Hui-Zhen Jia

Dual‐pH Sensitive Charge‐Reversal Polypeptide Micelles for Tumor‐Triggered Targeting Uptake and Nuclear Drug Delivery

A novel dual-pH sensitive charge-reversal strategy is designed to deliver antitumor drugs targeting to tumor cells and to further promote the nuclei internalization by a stepwise response to the mildly acidic extracellular pH (≈6.5) of a tumor and endo/lysosome pH (≈5.0). Poly(L-lysine)-block-poly(L-leucine) diblock copolymer is synthesized and the lysine amino residues are amidated by 2,3-dimethylmaleic anhydride to form β-carboxylic amide, making the polypeptides self-assemble into negatively charged micelles. The amide can be hydrolyzed when exposed to the mildly acidic tumor extracellular environment, which makes the micelles switch to positively charged and they are then readily internalized by tumor cells. A nuclear targeting Tat peptide is further conjugated to the polypeptide via a click reaction. The Tat is amidated by succinyl chloride to mask its positive charge and cell-penetrating function and thus to inhibit nonspecific cellular uptake. After the nanoparticles are internalized into the more acidic intracellular endo/lysosomes, the Tat succinyl amide is hydrolyzed to reactivate the Tat nuclear targeting function, promoting nanoparticle delivery into cell nuclei. This polypeptide nanocarrier facilitates tumor targeting and nuclear delivery simultaneously by simply modifying the lysine amino residues of polylysine and Tat into two different pH-sensitive β-carboxylic amides.

Multifunctional Theranostic Nanoplatform for Cancer Combined Therapy Based on Gold Nanorods

Nanomaterials that integrate diagnostic and therapeutic functions within a single nanoplatform promise great advances in revolutionizing cancer therapy. A smart multifunctional theranostic drug-delivery system (DDS) based on gold nanorods (abbreviated as GNR/TSDOX) is designed for cancer-targeted imaging and imaging-guided therapy. In this intelligent theranostic DDS, the active targeting ligand biotin is introduced to track cancer sites in vivo. With the aid of photothermal/photoacoustic imaging, GNR/TSDOX can ablate cancer specifically and effectively. When stimulated with a single near-infrared (NIR) light source, this NIR light energy is effectively absorbed and converted into heat by GNR/TSDOX for localized photothermal therapy and the increase in temperature also further triggers the cascaded release of the anticancer drug for combined thermo-chemotherapy. More importantly, the in vivo cure effect can be well guided by regulating the irradiation time and intensity of the NIR light.

Self-Assembled Vehicle Construction via Boronic Acid Coupling and Host–Guest Interaction for Serum-Tolerant DNA Transport and pH-Responsive Drug Delivery

By exploiting boronic acid coupling and host-guest chemistry, a pH-responsive drug/gene co-delivery nanoplatform is designed for cancer treatments with the excellently serum-tolerant transfection activity and the capability to load and release hydrophobic drugs in an acidity-accelerated manner. Via boronate linkage, γ-CD is allowed to spontaneously attach onto phenylboronic-acid-modified oligoethylenimine (PEI1.8K-PB2.9 ) at neutral condition. The formed vehicle/DNA nanoformulation is thus surrounded densely by γ-CD moieties to biomimic the carbohydrate-rich cell surface, providing a novel approach to overcome serum-susceptible drawbacks frequently associated with synthetic gene carriers. PEI1.8K-PB2.9 -γ-CD conjugates demonstrate significantly improved cell-biocompatibility and transfection activity over PEI1.8K-PB2.9 . Noticeably, serum-associated inhibition effect is negligible for PEI1.8K-PB2.9 -γ-CD-mediated transfection whereas marked transfection reduction occurs for PEI25K and PEI1.8K-PB2.9 upon serum exposure. Consequently, PEI1.8K-PB2.9 -γ-CDs afford much higher transfection efficiency, that is, 25-fold higher luciferase expression over PEI25K in presence of 30% serum. An anticancer drug of doxorubicin (DOX) is shown to be readily accommodated into the nanoformulation via host-guest chemistry and intracellularly co-delivered together with plasmid DNA. Due to the acidity-labile feature of boronate linkage, DOX/γ-CD inclusion complexes would be mostly detached from the nanoformulation triggered by acidity, leading to faster drug release. Furthermore, drug inclusion does not alter the serum-compatible transfection efficiency of PEI1.8K-PB2.9 -γ-CD.

