Bioconjug Chem. 2021 Jul 21;32(7):1263-1275.  doi: 10.1021/acs.bioconjchem.1c00172.  Epub 2021 May 30. The Influence of a Polyethylene Glycol Linker on the Metabolism and Pharmacokinetics of a 89Zr-Radiolabeled Antibody Abstract Most experimental work in the space of bioconjugation chemistry focuses on using new methods to construct covalent bonds between a cargo molecule and a protein of interest such as a monoclonal antibody (mAb).  Bond formation is important for generating new diagnostic tools, yet when these compounds advance to preclinical in vitro and in vivo studies, and later for translation to the clinic, understanding the fate of potential metabolites that arise from chemical or enzymatic degradation of the construct is important to obtain a full picture of the pharmacokinetic performance of a new compound.  In the context of designing new bioconjugate methods for labeling antibodies with the positron-emitting radionuclide 89Zr, we previously developed a photochemical process for making 89Zr-mAbs.  Experimental studies on [89Zr]ZrDFO-PEG3-azepin-mAb constructs revealed that incorporation of the tris-polyethylene glycol (PEG3) linker improved the aqueous phase solubility and radiochemical conversion.  However, the use of a PEG3 linker also has an impact on the whole-body residence time of the construct, leading to a more rapid excretion of the 89Zr activity when compared with radiotracers that lack the PEG3 chain.  In this work, we investigated the metabolic fate of eight possible metabolites that arise from the logical disconnection of [89Zr]ZrDFO-PEG3-azepin-mAb at bonds which are susceptible to chemical or enzymatic cleavage.  Synthesis combined with 89Zr-radiolabeling, small-animal positron emission tomography imaging at multiple time points from 0 to 20 h, and measurements of the effective half-life for whole-body excretion are reported.  The conclusions are that the use of a PEG3 linker is non-innocent in terms of its impact on enhancing the metabolism of [89Zr]ZrDFO-PEG3-azepin-mAbs.  In most cases, degradation can produce metabolites that are rapidly eliminated from the body, thereby enhancing image contrast by reducing nonspecific accumulation and retention of 89Zr in background organs such as the liver, spleen, kidney, and bone. For more product information, please contact us at: US Tel: 1-844-782-5734 US Tel: 1-844-QUAL-PEG CHN Tel: 400-918-9898 Email: sales@sinopeg.com

J Mater Chem B. 2021 May 5;9(17):3666-3676.  doi: 10.1039/d1tb00362c. PEG-PEI-modified gated N-doped mesoporous carbon nanospheres for pH/NIR light-triggered drug release and cancer phototherapy Abstract A novel hybrid drug carrier has been designed, taking N-doped mesoporous carbon (NMCS) as the core and PEG-PEI as the outer shell.  NMCS was functionalized with a photocleavable nitrobenzyl-based linker following a click reaction.  Gemcitabine was loaded into NMCS prior to the functionalization via π-π stacking interactions.  NIR and the pH-responsive behavior of NMCS-linker-PEG-PEI bestow the multifunctional drug carrier with the controlled release of gemcitabine triggered by dual stimuli.  The NMCS core upconverts NIR light to UV, which is absorbed by a photosensitive molecular gate and results in its cleavage and drug release.  Further, NMCS converts NIR to heat, which deforms the outside polymer shell, thus triggering the drug release process.  The release can be promptly arrested if the NIR source is switched off.  A promising gemcitabine release of 75% has been achieved within 24 h under the dual stimuli of pH and temperature.  NMCS-linker-PEG-PEI produced reactive oxygen species (ROS), which were verified in FaDu cells using flow cytometry.  In vitro experiments showed that the NMCS-linker-PEG-PEI-GEM hybrid particle can induce synergistic therapeutic effects in FADU cells when exposed to the NIR light. For more product information, please contact us at: US Tel: 1-844-782-5734 US Tel: 1-844-QUAL-PEG CHN Tel: 400-918-9898 Email: sales@sinopeg.com

