Chen Xiao

Within the past few years, cell derived microparticles (MPs) have emerged as a highly potent natural drug delivery system for tumor therapy. We and others have engineered different cells to obtain eleven kinds of MPs, which efficiently delivered antitumor agents to recipient cells and achieved ideal treatment outcomes in a great number of rodent tumor models. More significantly, autologous tumor cell derived MPs packaging chemotherapeutic drugs were demonstrated to be safe and tolerable and accomplished decent objective clinical response in lung cancer patients in clinical settings, leading to their approval as a novel biotherapy for treating malignancies in China. In this feature article, we review MP mediated tumor targeting delivery. The impact of tumor cell derived MPs on tumor progression and metastasis will be briefly summarized. Different means to prepare, label and characterize MPs will be introduced. Advantages and limitations of distinctive cargo encapsulation strategies will be outlined and compared. Tumor cell MP mediated in vivo transport processes will be reviewed comprehensively. Representative MPs shed by platelets, endothelial cells, macrophages, and dendritic cells will be selected to showcase their advantages in tumor targeting delivery. Multifarious therapeutic agents, including chemotherapeutic drugs, oncolytic adenovirus, nucleic acids, antigens, antibodies, to name a few, have been transported to their targets for corresponding cancer therapies. Current challenges and future opportunities on translating MPs for tumor targeting delivery will be provided in the end.

Modulating nanomedicine mechanical properties for enhanced drug delivery to tumors has attracted increasing attention in the past few decades. In this tutorial review, we analyze the impact of nanomedicine mechanical properties on in vivo transport processes and highlight the most recent advances in drug delivery efficiency and antitumor efficacy. Typical nanoparticles that have been explored for this purpose since 2000 are summarized while the methods to tune and the techniques to characterize nanomedicine mechanical properties are introduced. In the end, challenges and perspectives on tailoring nanomedicine mechanical properties for tumor targeting delivery are discussed.

The stiffness of cationized gelatin nanoparticles (CGNPs) dictates the siRNA delivery efficiency in myeloid leukemia cells.

Constructing a tumor microenvironment stimuli activatable theranostic nanoparticle with simple components and preparation procedures for multimodality imaging and therapy remains a major challenge for current theranostic systems. Here we report a novel and simple glutathione (GSH)-responsive turn-on theranostic nanoparticle for dual-modal imaging and combination therapy. The theranostic nanoparticle, DHP, consisting of a disulfide-bond-linked hydroxyethyl starch paclitaxel conjugate (HES-SS-PTX) and a near-infrared (NIR) cyanine fluorophore DiR, is prepared with a simple one-step dialysis method. As DiR is encapsulated within the hydrophobic core formed by HES-SS-PTX, the fluorescence of DiR is quenched by the aggregation-caused quenching (ACQ) effect. Nonetheless, once DHP is internalized by cancer cells, the disulfide bond of HES-SS-PTX can be cleaved by intracellular GSH, leading to the synchronized release of conjugated PTX and loaded DiR. The released PTX could exert its therapeutic effect, while DiR could adsorb onto nearby endosome/lysosome membranes and regain its fluorescence. Thus, DHP could monitor the release and therapeutic effect of PTX through the fluorescence recovery of DiR. Remarkably, DHP can also be used as an in vivo probe for both fluorescent and photoacoustic imaging and at the same time achieves potent antitumor efficacy through chemo-photothermal combination therapy. This study provides novel insights into designing clinically translatable turn-on theranostic systems.

Tumor penetration is the bottleneck for current cancer nanomedicine, limiting the ultimate antitumor efficacy in the clinic. Herein, by exploiting the well-known instability of indocyanine green (ICG), we report the preparation of near infrared (NIR) light responsive nanoparticles (NP) for enhanced tumor penetration. ICG crosslinks hydroxyethyl starch (HES) and doxorubicin (DOX) conjugates (HES-SS-DOX) via noncovalent interactions, facilitating the formation of ICG@HES-SS-DOX NP. The light triggered degradation of ICG leads to the dissociation of such NP, and the resulting HES-SS-DOX has been shown to penetrate deeper in both H22 tumor spheroids and tumor bearing mice, due to the photothermal effect of ICG. Therefore, the disintegrable ICG@HES-SS-DOX NP have better tumor penetration capacity than their counterparts, which originally cannot dissociate under NIR light stimulation. The reported ICG@HES-SS-DOX NP might be potent in treating malignant tumors with dense extracellular matrices, such as liver and pancreatic cancers. This study opens up a novel functionality of FDA-approved ICG for cancer nanotherapeutics.

Cis-platinum has been widely used as a first-line chemotherapy agent in clinics for more than 40 years. Although considerable efforts have been expended for developing platinum-based nano drug delivery systems (NDDS) to resolve the problems of low water solubility, short half-life, and severe side effects of cis-platinum, it remains challenging to apply these nanoplatforms to cancer treatments in clinics on account of the issues related to safety, complex fabrication procedures, and limited cellular uptake. Herein, we constructed a novel cis-platinum delivery system with hydroxyethyl starch (HES), which is a semisynthetic polysaccharide that has been used worldwide as colloidal plasma volume expanders (PVE) in clinics for several decades. By combining TEM, AFM, and DLS, we have found that HES particles are colloidal nanoparticles in solution, with diameters ranging from 15 to 40 nm as a function of molecular weight. We further revealed that HES adopted a hyperbranched colloidal structure with rather compact conformation. These results demonstrate that HES is a promising nanocarrier to deliver drug molecules. Taking advantage of the poly-hydroxyl sites of HES, we constructed a novel HES-based cis-platinum delivery nanoplatform. HES was directly conjugated with cis-platinum prodrug via an ester bond and decorated with an active targeting molecule, lactobionic acid (LA), contributing toward higher in vitro antitumor activity against hepatoma carcinoma cells as compared to cis-platinum. These results have significant implications for the clinically used plasma volume expander-HES and shed light on the clinical translation of HES-based nano drug delivery systems.

Herein, reduction-responsive disintegratable nanoclusters (NCs) were prepared as a novel nanovehicle for targeted drug delivery. The NCs, with a diameter of ∼170 nm, were self-assembled from hydrophobically modified and iRGD decorated hydroxyethyl starch (iRGD-HES-SS-C18). DOX was loaded into the NCs as a model drug. DOX@iRGD-HES-SS-C18 NCs can disintegrate into smaller ones and release DOX under reduction stimuli. Due to the ligand–receptor binding interactions between iRGD and integrin αV, DOX@iRGD-HES-SS-C18 NCs can specifically bind to the cell membranes of HepG-2 and 4T1 cells (integrin αV positive), resulting in enhanced cellular uptake as compared to DOX@HES-SS-C18 NCs. After cellular internalization, the NCs were transported to endosomes/lysosomes in which the reductive environment triggered the disintegration and DOX release. As a consequence, DOX@iRGD-HES-SS-C18 NCs exhibited an enhanced antitumor effect as compared to DOX@HES-SS-C18 NCs and free DOX, in an in vitro antitumor activity study. The reduction-responsive disintegratable NCs reported here were proved to be a safe and efficient nanoplatform, holding significant translation potential for tumor-targeted drug delivery.