Short Polyethylene Glycol Linker Research Articles

Abstract OT-06-01: Open-label, phase 1 study to evaluate duration of severe neutropenia after same-day dosing of eflapegrastim in patients with breast cancer receiving docetaxel and cyclophosphamide (NCT04187898)

Abstract Background: Eflapegrastim (Rolontis®, Efla) is a long-acting granulocyte-colony stimulating factor (G-CSF), consisting of a recombinant human G-CSF analog conjugated to a human IgG4 Fc fragment via a short polyethylene glycol linker. Efla is not a biosimilar and represents the first myeloid growth factor innovation in more than 15 years. In preclinical studies with chemotherapy-induced neutropenic rats, Efla showed ~3-fold higher exposure in serum and higher exposure in bone marrow at similar doses compared to pegfilgrastim (Peg). The duration of neutropenia (DN) was shown to be significantly shorter with Efla vs Peg when administered on the same day and 24-hours post-chemotherapy. Additionally, the DN after Efla administered on the same day as chemotherapy was similar to the DN 24 hours post-chemotherapy. Moreover, in two Phase 3 studies that randomized a total of 643 patients with early-stage breast cancer (ESBC) to either Efla (3.6 mg G-CSF n=314) or Peg (6 mg G-CSF n=329) given ~ 24 hours after docetaxel and cyclophosphamide (TC) administration, the duration of severe neutropenia (DSN) was statistically noninferior in patients treated with Efla compared to Peg. As a standard of practice, G-CSF products require administration 24 hours after chemotherapy. Since Efla preclinical and clinical results suggest that the increased activity of Efla may provide effective prophylaxis against chemotherapy-induced neutropenia when administered on the same day as chemotherapy, the purpose of this study is to assess the feasibility of Efla same-day (3 different dosing timepoints) in patients receiving TC for treatment of ESBC. Trial Design: This is a randomized, schedule finding, multicenter, Phase 1, open-label study evaluating the same-day administration of 13.2 mg/0.6 mL Efla (3.6 mg G-CSF) following IV infusion of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) in patients with ESBC. Patients will be randomized 1:1:1 to Efla dose schedules of 0.5, 3, and 5 hours after TC. The primary endpoint is DSN (ANC <0.5×109/L) in Cycle 1. The secondary endpoints for Cycle 1 administration include the incidence of SN, time to recovery from SN, incidence of Grade 3 febrile neutropenia, incidence of neutropenic complications, and pharmacokinetics (PK) of Efla. Blood for hematology will be drawn daily for the first 10 days and then on Day 1 of Cycles 2-4. Eligibility Criteria: This study is enrolling histologically confirmed (operable stage I-IIIA) patients with ESBC, who are >18 years of age, are candidates for neoadjuvant or adjuvant TC chemotherapy, have an ECOG of <2, with adequate hematological, renal, and hepatic function. Patients will be excluded if they have a known sensitivity or previous reaction to E. coli derived products, exposure to a G-CSF agent within 3 months, history of bone marrow or hematopoietic stem cell transplant, radiotherapy or surgery within 30 days, are pregnant, or are breast-feeding. Statistical Methods: A sample size of 15 patients per dosing schedule arm was determined to provide adequate precision for the 95% CI of the DSN and secondary endpoints, including PK parameters. The sample size produces a 2-sided 95% CI with a distance from the mean DSN to the limits that is equal to 0.554 using t-distribution when the estimated standard deviation is 1.0 days. A safety evaluation will be performed once the first three patients in each arm have completed Cycle 1. Target Accrual: 45 patients (15 subjects/arm). Enrollment began in April 2020. Citation Format: Lee S. Schwartzberg, Jawad Francis, Hlalah Osama, Manuel Modiano, Jayaram Bharadwaj, Shanta Chawla, Gajanan Bhat, Francois Lebel, Nishan Tchekmedyian. Open-label, phase 1 study to evaluate duration of severe neutropenia after same-day dosing of eflapegrastim in patients with breast cancer receiving docetaxel and cyclophosphamide (NCT04187898) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-06-01.

Open-Label, Phase 1 Study to Evaluate Duration of Severe Neutropenia after Same-Day Dosing of Eflapegrastim in Patients with Breast Cancer Receiving Docetaxel and Cyclophosphamide (NCT04187898)

