Short Polyethylene Glycol Research Articles

Comparison of Different Types of Poly-L-lactic Acid Microspheres In Vitro and In Vivo Studies

Abstract Background Biodegradable polymers are commonly used as dermal fillers in plastic surgery. Among these, poly-L-lactic acid (PLLA) distinguishes itself owing to its good biocompatibility, degradability, and ability to act as a collagen stimulator. Objectives In this study, the differential behavior of PLLA microspheres with varying microscopic morphology and surface hydrophilicity was investigated both in vitro and in vivo. Methods The introduction of short hydrophilic polyethylene glycol (PEG) chains into the PLLA molecule was employed to modify the morphology and enhance the surface hydrophilicity of the microspheres. The morphology and physicochemical properties of the PLLA and PLLA-b-PEG microspheres were characterized. Irregular PLLA particles, PLLA and PLLA-b-PEG microspheres were implanted into the subcutaneous tissue of rabbit models, and at 4, 26 and 52 weeks after implantation, biopsy samples were collected for hematoxylin and eosin (H&E) and Masson's trichrome staining to evaluate differences in the tissue response between different implants. Results The results of in vitro research demonstrated that while the addition of short-chain hydrophilic PEG afforded a smoother surface for the microspheres, it had no significant effect on the molecular weight and degradation rate of PLLA. The histological examination revealed that the PLLA-b-PEG microspheres exhibited enhanced biocompatibility compared to the pure PLLA microspheres, while the irregular PLLA particles showed the highest inflammatory response among the three materials. Conclusions In this study, we found that the properties of PLLA were improved upon modification by short-chain PEG without reducing the collagen regeneration ability, thereby affording a better histocompatibility.

Retraction: Short polyethylene glycol chains densely bound to soft nanotube channels for inhibition of protein aggregation.

[This retracts the article DOI: 10.1039/C6RA06793J.].

Pegylated surfactants based on fatty acids: 12-hydroxystearic acid versus stearic acid

We describe the aqueous behavior of short Polyethylene glycol (PEG) chains of Mw 4 kDa that are either mono-functionalized or di-functionalized by 12-hydroxy stearic acid (HSA), and stearic acid (SA), respectively. The end capping of the chains by the fatty acids is achieved by Steglich esterification, after a step of protection of the 12-OH functional group in the case of HSA. Small Angle Neutron Scattering (SANS) shows that mono-functionalized chains with both SA or HSA sticky ends self-assemble in star micelles in aqueous solution, and interact through repulsive steric interactions. The di-functionalized telechelic chains self-assemble in flower micelles that interact through interactions that are attractive on average due to the formation of bridges by chains that share their both ends in two different micelles. Solutions of telechelic chains undergo a phase separation between a dilute solution of micelles and a dense hexagonal crystalline network of flower micelles above a given polymer concentration threshold. This threshold is lower for SA-PEG-SA than for HSA-PEG-HSA. We postulate that this difference of behavior arises from the formation of hydrogen bonds between the OH groups at the C12 of the alkyl chain in case of HSA that increase the stability of the hydrophobic core of the micelles.

Study of ELU001, a C’Dot drug conjugate (CDC) targeting folate receptor α (FRα) overexpressing solid tumors.