Int J Mol Sci. 2023 Jun 5;24(11):9779.  doi: 10.3390/ijms24119779. A dePEGylated Lipopeptide-Based Pan-Coronavirus Fusion Inhibitor Exhibits Potent and Broad-Spectrum Anti-HIV-1 Activity without Eliciting Anti-PEG Antibodies Abstract We previously identified a lipopeptide, EK1C4, by linking cholesterol to EK1, a pan-CoV fusion inhibitory peptide via a polyethylene glycol (PEG) linker, which showed potent pan-CoV fusion inhibitory activity.  However, PEG can elicit antibodies to PEG in vivo, which will attenuate its antiviral activity.  Therefore, we designed and synthesized a dePEGylated lipopeptide, EKL1C, by replacing the PEG linker in EK1C4 with a short peptide.  Similar to EK1C4, EKL1C displayed potent inhibitory activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronaviruses.  In this study, we found that EKL1C also exhibited broad-spectrum fusion inhibitory activity against human immunodeficiency virus type 1 (HIV-1) infection by interacting with the N-terminal heptad repeat 1 (HR1) of viral gp41 to block six-helix bundle (6-HB) formation.  These results suggest that HR1 is a common target for the development of broad-spectrum viral fusion inhibitors and EKL1C has potential clinical application as a candidate therapeutic or preventive agent against infection by coronavirus, HIV-1, and possibly other class I enveloped viruses. Keywords: HIV-1;  broad-spectrum fusion inhibitor;  coronavirus;  six-helix bundle. For more product information, please contact us at: US Tel: 1-844-782-5734 US Tel: 1-844-QUAL-PEG CHN Tel: 400-918-9898 Email: sales@sinopeg.com

Mol Cancer Ther. 2017 Jan;16(1):116-123.  doi: 10.1158/1535-7163.MCT-16-0343.  Epub 2016 Nov 9. Optimization of a PEGylated Glucuronide-Monomethylauristatin E Linker for Antibody-Drug Conjugates Abstract The emergence of antibody-drug conjugates (ADC), such as brentuximab vedotin and ado-trastuzumab emtansine, has led to increased efforts to identify new payloads and develop improved drug-linker technologies.  Most antibody payloads impart significant hydrophobicity to the ADC, resulting in accelerated plasma clearance and suboptimal in vivo activity, particularly for conjugates with high drug-to-antibody ratios (DAR).  We recently reported on the incorporation of a discrete PEG24 polymer as a side chain in a β-glucuronidase-cleavable monomethylauristatin E (MMAE) linker to provide homogeneous DAR 8 conjugates with decreased plasma clearance and increased antitumor activity in xenograft models relative to a non-PEGylated control.  In this work, we optimized the drug-linker by minimizing the size of the PEG side chain and incorporating a self-stabilizing maleimide to prevent payload de-conjugation in vivo Multiple PEG-glucuronide-MMAE linkers were prepared with PEG size up to 24 ethylene oxide units, and homogeneous DAR 8 ADCs were evaluated.  A clear relationship was observed between PEG length and conjugate pharmacology when tested in vivo Longer PEG chains resulted in slower clearance, with a threshold length of PEG8 beyond which clearance was not impacted.  Conjugates bearing PEG of sufficient length to minimize plasma clearance provided a wider therapeutic window relative to faster clearing conjugates bearing shorter PEGs.  A lead PEGylated glucuronide-MMAE linker was identified incorporating a self-stabilizing maleimide and a PEG12 side chain emerged from these efforts, enabling highly potent, homogeneous DAR 8 conjugates and is under consideration for future ADC programs.  Mol Cancer Ther;  16(1);  116-23.  ©2016 AACR. For more product information, please contact us at: US Tel: 1-844-782-5734 US Tel: 1-844-QUAL-PEG CHN Tel: 400-918-9898 Email: sales@sinopeg.com

Materials (Basel).  2018 Dec 24;12(1):53.  doi: 10.3390/ma12010053. Tough and Elastic α-Tricalcium Phosphate Cement Composites with Degradable PEG-Based Cross-Linker Abstract Dual setting cements composed of an in situ forming hydrogel and a reactive mineral phase combine high compressive strength of the cement with sufficient ductility and bending strength of the polymeric network.  Previous studies were focused on the modification with non-degradable hydrogels based on 2-hydroxyethyl methacrylate (HEMA).  Here, we describe the synthesis of suitable triblock degradable poly(ethylene glycol)-poly(lactide) (PEG-PLLA) cross-linker to improve the resorption capacity of such composites.  A study with four different formulations was established.  As reference, pure hydroxyapatite (HA) cements and composites with 40 wt% HEMA in the liquid cement phase were produced.  Furthermore, HEMA was modified with 10 wt% of PEG-PLLA cross-linker or a test series containing only 25% cross-linker was chosen for composites with a fully degradable polymeric phase.  Hence, we developed suitable systems with increased elasticity and 5⁻6 times higher toughness values in comparison to pure inorganic cement matrix.  Furthermore, conversion rate from α-tricalcium phosphate (α-TCP) to HA was still about 90% for all composite formulations, whereas crystal size decreased.  Based on this material development and advancement for a dual setting system, we managed to overcome the drawback of brittleness for pure calcium phosphate cements. Keywords: HEMA;  bending strength;  calcium phosphate cement;  composite material;  dual setting system;  free radical polymerization;  hydroxyapatite. For more product information, please contact us at: US Tel: 1-844-782-5734 US Tel: 1-844-QUAL-PEG CHN Tel: 400-918-9898 Email: sales@sinopeg.com