Background: Eflapegrastim (Rolontis®, Efla) is a long-acting granulocyte-colony stimulating factor (G-CSF), consisting of a recombinant human G-CSF analog conjugated to a human IgG4 Fc fragment via a short polyethylene glycol linker. Efla is not a biosimilar and represents the first myeloid growth factor innovation in more than 15 years. In preclinical studies with chemotherapy-induced neutropenic rats, Efla showed ~3-fold higher exposure in serum and higher exposure in bone marrow at similar doses compared to pegfilgrastim (Peg). The duration of neutropenia (DN) was shown to be significantly shorter with Efla vs Peg when administered on the same day or 24-hours post-chemotherapy. Additionally, the DN after Efla administered on the same day as chemotherapy was similar to the DN 24 hours post-chemotherapy. Moreover, in two Phase 3 studies that randomized a total of 643 patients with early-stage breast cancer (ESBC) to either Efla (3.6 mg G-CSF n=314) or Peg (6 mg G-CSF n=329) given ~ 24 hours after docetaxel and cyclophosphamide (TC), the duration of severe neutropenia (DSN) was statistically noninferior in patients treated with Efla compared to Peg. As a standard of practice, G-CSF products require administration 24 hours after chemotherapy. Since Efla preclinical and clinical results suggest that the increased activity of Efla may provide effective prophylaxis against chemotherapy-induced neutropenia when administered on the same day as chemotherapy, the purpose of this study is to assess the feasibility of giving Efla same-day (at 3 different dosing timepoints) in patients receiving TC for the treatment of ESBC. Study Design and Methods : This is a randomized, schedule finding, multicenter, Phase 1, open-label study evaluating the same-day administration of 13.2 mg/0.6 mL Efla following IV infusion of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) in patients with ESBC. Treatment: On Cycle 1, Day 1, patients will be randomized 1:1:1 to Efla dose administration schedules of 0.5, 3, and 5 hours after TC. In Cycles 2-4, Efla will be administered ~ 24 hours following the administration of TC for all treatment arms. Clinical Endpoints: The primary endpoint is DSN (ANC <0.5×109/L) in Cycle 1. The secondary endpoints for Cycle 1 administration include the incidence of SN, time to recovery from SN, incidence of Grade 3 febrile neutropenia, incidence of neutropenic complications, and pharmacokinetics (PK) of Efla. Blood for hematology will be drawn daily for the first 10 days and then on Day 1 of Cycles 2-4. Inclusion Criteria: This study is enrolling histologically confirmed (operable stage I-IIIA) patients with ESBC, who are >18 years of age, are candidates for neoadjuvant or adjuvant TC, have an ECOG of <2, with adequate hematological, renal, and hepatic function. Exclusion Criteria: Patients will be excluded if they have an active or concurrent malignancy, or locally recurrent/metastatic or bilateral breast cancer, a life-threatening disease, a known sensitivity or previous reaction to E. coli derived products, exposure to a G-CSF agent within 3 months, history of bone marrow or hematopoietic stem cell transplant, radiotherapy or surgery within 30 days, are pregnant or are breast-feeding. Statistical Methods: A sample size of 15 patients per dosing schedule arm was determined to provide adequate precision for the 95% CI of the DSN and secondary endpoints, including PK parameters, assuming a standard deviation of 1.0 days based on the prior studies. A safety evaluation will be performed once the first three patients in each arm have completed Cycle 1. Target Accrual: 45 patients (15 subjects/arm). Enrollment began in April 2020. Disclosures Schwartzberg: Spectrum Pharmaceuticals, Inc.: Consultancy, Other: clinical investigator for trial. Francis:Spectrum Pharmaceuticals, Inc.: Other: clinical investigator for trial. Osama:Spectrum Pharmaceuticals, Inc.: Other: clinical investigator for trial. Modiano:Spectrum Pharmaceuticals, Inc.: Other: clinical investigator for trial. Bharadwaj:Spectrum Pharmaceuticals, Inc.: Other: clinical investigator for trial. Chawla:Spectrum Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Bhat:Spectrum Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Lebel:Spectrum Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Tchekmedyian:Spectrum Pharmaceuticals, Inc.: Other: clinical investigator for trial.

Eflapegrastim's enhancement of efficacy compared with pegfilgrastim in neutropenic rats supports potential for same-day dosing

Eflapegrastim (Rolontis) is a long-acting granulocyte colony-stimulating factor (G-CSF) with an IgG4 Fc fragment and short polyethylene glycol linker. Current G-CSF products are administered 24 hours after chemotherapy. The present study compares the duration of neutropenia (DN) with eflapegrastim or pegfilgrastim at 0, 2, 5, or 24 hours post chemotherapy. Eflapegrastim was evaluated by G-CSF receptor binding and bone marrow cell proliferation assays in vitro. Eflapegrastim-Fc component binding to Fcγ receptors C1q and FcRn was assessed by enzyme-linked immunosorbent assay. Neutropenia was induced in rats via intraperitoneal cyclophosphamide or docetaxel/cyclophosphamide. Rats received chemotherapy followed by vehicle, pegfilgrastim, or eflapegrastim at 2, 5, or 24 hours. The difference in DN after treatment was assessed. In vitro binding to G-CSF receptor of both agents was similar. Binding to FcRn and no binding to Fcγ receptors or C1q were observed with eflapegrastim. Studies in chemotherapy-induced neutropenic rats revealed shorter DN with eflapegrastim versus pegfilgrastim. Increased levels of G-CSF in serum and marrow were observed in groups treated with eflapegrastim versus those treated with pegfilgrastim. Although eflapegrastim and pegfilgrastim have similar in vitro binding affinity, the Fc fragment in eflapegrastim increases the uptake into bone marrow, resulting in increased therapeutic potential for chemotherapy-induced neutropenia. Eflapegrastim's greater marrow resident time provided a pharmacodynamic advantage over pegfilgrastim, translating into shortened duration of neutropenia. Our findings support eflapegrastim same-day administration with chemotherapy, warranting further evaluation in patients undergoing myelosuppressive chemotherapy.