TPS3173 Background: ELU001, pasifolate exatecan, is an ultra-small nanoparticle drug conjugate, known as a CDC (~6 nm), designed to target and penetrate into solid tumors. Due to its size, ELU001 exhibits rapid renal elimination which is expected to reduce or eliminate the toxicities associated with many antibody drug conjugates. ELU001 has ~13 folic acid targeting moieties and ~21 cathepsin-B cleavable exatecan topoisomerase-1 inhibitor payloads covalently bound to short polyethylene glycol chains surrounding a silica core, the C’Dot. ELU001 binds to cancer cells expressing FRα and is internalized into the lysosome where it releases the exatecan payload. ELU001’s dose escalation study reported at ESMO Congress 2023 (1), examined weekly, bi-weekly (Q2W), and tri-weekly schedules over a range of doses in 42 patients. The study revealed that ELU001 could be administered safely and identified a dose level and schedule for the Expansion Studies described below. 22 of the patients with ovarian or endometrial cancers had >1 post-baseline scan(s), of these 2 had a PR and 19 had SD by RECIST v1.1 criteria. ELU001 demonstrated activity against tumors across a range of FRα expression levels, from low to high, retrospectively assessed using the VENTANA FOLR1 RxDx assay and the PS2+ scoring system. Methods: The current multicenter, Tumor Group Expansion open-label phase 1/2 clinical trial investigates ELU001 in patients with ovarian and endometrial cancers and is enrolling three cohorts; 1) ovarian cancer with high FRα expression, 2) ovarian cancer with moderate and low expression and 3) endometrial cancer with low to high expression with assessments based upon the PS2+ scoring system (high = ≥ 75%, moderate = ≥ 50% to < 75%, low = 25% to < 50%, negative = <25% of tumor cells with 2+ or 3+ staining intensity). An initial exploratory dose of 2.0 mg/m2 Q2W was employed in all three cohorts and a second dose of 1.7 mg/m2 Q2W will be studied in the ovarian cancer cohorts. Patients will ultimately be randomized to one of two or more doses to optimize dosing for registration. Primary endpoint: Objective Response Rate (ORR); secondary endpoints include DOR, PFS, TFST, PFS2, OS, adverse events, PK, and ADA assessments. Approximately 20 patients per tumor group will be recruited in the U.S. 1. Ann. Oncol. (2023) 34 (suppl_2): S458-S497. Clinical trial information: NCT05001282 .

Polymer coating for antiicing and deicing

Ice accretion may cause serious safety risk and huge economic loss for outdoor facilities. Herein, we report a waterborne polymeric coating based on a copolymer network of methacrylic acid (MAA), acrylamide (AM), N-2-hydroxyethyl acrylamide (HEAA), and methoxypolyethylene glycol (MPEG) with free polyethylene glycol (PEG) dispersed in it. Owing to the good compatibility of free PEG chains and the PEG side chains of the copolymer, the hydrogen bonding between acrylic copolymer and PEG, the free PEG chains can well be trapped in the network with some segments out of the mesh as short PEG chains are grafted on the coating surface, so that the surface has liquid-like properties. Water droplets can readily slip off on the coating surface with a small sliding angle (<30°). Particularly, the surface can hold the properties for a long duration upon water flushing, cycle of wetting-drying, and salt spraying tests. The polymer coating can find application in icing prevention and removal.

Stratification of polyisocyanate in two-component waterborne polyurethane films

The coatings industry continually seeks advancements in waterborne two-component polyurethane (2 K WBPU) systems, given their potential for environmentally friendly applications and superior film properties. This study explores the mechanistic aspects of film formation in 2 K WBPU coatings formulated with an acrylic polyol and a polyisocyanate (PIC) derived from a trimer of hexamethylene diisocyanate (HDI-trimer). To enhance water dispersibility—a key parameter in industrial applications—the HDI-trimer is modified with a short polyethylene glycol, producing a hydrophilically modified PIC (hmPIC). While prior studies identified hmPIC as an effective reactive plasticizer for the polyol, the common practice of adding unmodified HDI-trimer (uPIC) to hmPIC for moisture sensitivity reduction necessitates a deeper understanding of film properties. Using fluorescence resonance energy transfer (FRET) and confocal fluorescence microscopy, we investigated the effects of blending uPIC with hmPIC on coalescence, phase separation, and film stratification in 2 K WBPU systems. Notably, environmental factors like relative humidity were found to influence film stratification significantly. This finding has critical implications for coating performance, such as durability and water resistance. A novel method was also introduced to monitor water permeation within stratified films, offering a valuable tool for optimizing film properties in real-world applications. This study underscores the importance of strategic component interactions in polymer coatings, suggesting that controlled film stratification can significantly enhance film performance in industrial settings.

Molecular designs with PEG groups for water-solubilization of sparsely substituted porphyrins

Two relatively short polyethylene glycol (PEG) groups suffice to impart aqueous solubility to an otherwise hydrophobic porphyrin.

Tumor targeted alpha particle therapy with an actinium-225 labelled antibody for carbonic anhydrase IX.