A Peptide Nanofibrous Indicator for Eye-detectable Cancer Cell Identification

A unique peptide nanofibrous indicator (NFI) is fabricated by mixing a borono-peptide with alizarin red S, followed by subsequent binding and self-assembly. The NFI thus obtained exhibits an intense response to sialyl Lewis X tetrasaccharide, which is overexpressed in human hepatocellular carcinoma cell lines. Importantly, this NFI has the capability of specifically recognizing human hepatocellular liver carcinoma (HepG2) cells through the eye-detectable color change resulting from strong binding-induced displacement. This novel technique for cancer cell identification through direct unaided eye judgment will open up an innovative platform for cancer cell detection.

Bioinspired Nano‐Prodrug with Enhanced Tumor Targeting and Increased Therapeutic Efficiency

Nanotechnology-based drug delivery has a great potential to revolutionize cancer treatment by enhancing anticancer drug efficacy and reducing drug toxicity. Here, a bioinspired nano-prodrug (BiNp) assembled by an antineoplastic peptidic derivative (FA-KLA-Hy-DOX), a folate acid (FA)-incorporated proapoptotic peptide (KLAKLAK)(2) (KLA) to doxorubicin (DOX) via an acid-labile hydrozone bond (Hy) is constructed. The hydrophobic antineoplastic agent DOX is efficiently shielded in the core of nano-prodrug. With FA targeting moieties on the surface, the obtained BiNp shows significant tumor-targeting ability and enhances the specific uptake of cancer cells. Upon the trigger by the intracellular acidic microenvironment of endosomes, the antineoplastic agent DOX is released on-demand and promotes the apoptosis of cancer cells. Simultaneously, the liberated FA-KLA can induce the dysfunction of mitochondria and evoke mitochondria-dependent apoptosis. In vitro and in vivo results show that the nano-prodrug BiNp with integrated programmed functions exhibits remarkable inhibition of tumor and achieves a maximized therapeutic efficiency with a minimized side effect.

Peptide decoration of nanovehicles to achieve active targeting and pathology-responsive cellular uptake for bone metastasis chemotherapy

To improve bone metastases chemotherapy, a peptide-conjugated diblock copolymer consisting of chimeric peptide, poly(ethylene glycol) and poly(trimethylene carbonate) (Pep-b-PEG-b-PTMC) is fabricated as a drug carrier capable of bone-seeking targeting as well as pathology-responsive charge reversal to ensure effective cellular uptake at the lesion sites. The chimeric peptide CKGHPGGPQAsp8 consists of an osteotropic anionic Asp8, a cathepsin K (CTSK)-cleavable substrate (HPGGPQ) and cationic residue tethered to polymer chain. Pep-b-PEG-b-PTMC can spontaneously self-assemble into negatively charged nanomicelles (~75 nm). As to the model drug of doxorubicin, Pep-b-PEG-b-PTM shows 30.0 ± 1 % and 90.1 ± 2 % for loading content and loading efficiency, respectively. High bone binding capability is demonstrated with that 66 % of Pep-b-PEG-b-PTMC micelles are able to bind to hydroxyl apatite, whereas less than 15 % is for Pep-free micelles. The nanomicelles exhibit a negative-to-positive charge conversion from -18.5 ± 1.9 mV to 15.2 ± 1.8 mV upon exposure to CTSK, an enzyme overexpressed in bone metastatic microenvironments. Such a pathology-responsive transition would lead to remarkably enhanced cellular uptake of the nanomicelles upon reaching lesion sites, thus improving the drug efficacy as verified by the in vitro cytotoxicity assay and the in vivo study in myeloma-bearing 5TGM1 mice model.

