Zwitterionic Cross-Linked Biodegradable Nanocapsules for Cancer Imaging.

Zwitterionic cross-linked biodegradable nanocapsules (NCs) were synthesized for cancer imaging. A polylactide (PLA)-based diblock copolymer with two blocks carrying acetylenyl and allyl groups respectively was synthesized by ring-opening polymerization (ROP). Azide-alkyne "click" reaction was conducted to conjugate sulfobetaine (SB) zwitterions and fluorescent dye Cy5.5 onto the acetylenyl-functionalized first block of the diblock copolymer. The resulting copolymer with a hydrophilic SB/Cy5.5-functionalized PLA block and a hydrophobic allyl-functionalized PLA block could stabilize miniemulsions because of its amphiphilic diblock structure. UV-induced thiol-ene "click" reaction between a dithiol cross-linker and the hydrophobic allyl-functionalized block of the copolymer at the peripheral region of nanoscopic oil nanodroplets in the miniemulsion generated cross-linked polymer NCs with zwitterionic outer shells. These NCs showed an average hydrodynamic diameter ( Dh) of 136 nm. They exhibited biodegradability, biocompatibility and high colloidal stability. In vitro study indicated that these NCs could be taken up by MIA PaCa-2 cancer cells. In vivo imaging study showed that, comparing to a small molecule dye, NCs had a longer circulation time, facilitating their accumulation at tumors for cancer imaging. Overall, this work demonstrates the applicability of zwitterionic biodegradable polymer-based materials in cancer diagnosis.

Ultra-small biocompatible jujube polysaccharide stabilized platinum nanoclusters for glucose detection.

The development of noble ultra-small biocompatible Pt nanoclusters (Pt NCs) for glucose detection has been drawing great attention. Herein, ultra-small biocompatible jujube polysaccharide (JP) stabilized platinum nanoclusters (Ptn-JP NCs) are prepared using natural JP as a reducing and solubilizing agent. Ptn-JP NCs were studied for the colorimetric detection of glucose. Ptn-JP NCs (n = 50, 200 and 400) had an average particle diameter of 1-2 nm. Particularly, the measurements of hydrodynamic sizes of Ptn-JP NCs indicated that they maintained good stability in solution for one week. Pt200-JP NCs showed good biocompatibility, and were not toxic against HeLa cells at a high concentration of 400 µg mL-1. Furthermore, Pt200-JP NCs catalyzed the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) with H2O2 to produce blue oxidized TMB (oxTMB). This reaction followed typical Michaelis-Menten kinetics. More importantly, the glucose concentration could be sensitively detected by the color change, and this process was not interfered by other sugars. The linear range for glucose concentration was from 0.01 to 1 mM with a detection limit of 5.47 µM. The glucose concentrations of real samples of serum using Pt200-JP NCs were 9.2, 4.9 and 6.5 mM, respectively. The prepared Ptn-JP NCs have great potential in various biomedical detection methods.

Nanotherapy silencing the interleukin-8 gene produces regression of prostate cancer by inhibition of angiogenesis.

Interleukin-8 (IL-8) is a pro-angiogenic cytokine associated with aggressive prostate cancer (CaP). We detected high levels of IL-8 in sera from patients with CaP compared with healthy controls and patients with benign prostatic hypertrophy. This study examines the role of IL-8 in the pathogenesis of metastatic prostate cancer. We developed a biocompatible, cationic polylactide (CPLA) nanocarrier to complex with and efficiently deliver IL-8 small interfering RNA (siRNA) to CaP cells in vitro and in vivo. CPLA IL-8 siRNA nanocomplexes (nanoplexes) protect siRNA from rapid degradation, are non-toxic, have a prolonged lifetime in circulation, and their net positive charge facilitates penetration of cell membranes and subsequent intracellular trafficking. Administration of CPLA IL-8 siRNA nanoplexes to immunodeficient mice bearing human CaP tumours produced significant antitumour activities with no adverse effects. Systemic (intravenous) or local intra-tumour administration of IL-8 siRNA nanoplexes resulted in significant inhibition of CaP growth. Magnetic resonance imaging and ultrasonography of experimental animals demonstrated reduction of tumour perfusion in vivo following nanoplex treatment. Staining of tumour sections for CD31 confirmed significant damage to tumour neovasculature after nanoplex therapy. These studies demonstrate the efficacy of IL-8 siRNA nanotherapy for advanced, treatment-resistant human CaP.

Microplastic pollution in typical seasonal rivers in northern China: temporal variation and risk assessment.

