Richen Li

Improving paclitaxel delivery: in vitro and in vivo characterization of PEGylated polyphosphoester-based nanocarriers.

Nanomaterials have great potential to offer effective treatment against devastating diseases by providing sustained release of high concentrations of therapeutic agents locally, especially when the route of administration allows for direct access to the diseased tissues. Biodegradable polyphosphoester-based polymeric micelles and shell cross-linked knedel-like nanoparticles (SCKs) have been designed from amphiphilic block-graft terpolymers, PEBP-b-PBYP-g-PEG, which effectively incorporate high concentrations of paclitaxel (PTX). Well-dispersed nanoparticles physically loaded with PTX were prepared, exhibiting desirable physiochemical characteristics. Encapsulation of 10 wt% PTX, into either micelles or SCKs, allowed for aqueous suspension of PTX at concentrations up to 4.8 mg/mL, as compared to <2.0 μg/mL for the aqueous solubility of the drug alone. Drug release studies indicated that PTX released from these nanostructures was defined through a structure-function relationship, whereby the half-life of sustained PTX release was doubled through cross-linking of the micellar structure to form SCKs. In vitro, physically loaded micellar and SCK nanotherapeutics demonstrated IC50 values against osteosarcoma cell lines, known to metastasize to the lungs (CCH-OS-O and SJSA), similar to the pharmaceutical Taxol formulation. Evaluation of these materials in vivo has provided an understanding of the effects of nanoparticle structure-function relationships on intratracheal delivery and related biodistribution and pharmacokinetics. Overall, we have demonstrated the potential of these novel nanotherapeutics toward future sustained release treatments via administration directly to the sites of lung metastases of osteosarcoma.

Multi-responsive Hydrogels Derived from the Self-assembly of Tethered Allyl-functionalized Racemic Oligopeptides

A multi-responsive triblock hydrogelator oligo(dl-allylglycine)-block-poly(ethylene glycol)-block-oligo(dl-allylglycine) (ODLAG-b-PEG-b-ODLAG) was synthesized facilely by ring-opening polymerization (ROP) of DLAG N-carboxyanhydride (NCA) with a diamino-terminated PEG as the macroinitiator. This system exhibited heat-induced sol-to-gel transitions and either sonication- or enzyme-induced gel-to-sol transitions. The β-sheeting of the oligopeptide segments was confirmed by attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) and wide-angle X-ray scattering (WAXS). The β-sheets further displayed tertiary ordering into fibrillar structures that, in turn generated a porous and interconnected hydrogel matrix, as observed via transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The reversible macroscopic sol-to-gel transitions triggered by heat and gel-to-sol transitions triggered by sonication were correlated with the transformation of nanostructural morphologies, with fibrillar structures observed in gel and spherical aggregates in sol, respectively. The enzymatic breakdown of the hydrogels was also investigated. This allyl-functionalized hydrogelator can serve as a platform for the design of smart hydrogels, appropriate for expansion into biological systems as bio-functional and bio-responsive materials.

Construction of a versatile and functional nanoparticle platform derived from a helical diblock copolypeptide-based biomimetic polymer

Sequential polymerization of N-carboxyanhydrides accelerated by nitrogen flow is utilized to generate a novel well-defined diblock copolypeptide (PDI = 1.08), with incorporation of alkyne-functionalized side-chain groups allowing for rapid and efficient thiol-yne click-type modifications, followed by self-assembly into nanopure water to construct a helical polypeptide-based versatile and functional nanoparticle platform.

Polyphosphoester nanoparticles as biodegradable platform for delivery of multiple drugs and siRNA

Delivery of multiple therapeutics and/or diagnostic agents to diseased tissues is challenging and necessitates the development of multifunctional platforms. Among the various strategies for design of multifunctional nanocarriers, biodegradable polyphosphoester (PPE) polymers have been recently synthesized via a rapid and simple synthetic strategy. In addition, the chemical structure of the polymer could be tuned to form nanoparticles with varying surface chemistries and charges, which have shown exceptional safety and biocompatibility as compared to several commercial agents. The purpose of this study was to exploit a mixture of PPE nanoparticles of cationic and neutral surface charges for multiple delivery of anticancer drugs (ie, sorafenib and paclitaxel) and nucleic acids (ie, siRNA). Cationic PPE polymers could efficiently complex siRNA, and the stability of the nanoparticles could be maintained in physiological solutions and upon freeze-drying and were able to deliver siRNA in vivo when injected intravenously in mice. Commercially available cationic polyethylenimine polymer had LD50 of ca. 61.7 mg/kg in mice, whereas no animal died after injection of the cationic PPE polymer at a dose of >130 mg/kg. Neutral PPE nanoparticles were able to encapsulate two hydrophobic drugs, namely, sorafenib and paclitaxel, which are commonly used for the treatment of hepatocellular carcinoma. Mixing the neutral and cationic PPE nanoparticles did not result in any precipitation, and the size characteristics of both types of nanoparticles were maintained. Hence, PPE polymers might have potential for the delivery of multiple drugs and diagnostic agents to diseased tissues via simple synthesis of the individual polymers and assembly into nanoparticles that can host several drugs while being mixed in the same administration set, which is of importance for industrial and clinical development.