PEG-Stabilized Micellar System with Positively Charged Polyester Core for Fast pH-Responsive Drug Release

ABSTRACTPurposeTo design functional drug carriers for fast pH-responsive drug release.MethodsFunctional diblock terpolymers of monomethoxy poly(ethylene glycol)-block- copoly(6,14-dimethyl-1,3,9,11-tetraoxa-6,14-diaza-cyclohexadecane-2,10-dione-co-ε-caprolactone) [mPEG-b-poly(ADMC-co-CL)] were fabricated via biosynthetic pathway. The self-assembled nanosphere and drug-loaded micelles of the copolymers were further prepared by dialysis method. The pH-tunable morphology variation and drug release pattern were observed at different pH.ResultsA collection of three PEGylated terpolymers with varied compositions in poly(ADMC-co-CL) block was designed with high cell-biocompatibility. The copolymers could readily self-assemble into nanoscale micelles (~ 100xa0nm) in aqueous medium and exhibit high stability over 80-h incubation in different mediums including deionized water, neutral NaCl solution, and heparin sodium solution. Due to the protonation-deprotonation of tertiary amine groups in ADMC units, acid-induced structural deformation of micelles was disclosed in terms of the variation in CAC value and hydrodynamic size at different pH. Drug loading efficiency was comparable to that of reported PEG-polyester micelles with specifically designed structures purposed for drug-loading improvement. Remarkably accelerated drug release triggered by acidity was distinctly detected for ibuprofen-loaded mPEG-b-poly(ADMC-co-CL) micelle system, suggesting a fast pH-responsive characteristic.ConclusionFunctional PEG-stabilized micellar carriers with positively charged polyester core were successfully developed for fast pH-responsive drug release.

Extraordinarily enhanced gene transfection and cellular uptake by aromatic hydrophobicization to PEI25K

Different from commonly used alkylation strategies, PEI25K was modified with rigid, highly hydrophobic aromatic moieties to develop superior gene vectors with multiple functions, including structural compatibility with the cell membrane as well as cooperative contribution of electrostatic and hydrophobic interactions to the transfer process. A facile preparation approach was proposed by directly reacting PEI25K with 5-benzyloxyl trimethylene carbonate (BTMC) while omitting reagent activation and catalyst aid. The hydrophobic interactions between PEI-BTMC molecules serves as hydrophobic “locks” to stabilize polyplexes. PEI-BTMC polyplexes were kept good stability in the presence of heparin and DNase. The transfections mediated by PEI-BTMC vectors were better than PEI25K control in different cell lines. Particularly in HeLa cells, such enhancement owing to BTMC attachment can reach even up to 150 times. Experimental data indicated that the highly enhanced transfection mediated by PEI-BTMC was possibly more dependent on the special functions caused by BTMC modification rather than the improved cell-biocompatibility. Confocal laser scanning microscopy (CLSM) studies revealed the considerably higher potency of PEI-BTMC in transporting DNA into HeLa cells in comparison with PEI25K. It is expected that useful information provided in the current study would prompt the advance of PEI-based gene vectors towards practical applications.

A pH-sensitive macro- and nanohydrogel constructed from cationic hydroxyl-containing hyperbranched polycarbonate

The present study reported a pH-sensitive hydrogel constructed from a cationic hyperbranched polycarbonate, namely poly(EHDO-co-ADMC), functionalized with many hydroxyl and amine groups. The selective solubility of this hyperbranched polymer permitted the fabrication of corresponding nanoparticles/nanohydrogels of around 169 nm through a simple dialysis method. By using Nile Red dye as a model, the experimental results suggested the structural stability of the nanohydrogel in a neutral pH environment, and adumbrated its potential use as a delivery carrier for poorly water-soluble drugs. The nanohydrogel morphology presented a fast pH-responsive change across a narrow pH range from 7.4 to 6.6. This nanohydrogel shows promising potential in the application of controlled drug delivery.

Design of a Cellular-Uptake-Shielding Magnetic Catcher for Cancer Cell Separation

Fluorescent-magnetic-biotargeting multifunctional microcapsules (FMBMMs) are designed and fabricated via layer-by-layer assembly. It is found that the arginine-glycine-aspartate-modified FMBMMs were capable of sensitively detecting and efficiently isolating approximately 80% target cancer cells within 20 min. More importantly, FMBMMs present a general template for identifying and separating multiple types of cancer cells simply by altering the recognition motif.