Abstract 2044: Chemotherapy induced neutropenia in rats following administration of eflapegrastim or pegfilgrastim on the same day at three different timepoints and at 24 hours post-chemotherapy

Abstract Background: Eflapegrastim is a long-acting G-CSF that is comprised of a G-CSF analog and a recombinant IgG4 Fc fragment conjugated at their N-termini via a short polyethylene glycol linker. Currently, G-CSF products are administered 24 hours after chemotherapy. We compared the duration of neutropenia (DN) after treatment with eflapegrastim and pegfilgrastim given on the same-day, at three different timepoints, and after 24 hours in chemotherapy-induced neutropenic rats. Method: Neutropenia was induced in rats via intraperitoneal administration of cyclophosphamide and docetaxel (TC) chemotherapy. Rats (5 animals per group) were assigned to dose groups of either vehicle or equivalent doses (based on human clinical doses) of pegfilgrastim (103.3 µg/kg) or eflapegrastim (61.8 µg/kg as G-CSF) on the same day as chemotherapy at 0, 2, and 5 hours or 24 hours after chemotherapy. The primary endpoint was the difference in DN after TC treatment and administration of eflapegrastim or pegfilgrastim at the specified timepoints. Results: In the vehicle group, the TC regimen induced neutropenia in all animals with an ANC nadir occurring on approximately Day 4 and a mean DN of nearly 7 days. The mean DN values for treatment with eflapegrastim on the same day, at 0, 2, and 5 hours, and after 24 hours were similar and the mean DN values for eflapegrastim were significantly lower than for pegfilgrastim at all dosing timepoints (Table). Time after Chemotherapy(hours)Mean Duration of Neutropenia (days)Difference (95% CI)Eflapegrastim Time vs 24 hoursDifference (95% CI)EflapegrastimPegfilgrastim00.62.2-1.6 (-3.067, -0.133)0.4 (-0.08, 1.28)20.21.8-1.6 (-2.84, -0.36)0 (-0.19, 0.59)50.01.2-1.2 (-1.20, -1.20)-0.2 (0, 0)240.21.8-1.6 (-2.84, -0.36)NA Conclusions: The DN for same-day treatment with eflapegrastim at 0, 2, and 5 hours was similar to that of the treatment after 24-hours. However, the mean DN values were significantly lower for eflapegrastim than pegfilgrastim at all time points. Further exploration of the potential advantage of same-day dosing with eflapegrastim in patients undergoing chemotherapy is warranted. Citation Format: Yu-Yon Kim, Eunjung Kim, Hyesun Han, Seungjae Baek, Shanta Chawla, Prasad Kolli, Gajanan Bhat, Francois Lebel. Chemotherapy induced neutropenia in rats following administration of eflapegrastim or pegfilgrastim on the same day at three different timepoints and at 24 hours post-chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2044.

Alpha radioimmunotherapy using 225Ac-proteus-DOTA for solid tumors - safety at curative doses.