Selective antibody targeted delivery of α particle emitting actinium-225 to tumors has significant therapeutic potential. This work highlights the design and synthesis of a new bifunctional macrocyclic diazacrown ether chelator, H2MacropaSqOEt, that can be conjugated to antibodies and forms stable complexes with actinium-225. The macrocyclic diazacrown ether chelator incorporates a linker comprised of a short polyethylene glycol fragment and a squaramide ester that allows selective reaction with lysine residues on antibodies to form stable vinylogous amide linkages. This new H2MacropaSqOEt chelator was used to modify a monoclonal antibody, girentuximab (hG250), that binds to carbonic anhydrase IX, an enzyme that is overexpressed on the surface of cancers such as clear cell renal cell carcinoma. This new antibody conjugate (H2MacropaSq-hG250) had an average chelator to antibody ratio of 4 : 1 and retained high affinity for carbonic anhydrase IX. H2MacropaSq-hG250 was radiolabeled quantitatively with [225Ac]AcIII within one minute at room temperature with micromolar concentrations of antibody and the radioactive complex is stable in human serum for >7 days. Evaluation of [225Ac]Ac(MacropaSq-hG250) in a mouse xenograft model, that overexpresses carbonic anhydrase IX, demonstrated a highly significant therapeutic response. It is likely that H2MacropaSqOEt could be used to modify other antibodies providing a readily adaptable platform for other actinium-225 based therapeutics.

Immuno-SPR biosensor for the detection of Brucella abortus

A proof of principle biosensor for the Brucella abortus recognition onsite is presented. The system is based on a plasmonic optical fiber probe functionalized with an oriented antibody layer immobilized on a short polyethyleneglycol (PEG) interface through carbodiimide chemistry and protein G as an intermediate layer. The biosensor is inserted in a holder built in 3D printing technology, obtaining a custom holder useful for housing the sample to be measured and the equipment. The removable sensor chip is a low-cost Surface Plasmon Resonance (SPR) platform based on D-shaped plastic optical fibers (POFs), built-in in 3D printed connectors, used here for the first time to detect bacteria via a bio-receptor layer specific for its membrane protein. The performances of the biosensor in Brucella abortus recognition are tested by using two different SPR-POF probes combined with the same bio-receptor layer. The best sensor configuration has presented a sensitivity at low concentrations of one order of magnitude greater than the other. A limit of detection (LoD) of 2.8 bacteria/mL is achieved well competitive with other systems but without the need for amplification or special sample treatments. Specificity has been tested using Salmonella bacteria, and reproducibility, regenerability and stability are moreover evaluated. These experimental results pave the way for building an efficient and specific biosensor system for Brucella abortus detection onsite and in a few minutes. Moreover, the proposed POF-based SPR biosensor device, with respect to the already available technologies, could be a Point-of-care-test (POCT), simple to use, small-size and portable, low-cost, don’t necessary of a microfluidic system, and can be connected to the Internet (IoT).

Endotyping of IgE-Mediated Polyethylene Glycol and/or Polysorbate 80 Allergy.

Polyethylene glycol (PEG) and polysorbate 80 (PS80) allergy preclude from SARS-CoV-2 vaccination. The mechanism(s) governing cross-reactivity and PEG molecular weight dependence remain unclear. To evaluate PEGylated lipid nanoparticle (LNP) vaccine (BNT162b2) tolerance and explore the mechanism of reactivity in PEG and/or PS80 allergic patients. PEG/PS80 dual- (n= 3), PEG mono- (n= 7), and PS80 mono-allergic patients (n= 2) were included. Tolerability of graded vaccine challenges was assessed. Basophil activation testing on whole blood (wb-BAT) or passively sensitized donor basophils (allo-BAT) was performed using PEG, PS80, BNT162b2, and PEGylated lipids (ALC-0159). Serum PEG-specific IgE was measured in patients (n= 10) and controls (n= 15). Graded BNT162b2 challenge in dual- and PEG mono-allergic patients (n= 3/group) was well tolerated and induced anti-spike IgG seroconversion. PS80 mono-allergic patients (n= 2/2) tolerated single-dose BNT162b2 vaccination. Wb-BAT reactivity to PEG-containing antigens was observed in dual- (n= 3/3) and PEG mono- (n= 2/3), but absent in PS80 mono-allergic patients (n= 0/2). BNT162b2 elicited the highest invitro reactivity. BNT162b2 reactivity was IgE mediated, complement independent, and inhibited in allo-BAT by preincubation with short PEG motifs, or detergent-induced LNP degradation. PEG-specific IgE was only detectable in dual-allergic (n= 3/3) and PEG mono-allergic (n= 1/6) serum. PEG and PS80 cross-reactivity is determined by IgE recognizing short PEG motifs, whereas PS80 mono-allergy is PEG-independent. PS80 skin test positivity in PEG allergics was associated with a severe and persistent phenotype, higher serum PEG-specific IgE levels, and enhanced BAT reactivity. Spherical PEG exposure via LNP enhances BAT sensitivity through increased avidity. All PEG and/or PS80 excipient allergic patients can safely receive SARS-CoV-2 vaccines.

