Jiehua Li

Self-assembly of biodegradable polyurethanes for controlled delivery applications

The self-assembly of biodegradable polyurethanes constitutes an important area of research for the development of polymeric materials in biomedicine. In particular, colloidal polyurethane assemblies can increase the solubility and stability of hydrophobic compounds, and improve the specificity and efficiency of drug action. Their nanoscale size and modular functionality make them promising for the injectable, targeted and controlled delivery of various therapeutic agents and imaging probes into required cells. Additionally, cationic polyurethanes are able to self-assemble with nucleic acids into nanoparticles to enter cells for efficient gene transfection. These emerging nanocarriers open the door for addressing the failure of traditional localized delivery systems, and present a compelling future opportunity to achieve personalized therapy as versatile candidates. This review article highlights the research progress in the self-assembly of biodegradable polyurethanes for controlled delivery applications, with particular attention being paid to some representative vehicles such as self-assembled polyurethane micelles, nanogels, and polyurethane/DNA complexes, which have emerged as the focus of interest in recent years.

Synthesis, Degradation, and Cytotoxicity of Multiblock Poly(ε-caprolactone urethane)s Containing Gemini Quaternary Ammonium Cationic Groups

Novel cationic biodegradable multiblock poly(epsilon-caprolactone urethane)s that contain gemini quaternary ammonium side groups on the hard segments were developed. To obtain these polyurethanes, a new L-lysine-derivatized diamine containing gemini quaternary ammonium side groups (GA8) was first synthesized and characterized by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectra (NMR), mass spectrometry (MS), and high-resolution mass spectra (HRMS). Then a series of gemini poly(epsilon-caprolactone urethane)s were designed and prepared using L-lysine ethyl ester diisocyanate (LDI), poly(epsilon-caprolactone) (PCL) diols, 1,4-butandiol (BDO), and GA8 and were terminated by methoxyl-poly(ethylene glycol) (m-PEG). The obtained polyurethanes were fully characterized by (1)H NMR, gel permeation chromatograph (GPC), differential scanning calorimetry (DSC), FTIR, and water contact angle (WCA) measurement. The gemini polyurethane shows a rapid rate of hydrolytic and enzymatic degradation, as demonstrated by weight loss and polarizing light microscopy (PLM) observations. In vitro cytotoxicity analysis suggests that both the polyurethanes and their degradation products do not show significant inhibition effect against fibroblasts. Our work provides a new way to synthesize nontoxic and amphiphilic multiblock polyurethanes with rapid degradation rate, and these new materials could be good candidates as biodegradable carriers for drug and gene delivery.

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.

Construction of Targeting-Clickable and Tumor-Cleavable Polyurethane Nanomicelles for Multifunctional Intracellular Drug Delivery

New strategies for the construction of versatile nanovehicles to overcome the multiple challenges of targeted delivery are urgently needed for cancer therapy. To address these needs, we developed a novel targeting-clickable and tumor-cleavable polyurethane nanomicelle for multifunctional delivery of antitumor drugs. The polyurethane was synthesized from biodegradable poly(ε-caprolactone) (PCL) and L-lysine ethyl ester diisocyanate (LDI), further extended by a new designed L-cystine-derivatized chain extender bearing a redox-responsive disulfide bond and clickable alkynyl groups (Cys-PA), and finally terminated by a detachable methoxyl-poly(ethylene glycol) with a highly pH-sensitive benzoic-imine linkage (BPEG). The obtained polymers show attractive self-assembly characteristics and stimuli-responsiveness, good cytocompatibility, and high loading capacity for doxorubicin (DOX). Furthermore, folic acid (FA) as a model targeting ligand was conjugated to the polyurethane micelles via an efficient click reaction. The decoration of FA results in an enhanced cellular uptake and improved drug efficacy toward FA-receptor positive HeLa cancer cells in vitro. As a proof-of-concept, this work provides a facile approach to the design of extracellularly activatable nanocarriers for tumor-targeted and programmed intracellular drug delivery.