Rivers are important channels for the transport of microplastics (MPs) from land to sea. In this work, the temporal variation and risk assessment of MP pollution in the surface water of the Wei River, a typical seasonal river in northern China, were quantified. The number abundance of MPs in the dry season was significantly higher than that in the wet season (p < 0.05). Fiber was the most abundant type of MP in both dry and wet seasons. Infrared spectrometer and Raman spectroscopy identification showed that polypropylene (PP) and polyethylene (PE) were the major polymers found in both dry and wet seasons, and the mixture of different MP polymers was more diverse in the dry season. The risk assessment showed that the average pollution load index (PLI) and risk quotient (RQ) were 2.10 and 1.19 in the dry season, which significantly decreased to 1.25 and 0.74, respectively, in the wet season (p < 0.05). In total, the results from this study highlight the characteristics of seasonal rivers that influence the temporal distribution and risk assessment of microplastics, providing scientific reference for policymakers and river managers to effectively deal with MP pollution.

A sulfobetaine zwitterionic polymer-drug conjugate for multivalent paclitaxel and gemcitabine co-delivery.

A zwitterionic polymer-drug conjugate (ZPDC) strategy is developed for the co-delivery of paclitaxel (PTX) and gemcitabine (GEM) chemotherapeutics, as well as a near-infrared fluorescence imaging agent cyanine5.5 (Cy5.5). The well-defined ZPDC is synthesized by tandem azide-alkyne and thiol-ene click functionalization of a biodegradable acetylenyl/allyl-functionalized polylactide and zwitterionic character is conferred by sulfobetaine. It has a number-average molecular weight of 53.6 kDa, comprising 6.5% PTX and 17.7% GEM by weight. Cy5.5 moieties are readily introduced to the ZPDC via conjugation. In aqueous solutions, the ZPDC exhibits a hydrodynamic diameter of 46 nm. In vitro MIA PaCa-2 human pancreatic cancer cells show strong ZPDC cellular uptake and cytotoxicity. In mice, the ZPDC exhibits long blood circulation, effective tumor accumulation, biocompatibility, therapeutic effect, and integrated imaging capacity. Overall, this work illustrates that ZPDCs are promising systems for chemotherapy delivery and bioimaging applications.

Ultra-small and biocompatible platinum nanoclusters with peroxidase-like activity for facile glucose detection in real samples.

The highly sensitive glucose detection based on the peroxidase-like properties of nanoclusters has been gained great interest. In this work, Pericarpium Citri Reticulatae polysaccharide (PCRP) stabilized platinum nanoclusters (Pt-PCRP NCs) were prepared by a green method in which potassium tetrachloroplatinate and PCRP were simply mixed without addition of other agents. Platinum nanoclusters (Pt NCs) had ultra-small size of 1.26 ± 0.34 nm. The hydrodynamic size of Pt-PCRP NCs was 29.7 nm, and zeta potential of which was -12.0 mV. Pt-PCRP NCs showed high biocompatibility toward HeLa cells and red blood cells. In addition, Pt-PCRP NCs catalyzed the decomposition of H2O2 to produce •OH, which further oxidized colorless 3,3'5,5'-tetramethylbenzidine (TMB) to blue oxidized 3,3',5,5'-tetramethylbenzidine (oxTMB), exhibiting peroxidase-like property. The kinetics followed the Michaelis-Menten equation. More importantly, the colorimetric method for glucose detection using Pt-PCRP NCs had high selectivity and low detection limit for 0.38 µM. The established method based on Pt-PCRP NCs was used to precisely detect glucose detection in human serum, saliva, and sweat. Taken together, the prepared ultra-small and biocompatible Pt-PCRP NCs have good potential glucose applications in clinical diagnosis in the future.

Crosslinked polymer nanocapsules for therapeutic, diagnostic, and theranostic applications.

Crosslinked polymer nanocapsules (CPNCs) are hollowed nanoparticles with network-like polymeric shells stabilized by primary bonds. CPNCs have drawn broad and significant interests as nanocarriers for biomedical applications in recent years. As compared with conventional polymeric nanoparticles systems without cavity and/or crosslinking architectures, CPNCs possess significant biomedical relevant advantages, including (a) superior structural stability against environmental conditions, (b) high loading capacity and ability for region-specific loading of multiple cargos, (c) tuneable cargo release rate via crosslinking density, and (d) high specific surface area to facilitate surface adsorption, modification, and interactions. With appropriate base polymers and crosslinkages, CPNCs can be biocompatible and biodegradable. While CPNC-based biomedical nanoplatforms can possess relatively stable physicochemical properties owing to their crosslinked architectures, various biomedically relevant stimuli-responsivities can be incorporated with them through specific structural designs. CPNCs have been studied for the delivery of small molecule drugs, genes, proteins, and other therapeutic agents. They have also been investigated as diagnostic platforms for magnetic resonance imaging, ultrasound imaging, and optical imaging. Moreover, CPNCs have been utilized to carry both therapeutics and bioimaging agents for theranostic applications. This article reviews the therapeutic, diagnostic and theranostic applications of CPNCs, as well as the preparation of these CPNCs, reported in the past decade. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Implantable Materials and Surgical Technologies > Nanomaterials and Implants Diagnostic Tools > in vivo Nanodiagnostics and Imaging.

