic applications.


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    Hsing-Wen Sung received his Ph.D. degree in Biomedical Engineering from the Georgia Institute of Technology in 1988. He currently serves as a Tsing Hua Chair Professor of Chemical Engineering at National Tsing Hua University, Taiwan. His main research interests focus on biomaterials applied for tissue engineering and drug/gene delivery.

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    Dr. Zhuang Liu is a Professor at Soochow University in China. He received his B.S. degree from Peking University (China) in 2004 and Ph.D. degree from Stanford University (USA) in 2008. In 2009, Dr. Liu joined Institute Functional Nano & Soft Materials (FUNSOM) at Soochow University. Dr. Liu's research in the past few years has been mostly focused on the development of functional nanomaterials for applications in biomedical imaging, drug delivery, phototherapy of cancer, and cell therapy studies.