Leilei Shi

Self-Assembled Nanoparticles of Amphiphilic Twin Drug from Floxuridine and Bendamustine for Cancer Therapy.

We report here an amphiphilic twin drug strategy directly using small molecular hydrophilic and hydrophobic anticancer drugs to self-assemble into nanoparticles with a high and fixed drug content, which can solve problems of anticancer drug delivery including poor water solubility, low therapeutic indices, and severe side effects. The twin drug has been prepared by the esterification of the hydrophilic anticancer drug floxuridine (FdU) with the hydrophobic anticancer drug bendamustine (BdM). Due to its inherent amphiphilicity, the FdU-BdM twin drug can self-assemble into stable and well-defined nanoparticles. After FdU-BdM twin drug enters into cells, the ester linkage between hydrophilic and hydrophobic drugs is readily cleaved by hydrolysis to release free FdU and BdM. Since both FdU and BdM can kill cancer cells, the FdU-BdM twin drug nanoparticles can overcome the multidrug resistance (MDR) of tumor cells and present an excellent anticancer activity. This strategy can be extended to other hydrophilic and hydrophobic anticancer drugs to synthesize amphiphilic twin drugs which can form nanoparticles to self-deliver drugs for cancer therapy.

Construction of a Supramolecular Drug–Drug Delivery System for Non-Small-Cell Lung Cancer Therapy

Nanoscale drug delivery systems (DDSs) are generally considered to be an effective alternative to small molecular chemotherapeutics due to improved accumulation in the tumor site and enhanced retention in blood. Nevertheless, most DDSs have low loading efficiency or even pose a high threat to normal organs from severe side effects. Ideally, a supramolecular drug-drug delivery system (SDDDS) composed of pure drugs via supramolecular interaction provides a hopeful approach for cancer treatment. Herein we propose a facile method to construct SDDDS via coassembly of gefitinib (GEF) and tripeptide tyroservatide (YSV), two kinds of chemotherapeutic pharmaceuticals for non-small-cell lung cancer (NSCLC) via multiple intermolecular interactions, including hydrogen bonding and π-π stacking. As shown through transmission electron microscopy (TEM) and dynamic light scattering (DLS), GEF and YSV self-assemble into nanoparticles with regular morphology and uniform size, which facilitates the delivery of both drugs. In vitro studies demonstrate that the SDDDS is much more efficient in entering cancer cells and inhibiting the proliferation of cancer cells compared with single GEF, YSV, or GEF/YSV drug mixture. In vivo experiments show that the SDDDS can selectively accumulate in tumor tissue, resulting in much better drug efficacy without evident side effects. Considering the advantages of the SDDDS, we believe this strategy provides a promising route for enhanced anticancer therapy in nanomedicine.

Nucleoside Analogue-Based Supramolecular Nanodrugs Driven by Molecular Recognition for Synergistic Cancer Therapy

The utilization of nanotechnology for the delivery of a wide range of anticancer drugs has the potential to reduce adverse effects of free drugs and improve the anticancer efficacy. However, carrier materials and/or chemical modifications associated with drug delivery make it difficult for nanodrugs to achieve clinical translation and final Food and Drug Administration (FDA) approvals. We have discovered a molecular recognition strategy to directly assemble two FDA-approved small-molecule hydrophobic and hydrophilic anticancer drugs into well-defined, stable nanostructures with high and quantitative drug loading. Molecular dynamics simulations demonstrate that purine nucleoside analogue clofarabine and folate analogue raltitrexed can self-assemble into stable nanoparticles through molecular recognition. In vitro studies exemplify how the clofarabine:raltitrexed nanoparticles could greatly improve synergistic combination effects by arresting more G1 phase of the cell cycle and reducing intracellular deoxynucleotide pools. More importantly, the nanodrugs increase the blood retention half-life of the free drugs, improve accumulation of drugs in tumor sites, and promote the synergistic tumor suppression property in vivo.

Molecular insights for the biological interactions between polyethylene glycol and cells

As the gold standard polymer for drug delivery system, polyethylene glycol (PEG) has excellent biocompatibility. Its reported that the low nonspecific interactions between PEG and body contribute to its biocompatibility. However, here we discover dynamic biological interactions exist between PEG and cells on the molecular level. PEG (2 kD) can induce metabolism modulations and survival autophagy by creating an intracellular hypoxic environment, which act as cellular survival strategies in response to the hypoxia. In the cellular adaption process during hypoxia, PEG-treated cells decrease energy consumption by reducing cell growth rate, increase energy supply by amino acid catabolism in a short period, and survival autophagy over a relatively long period, to keep energy homeostasis and survival. Our research provides molecular insights for understanding the mechanism underlying the excellent biocompatibility of PEG, which will be of fundamental importance for further related studies on other polymers and development of polymeric materials with improved characteristics.