Polymers in the Co-delivery of siRNA and Anticancer Drugs for the Treatment of Drug-resistant Cancers.

Recently, co-delivery of siRNA and anticancer drugs has drawn much attention in the treatment of drug-resistant cancers. Drug resistance is exhibited by cancer cells, which limits the efficacy of chemotherapy. When siRNA and anticancer drugs are delivered into cancer cells simultaneously, the siRNA is expected to silence the genes related to drug resistance, decreasing the drug efflux pumps and activating the cell's apoptosis pathways. In a timeframe following the release of siRNA, the accumulation of the co-delivered anti-cancer drug inside of the cancer cells will increase, resulting in promoted chemotherapeutic effects. Several classes of nanocarriers have been designed based on polymers for co-delivery, including surface-modified polymer nanoparticles (NPs), polymer micelles, dendrimers, polymer nanocapsules, polymer-modified liposomes, and polymer-modified silica and gold NPs. Compared with separate delivery, co-delivery showed significant advantages in the treatment of drug-resistant cancers. This review focuses on polymers in the co-delivery of siRNA and anticancer drugs, and summarizes key advances in the recent several years.

Biodegradable zwitterionic sulfobetaine polymer and its conjugate with paclitaxel for sustained drug delivery.

A fully biodegradable zwitterionic polymer and the corresponding conjugate with paclitaxel (PTX) were synthesized as promising biomaterials. Allyl-functionalized polylactide (PLA) was employed as the precursor of polymer backbones. UV-induced thiol-ene reaction was conducted to conjugate thiol-functionalized sulfobetaine (SB) with the PLA-based backbone. The resulting zwitterionic polymer did not exhibit considerable cytotoxicity. A polymer-drug conjugate was also obtained by thiol-ene reaction of both thiol-functionalized SB and PTX with allyl-functionalized PLA. The conjugate could readily form narrowly-dispersed nanoparticles in aqueous solutions with a volume-average hydrodynamic diameter (Dh,V) of 19.3 ±â€¯0.2 nm. Such a polymer-drug conjugate-based drug delivery system showed full degradability, well-suppressed non-specific interaction with biomolecules, and sustained drug release. In vitro assessments also confirmed the significant anti-cancer efficacy of the conjugate. After 72 h incubation with PLA-SB/PTX containing 10 µg/mL of PTX, the cell viabilities of A549, MCF7, and PaCa-2 cells were as low as 20.0 ±â€¯2.5%, 1.7 ±â€¯1.7%, and 14.8 ±â€¯0.9%, respectively. Both flow cytometry and confocal microscopy suggested that the conjugates could be easily uptaken by A549 cells before the major release of PTX moieties. Overall, this work elucidates promising potentials of biodegradable zwitterionic polymer-based materials in biomedical applications. STATEMENT OF SIGNIFICANCE: The applicability of FDA-approved biodegradable aliphatic polyesters has been significantly restricted because they are hydrophobic and lack functionalities. Recently zwitterionic polymers have emerged as promising hydrophilic biomaterials, but most of the reported zwitterionic polymers are non-biodegradable. This study reports a novel aliphatic polyester-based zwitterionic polymer and the corresponding polymer-drug conjugate. Their aliphatic polyester and zwitterionic components provide them with high enzymatic degradability and low nonspecific interactions with biomolecules, respectively. While the zwitterionic polymer did not show noticeable cytotoxicity, the corresponding polymer-anticancer drug conjugate exhibited acid-sensitive sustained drug release, remarkable effectiveness in killing cancer cells, as well as the ready cellular internalization. This work lays a foundation for the further development of synthetic biodegradable zwitterionic polymer-based materials which potentially may have broad and significant biomedical applications.

A porphyrin-PEG polymer with rapid renal clearance.

Tetracarboxylic porphyrins and polyethylene glycol (PEG) diamines were crosslinked in conditions that gave rise to a water-soluble porphyrin polyamide. Using PEG linkers 2 kDa or larger prevented fluorescence self-quenching. This networked porphyrin mesh was retained during dialysis with membranes with a 100 kDa pore size, yet passed through the membrane when centrifugal filtration was applied. Following intravenous administration, the porphyrin mesh, but not the free porphyrin, was rapidly cleared via renal excretion. The process could be monitored by fluorescence analysis of collected urine, with minimal background due to the large Stokes shift of the porphyrin (230 nm separating excitation and emission peaks). In a rhabdomyolysis mouse model of renal failure, porphyrin mesh urinary clearance was significantly impaired. This led to slower accumulation in the bladder, which could be visualized non-invasively via fluorescence imaging. Without further modification, the porphyrin mesh was chelated with (64)Cu for dynamic whole body positron emission tomography imaging of renal clearance. Together, these data show that small porphyrin-PEG polymers can serve as effective multimodal markers of renal function.