Triglyceride-Rich Lipoprotein-Mediated Polymer Dots for Multimodal Imaging Interscapular Brown Adipose Tissue Capillaries.

Brown adipose tissues (BATs) have been identified as a promising target of metabolism disorders. [18F]FDG-PET (FDG = fluorodeoxyglucose; PET = positron emission tomography) has been predominantly employed for BAT imaging, but its limitations drive the urgent need for novel functional probes combined with multimodal imaging approaches. It has been reported that polymer dots (Pdots) display rapid BAT imaging without additional cold stimulation. However, the mechanism by which Pdots image BAT remains unclear. Here, we made an intensive study of the imaging mechanism and found that Pdots can bind to triglyceride-rich lipoproteins (TRLs). By virtue of their high affinity to TRLs, Pdots selectively accumulate in capillary endothelial cells (ECs) in interscapular brown adipose tissues (iBATs). Compared to poly(styrene-co-maleic anhydride)cumene terminated (PSMAC)-Pdots with a short half-life and polyethylene glycol (PEG)-Pdots with low lipophilicity, naked-Pdots have good lipophilicity, with a half-life of about 30 min and up to 94% uptake in capillary ECs within 5 min, increasing rapidly after acute cold stimulation. These results suggested that the accumulation changes of Pdots in iBAT can reflect iBAT activity sensitively. Based on this mechanism, we further developed a strategy to detect iBAT activity and quantify the TRL uptake in vivo using multimodal Pdots.

Three generations of thiolated cyclodextrins: A direct comparison of their mucus permeating and mucoadhesive properties

AimThis study aims to compare the mucus permeating and mucoadhesive properties of three generations of thiolated cyclodextrins (CDs). MethodsFree thiol groups of thiolated γ-CDs (CD-SH) were S-protected with 2-mercaptonicotinic acid (MNA), leading to a second generation of thiolated CDs (CD-SS-MNA) and with 2 kDa polyethylene glycol (PEG) bearing a terminal thiol group leading to a third generation of thiolated CDs (CD-SS-PEG). The structure of these thiolated CDs was confirmed and characterized by FT-IR, 1H NMR and colorimetric assays. Thiolated CDs were evaluated regarding viscosity, mucus diffusion, and mucoadhesion. ResultsThe viscosity of the mixture of CD-SH, CD-SS-MNA, or CD-SS-PEG with mucus increased up to 11-, 16-, and 14.1-fold compared to unmodified CD within 3 hours, respectively. Mucus diffusion increased in the following rank order: unprotected CD-SH < CD-SS-MNA < CD-SS-PEG. The residence time of CD-SH, CD-SS-MNA, and CD-SS-PEG on porcine intestine was up to 9.6-, 12.55-, and 11.2-fold prolonged compared to native CD, respectively. ConclusionAccording to these results, S-protection of thiolated CDs can be a promising approach to improve their mucus permeating and mucoadhesive properties. Statement of significanceThree generations of thiolated cyclodextrins (CDs) with different types of thiol ligands have been synthesized to improve mucus interaction. 1st generation of thiolated CDs was synthesized by converting hydroxyl groups into thiols by reaction with Thiourea. For 2nd generation, free thiol groups were S-protected by reaction with 2-mercaptonicotinic acid (MNA), resulting in high reactive disulfide bonds. For 3rd generation, terminally thiolated short PEG chains (2 kDa) were used for S-protection of thiolated CDs. Mucus penetrating properties were found to be increased as follows: 1st generation < 2nd generation < 3rd generation. Furthermore, mucoadhesive properties were improved in the following rank order: 1st generation < 3rd generation < 2nd generation. This study suggests that the S-protection of thiolated CDs can enhance mucus penetrating and mucoadhesive properties.