Phys Chem Chem Phys. 2022 Jan 26;24(4):2176-2184. doi: 10.1039/d1cp04487g. Structural order of water molecules around polyrotaxane including PEG, α-cyclodextrin, and α-lipoic acid linker on gold surface by molecular dynamics simulations Abstract In materials science, water plays an important part, especially at the molecular level. It shows various properties when sorbed onto surfaces of polymers. The structure of the molecular water ensemble in the vicinity of the polymers is under discussion. In this study, we used molecular dynamics methods to analyze the structure of water in the vicinity of the polymer polyrotaxane (PR), composed of α-cyclodextrins (α-CDs), a poly(ethylene glycol) (PEG) axial chain, and α-lipoic acid linkers, at various temperatures. The distribution of water around the functional groups, hydrogen bond network, and tetrahedral order were analyzed to classify the various types of water around the polymer. We found that the tetrahedral order of water had a strained relationship from the XES experiment. Four water regions were separated from each other in the vicinity of 1 to 5 Å around PR. The intermediate and non-freezing water were formed due to the interaction between water molecules and the functional groups, such as hydroxyl, ether, and ester. For more product information, please contact us at: US Tel: 1-844-782-5734 US Tel: 1-844-QUAL-PEG CHN Tel: 400-918-9898 Email: sales@sinopeg.com

Pharmaceutics. 2022 Aug 2;14(8):1614. doi: 10.3390/pharmaceutics14081614. PEG Spacer Length Substantially Affects Antibody-Based Nanocarrier Targeting of Dendritic Cell Subsets Abstract Successful cell targeting depends on the controlled positioning of cell-type-specific antibodies on the nanocarrier's (NC) surface. Uncontrolled antibody immobilization results in unintended cell uptake due to Fc-mediated cell interaction. Consequently, precise immobilization of the Fc region towards the nanocarrier surface is needed with the Fab regions staying freely accessible for antigen binding. Moreover, the antibody needs to be a certain distance from the nanocarrier surface, influencing the targeting performance after formation of the biomolecular corona. This can be achieved by using PEG linker molecules. Here we demonstrate cell type-specific targeting for dendritic cells (DC) as cellular key regulators of immune responses. However, to date, dendritic cell targeting experiments using different linker lengths still need to be conducted. Consequently, we focused on the surface modification of nanocarriers with different molecular weight PEG linkers (0.65, 2, and 5 kDa), and their ability to reduce undesired cell uptake, while achieving efficient DC targeting via covalently immobilized antibodies (stealth targeting). Our findings demonstrate that the PEG linker length significantly affects active dendritic cell targeting from cell lines (DC2.4) to primary cells (BMDCs, splenocytic conventional DCs type 1 (cDC1)). While antibody-functionalized nanocarriers with a shorter PEG length (0.65 kDa) showed the best targeting in DC2.4, a longer PEG length (5 kDa) was required to specifically accumulate in BMDCs and splenocytic cDC1. Our study highlights that these crucial aspects must be considered when targeting dendritic cell subsets, which are of great importance in the fields of cancer immunotherapy and vaccine development. Keywords: PEG; antibody functionalization; dendritic cell targeting; nanoparticles; nanovaccine. For more product information, please contact us at: US Tel: 1-844-782-5734 US Tel: 1-844-QUAL-PEG CHN Tel: 400-918-9898 Email: sales@sinopeg.com

Chembiochem. 2023 Jun 1;24(11):e202200774. doi: 10.1002/cbic.202200774. Epub 2023 May 4. Incorporating a Polyethyleneglycol Linker to Enhance the Hydrophilicity of Mitochondria-Targeted Triphenylphosphonium Constructs Abstract The targeting of bioactive molecules and probes to mitochondria can be achieved by coupling to the lipophilic triphenyl phosphonium (TPP) cation, which accumulates several hundred-fold within mitochondria in response to the mitochondrial membrane potential (Δψm ). Typically, a simple alkane links the TPP to its "cargo", increasing overall hydrophobicity. As it would be beneficial to enhance the water solubility of mitochondria-targeted compounds we explored the effects of replacing the alkyl linker with a polyethylene glycol (PEG). We found that the use of PEG led to compounds that were readily taken up by isolated mitochondria and by mitochondria inside cells. Within mitochondria the PEG linker greatly decreased adsorption of the TPP constructs to the matrix-facing face of the mitochondrial inner membrane. These findings will allow the distribution of mitochondria-targeted TPP compounds within mitochondria to be fine-tuned. Keywords: biological membrane; lipophilic cation; mitochondria-targeting; polyethylene glycol. For more product information, please contact us at: US Tel: 1-844-782-5734 US Tel: 1-844-QUAL-PEG CHN Tel: 400-918-9898 Email: sales@sinopeg.com