Tumor Microenvironment Sensitive Nanocarriers for Bioimaging and Therapeutics.

The tumor microenvironment (TME), which is composed of cancer cells, stromal cells, immune cells, and extracellular matrices, plays an important role in tumor growth and progression. Thus, targeting the TME using a well-designed nano-drug delivery system is emerging as a promising strategy for the treatment of solid tumors. Compared to normal tissues, the TME presents several distinguishable physiological features such as mildly acidic pH, hypoxia, high level of reactive oxygen species, and overexpression of specific enzymes, that are exploited as stimuli to induce specific changes in the nanocarrier structures, and thereby facilitates target-specific delivery of imaging or chemotherapeutic agents for the early diagnosis or effective treatment, respectively. Recently, smart nanocarriers that respond to more than one stimulus in the TME have also been designed to elicit a more desirable spatiotemporally controlled drug release. This review highlights the recent progress in TME-sensitive nanocarriers designed for more efficient tumor therapy and imaging. In particular, the design strategies, challenges, and critical considerations involved in the fabrication of TME-sensitive nanocarriers, along with their in vitro and in vivo evaluations are discussed.

Polymer/Aptamer-Integrated Gold Nanoconstruct Suppresses the Inflammatory Process by Scavenging ROS and Capturing Pro-inflammatory Cytokine TNF-α.

In the present study, we report a rationally designed polymer/aptamer-integrated gold (Au) nanoconstruct capable of scavenging reactive oxygen species (ROS) and capturing tumor necrosis factor alpha (TNF-α) and investigate its potential as an anti-inflammatory agent for the treatment of peritonitis. By taking advantage of specific interactions between ATP and both ATP aptamer and polymeric phenylboronic acid (pPBA), we construct a unique polymer-coated Au nanoconstruct equipped with TNF-α aptamer and ATP aptamer. The formed phenylboronic ester and TNF-α aptamer in the nanoconstruct is capable of scavenging ROS and capturing of TNF-α, respectively. Thus, this combined characteristics enable the nanoconstruct an additive anti-inflammatory effect. Furthermore, we demonstrate the high anti-inflammatory effect of the nanoconstruct in vitro and in vivo using the peritonitis model by monitoring ROS and pro-inflammatory cytokine levels.

Polymersomes with singlet oxygen-labile poly(ß-aminoacrylate) membrane for NIR light-controlled combined chemo-phototherapy.

Engineering the membrane of the polymersomes with biologically relevant stimuli-responsive units enables spatial and temporal controlled drug release for effective therapy. Herein, we introduce a new-type of polymersomes featuring reactive oxygen species singlet oxygen (1O2)-labile membrane by employing a versatile stereoregular amphiphilic poly(ethylene glycol)-block-poly(ß-aminoacrylate)-block-poly(ethylene glycol) copolymers, which are synthesized through a facile one pot modular amino-alkynoate click polymerization between secondary amines and activated alkynes. These polymersomes readily co-encapsulate an anticancer drug doxorubicin (DOX) and a near infrared (NIR) photosensitizer IR-780 with hydrophobic characteristics in the membrane, and the resulting polymersomes show efficient uptake by the tumor cells. NIR light irradiation on the tumors, following intraperitoneal injection of the IR-780/DOX co-encapsulated polymersomes, facilitates tumor-specific release of DOX through disassembly of the polymersome nanostructure via 1O2-mediated photocleavage of the membrane. Moreover, IR-780 dye can convert NIR light energy into heat in addition to the generation of 1O2, thus allows to realize both photothermal and photodynamic therapy. Accordingly, the NIR light-mediated on demand chemotherapy, in combination with appreciable phototherapy, of IR-780/DOX co-loaded polymersomes demonstrate an efficient tumor suppression in vivo.

In vivo self-degradable graphene nanomedicine operated by DNAzyme and photo-switch for controlled anticancer therapy.

Although graphene oxide (GO) possesses many beneficial functionalities for biomedical usage as itself, modification of GO surface with several polymers or protein is inevitable for in vivo applications; however, such modification limits the degradability of GO due to the steric hindrance. In that context, designing of a surface modified GO carrier that is going to be degraded after its biological function (i.e., drug delivery) is highly desired, especially at complex in vivo level. Herein, we design an unprecedented "catalytic GO nanomedicine" by applying the catalytic DNA, achieving self-degradation of GO in systemic level in the body after the therapy following surface modification. Once the catalytic GO nanomedicines are taken up by mucin1 (MUC1) aptamer-facilitated endocytosis, a photo-switch triggers the release of doxorubicin from the DNA. The single stranded G-quadruplex sequence on the surface of GO forms a quartet structure and becomes DNAzyme by binding with hemin on the GO surface, exhibiting peroxidase effect. Due to the high H2O2 concentration in cancer cells, the catalytic GO nanomedicine generates sufficient amount of strong oxidant, hypochlorous acid (HOCl), inducing GO degradation into small fragments for potential clearance. We demonstrate the potential of our catalytic GO nanomedicine for both therapy and degradation at cellular and complex in vivo environment.

A Pt(iv)-mediated polymer architecture for facile and stimuli-responsive intracellular gene silencing with chemotherapy.