Phase 1 trial of a novel C’Dot drug conjugate (CDC), ELU001, in patients with solid tumors known to overexpress folate receptor alpha (FRα).

TPS3159 Background: ELU001 is a novel first-in-class nanoparticle drug conjugate that consists of ~13 folic acid targeting moieties and a payload of ~22 molecules of the topoisomerase-1 inhibitor, exatecan. Folic acid and exatecan are covalently bound by non-cleavable and cathepsin-B cleavable linkers, respectively, to short polyethylene glycol chains which surround the C’Dot’s silica core. CDCs are very small (~6 nm), allowing for more efficient penetration into solid tumors compared to ADCs and a rapid elimination by the kidneys, which is expected to lead to less toxicity than ADCs that have a longer half-life in circulation. ELU001’s high avidity is designed to promote binding to FRα on the surface of cancer cells that express any level of antigen (low to high). ELU001 then internalizes into the tumor cell and traffics to the lysosome where enzymatic cleavage releases the exatecan payload. ELU001 has demonstrated efficacy in preclinical models with low, moderate and high levels of FRα. The first-in-human trial, ELU-FRα-1, is currently recruiting patients with ovarian, endometrial, colorectal, gastric, gastroesophageal junction, triple negative breast, or non-small cell lung cancers, or cholangiocarcinoma cancers, and, in the opinion of the Investigator, have no meaningful life-prolonging therapy option available. Methods: This is a Phase 1 / 2 multicenter, open label clinical trial with two parts: Part 1 Dose Escalation and Part 2 Tumor Group Expansion Cohort(s). In Part 1, patients with cancer types with a high likelihood of having FRα overexpressing tumors, (ovarian, endometrial, colorectal, gastric, gastroesophageal junction, triple negative breast, or non-small cell lung cancers, or cholangiocarcinoma) will be enrolled. FRα expression is determined retrospectively. ELU001 is administered either weekly (QW) (once a week for 3 weeks, 1 week rest), every other week (Q2W, with no rest between cycles), or every three weeks (Q3W). Initial Part 2 expansion cohorts are planned in ovarian cancer with high FRα expression, ovarian cancer with moderate or low FRα expression, and endometrial cancer with any positive FRα expression. Here, FRα will be prospectively determined. Other cancer types may be assessed in the future. The primary objective for Part 1 is to identify the MTD/RP2D. The primary objective for Part 2 is to determine the ORR. Secondary objectives include DOR, PFS, TFST, PFS2, OS, frequency, severity and tolerability of adverse events, PK, ADA, and FRα expression assessments. Part 1 Dose Escalation will recruit about 2-5 patients at each dose for each regimen (QW; Q2W; Q3W). Part 2 Stage 1 will recruit about 15 patients per tumor group expansion cohort and is expected to begin recruitment in the second half of 2023. The study is enrolling in Part 1 Q2W Cohort 301 and Q3W Cohort A in the US. Clinical trial information: NCT05001282 .

Abstract CT255: ELU-FRα-1: a study to evaluate ELU001 in patients with solid tumors that overexpress folate receptor alpha (FRα)