Celecoxib-Induced Self-Assembly of Smart Albumin-Doxorubicin Conjugate for Enhanced Cancer Therapy

Recent years have witnessed the great contributions that drug combination therapy has made for enhanced cancer therapy. However, because of the complicated pharmacokinetics of combined drug formulations, the majority of combination strategies show severe adverse effects at high dosage and poor biodistribution in vivo. To overcome these deficiencies and achieve enhanced cancer therapy, we put forward a method to construct a smart albumin-based nanoplatform, denoted as K237-HSA-DC, for codelivery of cyclooxygenase-2 (COX-2) inhibitor (celecoxib) and chemotherapeutic agent (doxorubicin, DOX). Both in vitro and in vivo studies indicate that K237-HSA-DC exhibits the best therapeutic efficacy on tumor cells compared with all the other formulations. Moreover, K237-HSA-DC shows fewer side effects on normal organs in contrast to other formulations. To understand the reasons behind the improved drug efficacy in depth, we performed a cell metabonomics-based mechanism study and found that celecoxib could enhance the inhibitory effect of DOX on the transport of glucose into cells and then lead to subsequent significant energy metabolism inhibition. Considering the above-mentioned advantages of K237-HSA-DC, we believe the smart albumin-based nanoplatform can serve as a promising drug delivery system for enhanced cancer therapy.

Endoplasmic Reticulum–Targeted Fluorescent Nanodot with Large Stokes Shift for Vesicular Transport Monitoring and Long‐Term Bioimaging

Herein, a highly stable aggregation-induced emission (AIE) fluorescent nanodot assembled by an amphiphilic quinoxalinone derivative-peptide conjugate, namely Quino-1-Fmoc-RACR (also termed as Q1-PEP), which exhibits large Stokes shift and an endoplasmic reticulum (ER)-targeting capacity for bioimaging is reported. It is found that the resulting nanodot can effectively enter the ER with high fluorescent emission. As the ER is mainly involved in the transport of synthesized proteins in vesicles to the Golgi or lysosomes, the Q1-PEP nanodot with ER-targeting capacity can be used to monitor vesicular transport inside the cells. Compared to conventional fluorescent dyes with small Stokes shifts, the self-assembled fluorescent nanodot shows superior resistance to photobleaching and aggregation-induced fluorescence quenching, and elimination of the spectra overlap with autofluorescence of biosubstrate owning to their AIE-active and red fluorescence emission characteristics. All these optical properties make the fluorescent nanodot suitable for noninvasive and long-term imaging both in vitro and in vivo.

Short-term urea cycle inhibition in rat liver cells induced by polyethylene glycol

Polyethylene glycol (PEG) is widely used in the biomedical field due to its outstanding properties. There are plenty of reports on the safety of PEG, but they are mostly restricted to its pharmacokinetic behaviour and pathological effect in vivo, and fail to elucidate its biological effects on cells at the molecular level. Consequently, here we illuminate the biological effect of PEG on a specific cellular pathway. We found that PEG could induce short-term urea cycle inhibition in rat liver cells in vitro without damaging the mitochondria and cells, which was proven to be an adaptive and reversible response to PEG at the molecular level. PEG could also induce a transient hepatic stress response in vivo, which was closely related with the urea cycle disorder. As a mechanistic study on the interactions between a synthetic biomedical polymer and cells at the molecular level, our work provides novel insights into the biological effects of polymers on a cellular system and is fundamental to the development of biomedical polymers.

Reaction-Based Color-Convertible Fluorescent Probe for Ferroptosis Identification

Ferroptosis is an iron-mediated, caspase-independent pathway of cell death that is accompanied with the accumulations of reactive oxygen species (ROS) and oxygenases, as well as being involved in many other pathophysiological procedures. However, specific and rapid monitoring of ferroptosis in living cells or tissues has not been achieved so far. Herein, a quinoxalinone-based fluorescent probe (termed as Quinos-4, or QS-4) with a reactive aromatic thioether moiety was designed for ferroptosis identification. Upon exposing it to high levels of ROS and hemeoxygenase-1 (HO-1), which are considered as the biochemical characteristics of ferroptosis, QS-4 could be oxidized into a sulfoxide derivative (QSO-4) and its original aggregation-induced enhanced red fluorescence emission could be converted to green fluorescence emission sharply. On the basis of this unique reaction-induced color conversion, this molecular probe can be employed for identifying the occurrence of ferroptosis both in vitro and in vivo.