Conventional chemotherapy has been impeded by the inherent characteristics of cancer including fast mutagenesis and drug resistance; thus a combination therapy consisting of multiple therapeutic strategies has attracted much attention. However, the loading processes of multiple therapeutic molecules affect each other; thus the development of a nanocarrier that enables independent loading of the cargo molecules has been demanded. Herein, we report an ingeniously designed Pt(iv)-mediated polymeric architecture (Pt-PA) for combinatorial gene and chemotherapy to address the issue, prepared by crosslinking a cationic polymer (polyethylenimine, PEI) with a Pt(iv) prodrug. Therapeutic siRNA (anti-BCL2) was simply loaded by electrostatic interaction to form a stable nanocomplex. In the cellular study, the simultaneous release of both the active Pt(ii) drug and siRNA was monitored under the intracellular reducing environment, driven by dissociation of the polymer architecture due to an inherent characteristic of the Pt(iv) crosslinker. Therefore, an enhanced gene silencing effect and an anticancer effect were observed. Furthermore, in the animal study, an improved therapeutic effect of the nanocomplex was observed, which can be explained by tumor targeting via the EPR effect, and enhanced drug and siRNA release at the intracellular environment simultaneously. Taken together, the overall results from in vitro and in vivo studies strongly suggest the therapeutic potential of our precisely designed Pt(iv)-mediated polymer architecture.

Functional-DNA-Driven Dynamic Nanoconstructs for Biomolecule Capture and Drug Delivery.

The discovery of sequence-specific hybridization has allowed the development of DNA nanotechnology, which is divided into two categories: 1) structural DNA nanotechnology, which utilizes DNA as a biopolymer; and 2) dynamic DNA nanotechnology, which focuses on the catalytic reactions or displacement of DNA structures. Recently, numerous attempts have been made to combine DNA nanotechnologies with functional DNAs such as aptamers, DNAzymes, amplified DNA, polymer-conjugated DNA, and DNA loaded on functional nanoparticles for various applications; thus, the new interdisciplinary research field of "functional DNA nanotechnology" is initiated. In particular, a fine-tuned nanostructure composed of functional DNAs has shown immense potential as a programmable nanomachine by controlling DNA dynamics triggered by specific environments. Moreover, the programmability and predictability of functional DNA have enabled the use of DNA nanostructures as nanomedicines for various biomedical applications, such as cargo delivery and molecular drugs via stimuli-mediated dynamic structural changes of functional DNAs. Here, the concepts and recent case studies of functional DNA nanotechnology and nanostructures in nanomedicine are reviewed, and future prospects of functional DNA for nanomedicine are indicated.

Miktoarm Amphiphilic Block Copolymer with Singlet Oxygen-Labile Stereospecific ß-Aminoacrylate Junction: Synthesis, Self-Assembly, and Photodynamically Triggered Drug Release.

Incorporation of a desired stimuli-responsive unit in a stereospecific manner at the specific location within a nonlinear block copolymer architecture is a challenging task in synthetic polymer chemistry. Herein, we report a facile and versatile method to synthesize AB2 miktoarm block copolymers bearing a singlet oxygen (1O2)-labile regio and stereospecific ß-aminoacrylate linkage with 100% E-configuration at the junction via a combination of amino-yne click chemistry and ring opening polymerization. Using this strategy, a series of 1O2-responsive AB2 amphiphilic miktoarm (MA) copolymers composed of hydrophilic polyethylene glycol (PEG) as the A constituent and hydrophobic polycaprolactone (PCL) as the B constituent (MA-PEG- b-PCL2) was synthesized by varying the block length of PCL. The self-assembly characteristics of these well-defined MA-PEG- b-PCL2 copolymers in an aqueous condition were studied by solvent displacement and thin-film hydration method, and their morphologies were investigated using transmission electron microscopy. The copolymers formed spherical, cylindrical, or lamella morphologies, depending on the chain length and preparation conditions. A hydrophobic photosensitizer chlorin e6 (Ce6) and anticancer drug doxorubicin (DOX) were efficiently encapsulated into the hydrophobic core of MA-PEG- b-PCL2 copolymer micelles. These coloaded micelles were taken up by human breast cancer (MDA-MB-231) cells. Upon red laser light irradiation, the 1O2-generated by the Ce6 induced photocleavage of the ß-aminoacrylate moiety, leading to the dissociation of the micellar structure and triggered intracellular drug release for effective therapy. Overall, rapid disassembly upon 1O2 generation and subsequent controlled intracellular drug release suggested that these micelles bearing ß-aminoacrylate linkage have a huge potential for on-demand drug delivery.

Poly-paclitaxel/cyclodextrin-SPION nano-assembly for magnetically guided drug delivery system.

This work demonstrates the development of magnetically guided drug delivery systems and its potential on efficient anticancer therapy. The magnetically guided drug delivery system was successfully developed by utilizing superparamagnetic iron oxide nanoparticle, ß-cyclodextrin, and polymerized paclitaxel. Multivalent host-guest interactions between ß-cyclodextrin-conjugated superparamagnetic iron oxide nanoparticle and polymerized paclitaxel allowed to load the paclitaxel and the nanoparticle into the nano-assembly. Clusterized superparamagnetic iron oxide nanoparticles in the nano-assembly permitted the rapid and efficient targeted drug delivery. Compared to the control groups, the developed nano-assembly showed the enhanced anticancer effects in vivo as well as in vitro. Consequently, the strategy of the use of superparamagnetic nanoparticles and multivalent host-guest interactions has a promising potential for developing the efficient drug delivery systems.