Abstract Background: ELU001 is a novel, first-in-class, new molecular entity described as a C’Dot Drug Conjugate (CDC). ELU001 consists of ~13 folic acid targeting moieties and a payload of ~22 molecules of the topoisomerase-1 inhibitor, exatecan. Folic acid and exatecan are covalently bound by non-cleavable and cathepsin-B cleavable linkers, respectively, to short polyethylene glycol chains which surround the C’Dot’s silica core. CDCs are very small (~6 nm), allowing greater ability to penetrate more efficiently into solid tumors compared to ADCs. CDCs are rapidly eliminated by the kidneys, which is expected to lead to less toxicity than ADCs that have a longer half-life in circulation. ELU001’s high avidity is designed to promote binding to FRα on the surface on FRα overexpressing cancer cells with a wide range of antigen expression including high, moderate and low expressing tumor cells. Following antigen binding, ELU001 internalizes into the tumor cell, and traffics to the lysosome where enzymatic cleavage releases the exatecan payload. The first-in-human trial, ELU-FRα-1, is currently recruiting patients that have advanced, recurrent or refractory tumors associated with indications that are known to potentially overexpress FRα and have been shown to be topoisomerase 1 inhibitor-sensitive, and, in the opinion of the Investigator, have no satisfactory therapeutic options available. Methods: This is a Phase 1/2 multicenter, open label clinical trial with two parts: Part 1 Dose Escalation and Part 2 Tumor Group Expansion Cohort(s). Part 1 is a basket trial enrolling patients with cancer types with a high likelihood of having FRα overexpressing tumors, (specifically, ovarian, endometrial, colorectal, gastric, gastroesophageal junction, triple negative breast, or non-small cell lung cancers, or cholangiocarcinoma). Patients are receiving ELU001 weekly (QW) (once a week for 3 weeks, 1 week rest), every other week (Q2W, with no rest between cycles), or every three weeks (Q3W). Analysis of FRα expression will be retrospectively determined. Part 2 will use Simon’s Two-Stage design to evaluate 4-6 Expansion Cohorts, comprised of tumor histologies anticipated to have greatest activity to ELU001 treatment. FRα will be prospectively determined. The primary objective for Part 1 is to identify the MTD/RP2D. The primary objective for Part 2 is to determine the ORR. Secondary objectives include DOR, PFS, TFST, PFS2, OS, frequency, severity and tolerability of adverse events, PK, ADA, and FRα expression assessments. Part 1 Dose Escalation will recruit about 25 patients per dose regimen (QW; Q2W; Q3W). The first stage of Part 2 (Dose Expansion) will recruit about 15 patients per tumor group expansion cohort. The study is actively enrolling in the US and currently recruiting in Q2W Cohort 201 and Q3W Cohort A. QW Cohorts 1-3 and Q2W Cohort 101 are complete. Clinical trial information: NCT05001282. Citation Format: Wen Wee Ma, Anthony Tolcher, Cesar A. Perez, Douglass Orr, Erika Hamilton, Yujie Zhao, Yonina Murciano-Goroff, Carey Anders, Gregory P. Adams, Catherine W. Reddick, Eliel Bayever. ELU-FRα-1: a study to evaluate ELU001 in patients with solid tumors that overexpress folate receptor alpha (FRα) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT255.

Abstract 837: Preclinical development of ELU001: A folate receptor alpha (FRα)-targeted C’Dot drug conjugate (CDC) for the treatment of brain metastases

Abstract Antibody-drug conjugates (ADCs) exhibit limited efficacy against brain malignancies due to their inability to cross the blood-brain barrier (BBB) and penetrate into solid tumors. In clinical imaging studies C’Dots readily crossed tumor-disrupted BBB and penetrated across/localized in tumors in the brain avoiding healthy brain. CDCs are ultra-small (6-7 nm) nanoparticles with a silica core coated by short polyethylene glycol chains conjugated to up to 80 small payload and targeting moieties, creating highly potent and avid agents. CDCs’ small size mediates rapid renal clearance leading to limited exposure to healthy tissues. ELU001 is a potent anti-FRα CDC with an average of 21 exatecan topoisomerase-1 inhibitor payload molecules and 13 folic acid targeting molecules on its surface. ELU001 is currently in a dose escalation trial in patients with systemic solid tumor indications that have the potential to overexpress FRα. Early signs of activity with a manageable safety profile have been seen across antigen expression levels. ELU001 exhibits in vitro potency in the sub/low nanomolar range against cancer cell lines that express 3+, 2+ or 1+ levels of FRα. In studies performed in immunodeficient mice bearing intracranial NCI-H2228-luc bioluminescent non-small cell lung cancer tumors, ELU001 was observed to penetrate across disrupted BBB and localize in tumors. Microscopic analysis revealed that ELU001 distributed throughout the tumors but not into the healthy brain. Treatment with a single cycle of ELU001 Q3Dx3 in mice bearing either early (Day 7) or late (Day 14) brain tumors was well tolerated and resulted in significant reduction in tumor burden measured by bioluminescence as well as a prolonged survival benefit. Retreatment of these animals resulted in an additional decrease in tumor burden. These results suggest that ELU001 may have promise for the treatment of metastatic brain tumors that are difficult to treat with currently available agents. Citation Format: Gregory P. Adams, Tin Khor, Feng Chen, Kai Ma, Marion Scocca, Aranapakam Venkatesan, Cathy Reddick, Mary Hilgart, Thomas Gardinier, Fei Wu, Melik Turker, Peiming Chen, Vaibhav Patel, Eliel Bayever. Preclinical development of ELU001: A folate receptor alpha (FRα)-targeted C’Dot drug conjugate (CDC) for the treatment of brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 837.

