Xueling He

Toward the Next-Generation Nanomedicines: Design of Multifunctional Multiblock Polyurethanes for Effective Cancer Treatment

Specific accumulation of therapeutics at tumor sites to improve in vivo biodistribution and therapeutic efficacy of anticancer drugs is a major challenge for cancer therapy. Herein, we demonstrate a new generation of intelligent nanosystem integrating multiple functionalities in a single carrier based on multifunctional multiblock polyurethane (MMPU). The smart nanocarriers equipped with stealth, active targeting, and internalizable properties can ferry paclitaxel selectively into tumor tissue, rapidly enter cancer cells, and controllably release their payload in response to an intracellular acidic environment, thus resulting in an improved biodistribution and excellent antitumor activity in vivo. Our work provides a facile and versatile approach for the design and fabrication of smart intracellular targeted nanovehicles for effective cancer treatment, and opens a new era in the development of biodegradable polyurethanes for next-generation nanodelivery systems.

Cellular uptake of polyurethane nanocarriers mediated by gemini quaternary ammonium.

The effective passage of drug formulations into tumor cells is a key factor in the development of nanoscale delivery systems. However, rapid cellular uptake with reduced toxicity remains a great challenge for efficient and safe delivery. In this study, we first use gemini quaternary ammonium (GQA) as a cell internalization promoter to enhance the cellular uptake of drug nanocarriers. It is found that a twenty times faster cell internalization could be achieved by introducing GQA into biodegradable multiblock polyurethane nanomicelles, as confirmed by flow cytometry and confocal laser scanning microscopy (CLSM) studies. Meanwhile, an added methoxyl-poly(ethylene glycol) (mPEG) outer corona could protect these cationic micelles from cytotoxicity at high concentrations, as verified by methyl tetrazolium (MTT) assay. Moreover, GQA not only acts as an enhancer for rapid cellular entry, but also plays an important role in controlled self-assembly and high drug loading capacity. Our work offers a new understanding on the role of cationic surfactants; and provides a facile and economical approach for the design of versatile drug nanocarriers to achieve efficient delivery and good biocompatibility.

Synthesis and characterization of novel biodegradable folate conjugated polyurethanes

In order to obtain targeting polyurethane micelle drug carriers, a series of biodegradable folate conjugated polyurethanes (FPUs) were synthesized using poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) as soft segments, L-lysine ethyl ester diisocyanate (LDI) and 1,3-propanediol (PDO) as hard segments, and folic acid-ethylenediamine conjugate (FA-EDA) as an end-capping reagent. The resultant FPUs were fully characterized by (1)H NMR, Fourier-transform infrared (FTIR) spectroscopy, ultraviolet spectrophotometry (UV), gel permeation chromatography (GPC), and differential scanning calorimetry (DSC). These polymers can self-assemble into micelles in aqueous solutions confirmed by dynamic light scattering (DLS), pyrene fluorescence probe techniques, and transmission electron microscopy (TEM). The results indicated that the bulk structures and micellar properties of the prepared polyurethanes could be controlled by varying the PEG content in the soft segments. The present work provides a facile approach to prepare amphiphilic multiblock copolymers with tumor targeting moiety, which is a good candidate as biodegradable carriers for active intracellular drug delivery.

Multifunctional Mixed Micelles Cross-Assembled from Various Polyurethanes for Tumor Therapy

A challenge in the development of multifunctional drug delivery systems is to establish a reasonable and effective synthetic route for multifunctional polymer preparation. Herein, we propose a unique protocol to prepare multifunctional micelles by a cross-assembly process using three different functional polyurethanes incorporating acidic sensitive hydrazone, folic acid for active targeting, and gemini quaternary ammonium (GQA) as efficient cell uptake ligands, respectively. These multifunctional mixed micelles (GFHPMs) have been endowed tunable particle sizes and zeta potential and a unique three-order-layer cross-assemble structure. Their drug-loading contents have been significantly improved, and drug release profiles displayed controlled release of their payloads under acid condition. The folate and GQA ligands showed a synergistic effect to enhance the cell uptake. Biodistribution and antitumor effect of these micelles were systematically investigated in vivo, the mixed micelles could penetrate into the depths of tumors, and drug concentrations in tumors reached the maximum of 6.5% ID/g at 24 h, resulting in an excellent therapeutic effect that the volumes of tumors treated with GFHPM are five times smaller than those treated with blank micelles. Our present work provides an effective approach to the design of multifunctional nanocarriers for tumor-targeted and programmed intracellular drug delivery.

Effect of Trastuzumab on the Micellization Properties,Endocytic Pathways and Antitumor Activities of Polyurethane-based Drug Delivery System

Polyurethane micelles (PM)-based nanovehicles have shown great potential in targeted delivery of therapeutics and diagnostics into tumors. However, the pathways of PMs entering cancer cells and the action mechanism of targeting ligands have yet to be understood. In this contribution, the actively-targeted PM were developed using trastuzumab as a model targeting group. It was found that PM were mainly taken up by SKOV-3 tumor cells via a micropinocytosis process, while the incorporation of trastuzumab to PM enabled a receptor-mediated endocytosis of nanocarriers in cancer cells, leading to more efficient cell entry and enhanced anticancer efficacy of chemotherapeutic drugs both in vitro and in vivo. This study is advantageous to the understanding of the action mechanism of trastuzumab, and significant for the construction of improved formulations for targeted delivery and precise therapy.