Chemical Design of Both a Glutathione-Sensitive Dimeric Drug Guest and a Glucose-Derived Nanocarrier Host to Achieve Enhanced Osteosarcoma Lung Metastatic Anticancer Selectivity

Although nanomedicines have been pursued for nearly 20 years, fundamental chemical strategies that seek to optimize both the drug and drug carrier together in a concerted effort remain uncommon yet may be powerful. In this work, two block polymers and one dimeric prodrug molecule were designed to be coassembled into degradable, functional nanocarriers, where the chemistry of each component was defined to accomplish important tasks. The result is a poly(ethylene glycol) (PEG)-protected redox-responsive dimeric paclitaxel (diPTX)-loaded cationic poly(d-glucose carbonate) micelle (diPTX@CPGC). These nanostructures showed tunable sizes and surface charges and displayed controlled PTX drug release profiles in the presence of reducing agents, such as glutathione (GSH) and dithiothreitol (DTT), thereby resulting in significant selectivity for killing cancer cells over healthy cells. Compared to free PTX and diPTX, diPTX@CPGC exhibited improved tumor penetration and significant inhibition of tumor cell growth toward osteosarcoma (OS) lung metastases with minimal side effects both in vitro and in vivo, indicating the promise of diPTX@CPGC as optimized anticancer therapeutic agents for treatment of OS lung metastases.

Functional, Degradable Zwitterionic Polyphosphoesters as Biocompatible Coating Materials for Metal Nanostructures

A zwitterionic polyphosphoester (zPPE), specifically l-cysteine-functionalized poly(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane (zPBYP), has been developed as a poly(ethylene glycol) (PEG) alternative coating material for gold nanoparticles (AuNPs), the most extensively investigated metal nanoparticulate platform toward molecular imaging, photothermal therapy, and drug delivery applications. Thiol-yne conjugation of cysteine transformed an initial azido-terminated and alkynyl-functionalized PBYP homopolymer into zPBYP, offering hydrolytic degradability, biocompatibility, and versatile reactive moieties for installation of a range of functional groups. Despite minor degradation during purification, zPPEs were able to stabilize AuNPs presumably through multivalent interactions between combinations of the side chain zwitterions (thioether and phosphoester groups of the zPPEs with the AuNPs). 31P NMR studies in D2O revealed ca. 20% hydrolysis of the phosphoester moieties of the repeat units had occurred during the workup and purification by aqueous dialysis at pH 3 over ca. 1 d, as observed by the 31P signal of the phosphotriesters resonating at ca. -0.5 to -1.7 shifting downfield to ca. 1.1 to -0.4 ppm, attributed to transformation to phosphates. Further hydrolysis of side chain and backbone units proceeded to an extent of ca. 75% over the next 2 d in nanopure water (pH 5-6). The NMR degradation results were consistent with the broadening and red-shift of the surface plasmon resonance (SPR) observed by UV-vis spectroscopy of the zPPE-coated AuNPs in water over time. All AuNP formulations in this study, including those with citrate, PEG, and zPPE coatings, exhibited negligible immunotoxicity, as determined by cytokine overexpression in the presence of the nanostructures relative to those in cell culture medium. Notably, the zPPE-coated AuNPs displayed superior antifouling properties, as assessed by the extent of cytokine adsorption relative to both the PEGylated and citrate-coated AuNPs. Taken together, the physicochemical and biological evaluations of zPPE-coated AuNPs in conjunction with PEGylated and citrate-coated analogues indicate the promise of zPPEs as favorable alternatives to PEG coatings, with negligible immunotoxicity, good antifouling performance, and versatile reactive groups that enable the preparation of highly tailored nanomaterials for diverse applications.