Pegylation – in search of balance and enhanced bioavailability

In the process of finding better therapeutics, thousands of new molecules are synthesised every day. Many of these can be poorly soluble in water, leading to a potentially promising drug being rejected during testing due to its poor solubility. Polyethylene glycol (PEG) has become known as an excellent modification to remedy this and was initially used to increase circulation time and reduce the immunogenicity of therapeutic proteins. Thus significantly increasing their safety and range of use. Another group of compounds in which significant benefits of pegylation have been seen are photosensitisers. Used in photodynamic therapy, they are often characterised by very high hydrophobicity. Pegylation of their structure significantly increases their affinity for cancer cells and facilitates their penetration through cell membranes. Classical small-molecule drugs can benefit from temporary combinations hydrolysed in the body or very short PEG chains. This approach allows a significant increase in the bioavailability of the drug while avoiding the disadvantages of small molecule pegylation. However, the most common motive for pegylation recently is the creation of drug carriers. Liposomes and nanoparticles make it possible to exploit the advantages of PEG to stabilise their structure and increase circulation time while not modifying the structure of the active compound. Unfortunately, PEGs also have their drawbacks. The first is their high molecular weight range, especially for longer chains, which poses difficulties in purification. Another is the emergence of antibodies directed against PEG. Nevertheless, pegylation is still an up-and-coming method for modifying pharmaceutically active molecules.

Influence of PEG Subunit on the Biological Activity of Ionenes: Synthesis of Novel Polycations, Antimicrobial and Toxicity Studies.

An alarming increase of antibiotic resistance among pathogens creates an urgent need to develop new antimicrobial agents. Many reported polycations show high antimicrobial activity along with low hemolytic activity. Unfortunately, most of those molecules remain highly cytotoxic against various mammalian cells. In this work, a systematic study on the impact of triethylene glycol monomethyl ether side groups (short polyethylene glycol (PEG) analog) on antimicrobial, hemolytic, and cytotoxic properties of novel amphiphilic ionenes is presented. A detailed description of synthesis, leading to well-defined alternating polymers, which differ in structural elements responsible for hydrophilicity (PEG) and hydrophobicity (alkyl chain), is presented. Obtained results show that the PEG moiety and fine-tuned hydrophilic-lipophilic balance of ionenes synergistically lead to low cytotoxic, low hemolytic molecules with high activity against S. aureus, including methicillin-resistant strains (MRSA). Additionally, the results of mechanistic studies on bacterial cells and fluorescently labeled liposomes are also discussed.

Pasteurization, storage conditions and viral concentration methods influence RT-qPCR detection of SARS-CoV-2 RNA in wastewater

The COVID-19 pandemic presents many public health challenges including the tracking of infected individuals from local to regional scales. Wastewater surveillance of viral RNA has emerged as a complementary approach to track and monitor the presence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in a variety of communities of different land use and population size. In the present study, we investigate how five different parameters (pasteurization, storage temperature, storage time, polyethylene glycol (PEG) concentration, and pellet mass) affect the detection of the SARS-CoV-2 N gene and fecal abundance indicator pepper mild mottle virus (PMMoV) gene. Pre-treatment of 24-h composite wastewater samples (n = 14) by pasteurization at 60 °C resulted in a significant reduction of total RNA concentration and copies of the SARS-CoV-2 N gene copies/L (paired Student's t-test, P < 0.05). Comparing the wastewater samples collected from 6 wastewater treatment plants (WWTPs) for a storage period of 7 and 14 days at 4 °C, −20 °C and −80 °C, demonstrated a decrease in SARS-CoV-2 N gene copies/L when samples were stored for 14 days at −20 °C. Polyethylene glycol-NaCl for purification and concentration of viral particles from the wastewater samples demonstrated that a short PEG incubation of 2 h during centrifugation at 4 °C was sufficient for the consistent detection of the SARS-CoV-2 N gene from a 30 mL sample volume. Combined, this paper presents method recommendations for developing a reliable, accurate, sensitive, and reproducible estimation of the SARS-CoV-2 virus in diverse domestic wastewater samples.