Preparation and rapid degradation of nontoxic biodegradable polyurethanes based on poly(lactic acid)-poly(ethylene glycol)-poly(lactic acid) and L-lysine diisocyanate

To obtain rapid biodegradable biomaterials, a biodegradable triblock oligomer poly(lactic acid)-poly(ethylene glycol)-poly(lactic acid) (PLA-PEG-PLA) was designed and synthesized as a soft segment of polyurethane. Then new nontoxic biodegradable polyurethanes were prepared using the same stoichiometric ratio of PLA-PEG-PLA, L-lysine ethyl ester diisocyanate (LDI), and 1,4-butanediol (BDO). The molecular weights of polyurethanes were controlled by adjusting the polymerization temperature. The resulting polyurethanes were characterized by gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). Furthermore, the biodegradability of the synthesized polyurethanes was evaluated at 37 °C in phosphate buffer solutions (PBS) under different pH values and enzymatic solution at pH 7.4. The results showed that these polyurethanes could be rapidly degraded in PBS and enzymatic solution, as demonstrated by weight loss measurements and scanning electron microscope (SEM) observations. The degradation rates of these polyurethanes were mainly regulated by microphase separation degree, and could be restrained in lower pH value PBS. Moreover, the degradation products did not significantly decrease the pH value of incubation media, which would be useful to improve biocompatibilities of these polyurethanes in vivo. The current work provides a more promising approach to prepare nontoxic biodegradable polyurethanes with rapid degradation rates. These new materials may find potential use for drug delivery systems and magnetic resonance imaging (MRI) contrast agents.

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.

Biodegradable gemini multiblock poly(ε-caprolactone urethane)s toward controllable micellization

Unique self-assembly behavior of novel nontoxic gemini cationic biodegradable multiblock poly(e-caprolactone urethane)s which contain both gemini quaternary ammonium and PEG groups is firstly reported. The micellar size, size distributions, zeta potential, CMC and Kv could be well-tailored for application in drug and gene delivery.

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.

Effect of PEG content on the properties of biodegradable amphiphilic multiblock poly(ε-caprolactone urethane)s

We have recently developed a new group of cationic biodegradable multiblock poly(e-caprolactone urethane)s bearing gemini quaternary ammonium pendant groups and methoxyl-poly(ethylene glycol) (m-PEG) end chains. In this study, to endow polyurethane with attractive amphiphilicity and good biocompatibility, and to achieve a fundamental understanding on the structure-property relationship of these polyurethanes in favor of designing and preparing new generation of polyurethanes with more attractive amphiphilicity and better biocompatibility, varying amounts of m-PEG were introduced into the polyurethane chains and the effect of PEG content on the polymer bulk properties was investigated in detail by using Fourier transform infrared (FTIR) spectra, differential scanning calorimetry (DSC), water contact angle (WCA) measurements, polarizing light microscopy (PLM) and in vitrodegradation studies. It was found that the incorporation of PEG has direct effects on the phase behaviors, thermal properties, hydrophilicity and degradable ability of poly(e-caprolactone urethane)s. Moreover, these polyurethanes exhibit good cytocompatibility, which are promising biodegradable carrier materials in drug delivery and interesting candidates for further study.

Fabrication and characterization of waterborne biodegradable polyurethanes 3-dimensional porous scaffolds for vascular tissue engineering.

In this study, a series of 3-D interconnected porous scaffolds with various pore diameters and porosities was fabricated by freeze-drying with non-toxic biodegradable waterborne polyurethane (WBPU) emulsions of different concentration. The structures of these porous scaffolds were characterized by scanning electron microscopy (SEM), and the pore diameters were calculated using CIAS 3.0 software. The pores obtained were 3-D interconnected in the scaffolds. The scaffolds obtained at different pre-freeze temperatures showed a pore diameter ranging from 2.8 to 99.9 μm with a pre-freezing temperature of −60°C and from 13.1 to 229.1 μm with a pre-freezing temperature of −25°C. The scaffolds fabricated with WBPU emulsions of different concentration at the same pre-freezing temperature (−25°C) had pores with mean pore diameter between 90.8 and 39.6 μm and porosity between 92.0 and 80.0%, depending on the emulsion concentration. The effect of porous structure of the scaffolds on adhesion and proliferation of human umbilical vein endothelial cells (HUVECs) cultured in vitro was evaluated using the MTT assay and environmental scanning electron microscopy (ESEM). It was found that the better adhesion and proliferation of HUVECs on 3-D scaffolds of WBPU with relative smaller pore diameter and lower porosity than those on scaffolds with larger pore and higher porosity and film. Our work suggests that fabricating a scaffold with controllable pore diameter and porosity could be a good method to be used in tissue-engineering applications to obtain carriers for cell culture in vitro.