Robust Reductions of Body Weight and Food Intake by an Oxytocin Analog in Rats.

Background: Oxytocin is a hypothalamic neuropeptide that participates in the network of appetite regulation. Recently the oxytocin signaling pathway has emerged as an attractive target for treating obesity. However, the short half-life limits its development as a clinical therapeutic. Here we provide results from testing a long-lasting, potent and selective oxytocin analog ASK1476 on its efficacy to reduce food intake and body weight in comparison to the native oxytocin peptide.Methods: ASK1476 features two specific amino acid substitutions in positions 7 and 8 combined with a short polyethylene glycol spacer. Short time dose escalation experiments testing increasing doses of 3 days each were performed in diet-induced overweight (DIO) male rats assessing effects on body weight as well as changes in food intake. Furthermore, DIO rats were tested for changes in body weight, food intake, temperature, and locomotor activity over 28 days of treatment (oxytocin, ASK1476, or vehicle).Results: In dose escalation experiments, significant reductions in food intake relative to baseline were detected beginning with doses of 15 nmol/kg ASK1476 (−15.2 ± 2.3 kcal/d, p = 0.0017) and 20 nmol/kg oxytocin (−11.2.9 ± 2.4 kcal/d, p = 0.0106) with corresponding significant changes in body weight (ASK1476: −5.2 ± 0.8 g, p = 0.0016; oxytocin: −2.6 ± 0.7 g, p = 0.0326). In long-term experiments, there was no difference on body weight change between 120 nmol/kg/d ASK1476 (−71.4 ± 34.2 g, p = 0.039) and 600 nmol/kg/d oxytocin (−91.8 ± 32.2 g, p = 0.035) relative to vehicle (706.9 ± 28.3 g), indicating a stronger dose response for ASK1476. Likewise, both ASK1476 and oxytocin at these doses resulted in similar reductions in 28-day cumulative food intake (ASK1476: −562.7 ± 115.0 kcal, p = 0.0001; oxytocin: −557.1 ± 101.3 kcal, p = 0.0001) relative to vehicle treatment (2716 ± 75.4 kcal), while no effects were detected on locomotor activity or body temperature.Conclusion: This study provides proof-of-concept data demonstrating an oxytocin analog with extended in vivo stability and improved potency to reduce food intake and body weight in DIO animals which could mark a new avenue in anti-obesity drug interventions.

Thiolate end-group regulates ligand arrangement, hydration and affinity for small compounds in monolayer-protected gold nanoparticles

The ability to control the properties of monolayer protected gold nanoparticles (MPNPs) discloses unrevealed features stemming from collective properties of the ligands forming the monolayer and presents opportunities to design new materials. To date, the influence of ligand end-group size and capacity to form hydrogen bonds on structure and hydration of small MPNPs (<5 nm) has been poorly studied. Here, we show that both features determine ligands order, solvent accessibility, capacity to host hydrophobic compounds and interfacial properties of MPNPs. The polarity perceived by a radical probe and its binding constant with the monolayer investigated by electron spin resonance is rationalized by molecular dynamics simulations, which suggest that larger space-filling groups – trimethylammonium, zwitterionic and short polyethylene glycol – favor a radial organization of the thiolates, whereas smaller groups – as sulfonate – promote the formation of bundles. Zwitterionic ligands create a surface network of hydrogen bonds, which affects nanoparticle hydrophobicity and maximize the partition equilibrium constant of the probe. This study discloses the role of the chemistry of the end-group on monolayer features with effects that span from molecular- to nano-scale and opens the door to a shift in the conception of new MPNPs exploiting the end-group as a novel design motif.