This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using 225Ac and its theranostic pair, 111In. We call our novel tumor-targeting DOTA-hapten PRIT system “proteus-DOTA” or “Pr.” Herein we report the first results of radiochemistry development, radiopharmacology, and stoichiometry of tumor antigen binding, including the role of specific activity, anti-tumor efficacy, and normal tissue toxicity with the Pr-PRIT approach (as α-DOTA-PRIT). A series of α-DOTA-PRIT therapy studies were performed in three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2), including evaluation of chronic toxicity at ~20 weeks of select survivors.Methods: Preliminary biodistribution experiments in SW1222 tumor-bearing mice revealed that 225Ac could not be efficiently pretargeted with current DOTA-Bn hapten utilized for 177Lu or 90Y, leading to poor tumor uptake in vivo. Therefore, we synthesized Pr consisting of an empty DOTA-chelate for 225Ac, tethered via a short polyethylene glycol linker to a lutetium-complexed DOTA for picomolar anti-DOTA chelate single-chain variable fragment (scFv) binding. Pr was radiolabeled with 225Ac and its imaging surrogate, 111In. In vitro studies verified anti-DOTA scFv recognition of [225Ac]Pr, and in vivo biodistribution and clearance studies were performed to evaluate hapten suitability and in vivo targeting efficiency.Results: Intravenously (i.v.) administered 225Ac- or 111In-radiolabeled Pr in mice showed rapid renal clearance and minimal normal tissue retention. In vivo pretargeting studies show high tumor accumulation of Pr (16.71 ± 5.11 %IA/g or 13.19 ± 3.88 %IA/g at 24 h p.i. for [225Ac]Pr and [111In]Pr, respectively) and relatively low uptake in normal tissues (all average ≤ 1.4 %IA/g at 24 h p.i.). Maximum tolerated dose (MTD) was not reached for either [225Ac]Pr alone or pretargeted [225Ac]Pr at administered activities up to 296 kBq/mouse. Single-cycle treatment consisting of α-DOTA-PRIT with either huA33-C825 bispecific anti-tumor/anti-DOTA-hapten antibody (BsAb), anti-HER2-C825 BsAb, or hu3F8-C825 BsAb for targeting GPA33, HER2, or GD2, respectively, was highly effective. In the GPA33 model, no complete responses (CRs) were observed but prolonged overall survival of treated animals was 42 d for α-DOTA-PRIT vs. 25 d for [225Ac]Pr only (P < 0.0001); for GD2, CRs (7/7, 100%) and histologic cures (4/7, 57%); and for HER2, CRs (7/19, 37%) and histologic cures (10/19, 56%) with no acute or chronic toxicity.Conclusions: [225Ac]Pr and its imaging biomarker [111In]Pr demonstrate optimal radiopharmacologic behavior for theranostic applications of α-DOTA-PRIT. For this initial evaluation of efficacy and toxicity, single-cycle treatment regimens were performed in all three systems. Histologic toxicity was not observed, so MTD was not observed. Prolonged overall survival, CRs, and histologic cures were observed in treated animals. In comparison to RIT with anti-tumor IgG antibodies, [225Ac]Pr has a much improved safety profile. Ultimately, these data will be used to guide clinical development of toxicity and efficacy studies of [225Ac]Pr, with the goal of delivering massive lethal doses of radiation to achieve a high probability of cure without toxicity.

Site-specific labeling of an anti-MUC1 antibody: probing the effects of conjugation and linker chemistry on the internalization process.

Antibody-drug conjugates (ADCs) have recently received enormous attention as an attractive approach for cancer therapy. Although ADC design has been believed to be important for the relative efficacy of ADCs, it remains unexplored how the structural characteristics of ADCs would impact the internalization process and intracellular trafficking of the molecules. Herein, we report our efforts in investigating the cellular endocytosis implications of the conjugation and linker chemistry in designing antibody-based agents. A series of anti-MUC1 single-chain variable fragment (scFv-SM3) conjugates were designed with unique structural characteristics ranging from conjugation methods, sites of attachment and linker chemistry. In vitro confocal imaging showed that both random lysine-conjugation and site-specific conjugation, including C-terminus modification or internal site conjugation, could afford antibody conjugates with similar binding affinity and cellular uptake to target-expressing cells. Time-course internalization studies demonstrated that SM3-conjugates with short polyethylene glycol linkers outcompeted those that lack any hydrophilic linkers for higher cellular uptake and faster internalization rate. The SM3-conjugates with the highest affinity and internalization rate were also tested in mouse xenograft models using MUC1-overexpressing tumor cells. Our results indicate that the linker and conjugation chemistry play an important role in the internalization process of antibody conjugates, and this in turn could impact the therapeutic effects of ADCs.

Uptake Pathways of Protein-Coated Magnetic Nanoparticles in Platelets.

Magnetic nanoparticles have recently shown great potential in nonradioactive labeling of platelets. Platelet labeling efficiency is enhanced when particles are conjugated with proteins like human serum albumin (HSA). However, the optimal HSA density coated on particles and the uptake mechanism of single particles in platelets remain unclear. Here, we utilized single-molecule force spectroscopy (SMFS) and other complementary methods to characterize the interaction of particles when interacting with platelets and to determine the optimal HSA amount required to coat particles. An HSA concentration of 0.5-1.0 mg/mL for coating particles is most efficient for platelet labeling. Binding pathways could be elucidated by linking a single HSA particle to SMFS tips via polyethylene glycol (PEG) linkers of different lengths and allowing them to interact with immobilized platelets on the substrate. Depending on the PEG length (i.e., short ∼2 nm, medium ∼30 nm, and long ∼100 nm), particles interact differently with platelets as shown by one, two, or three force distributions, which correspond up to three different binding pathways, respectively. We propose a model that the short PEG linker allows the particle to interact only with the platelet membrane, whereas the medium and long PEG linkers promote the particle to transfer from open canalicular system to another target inside platelets. Our study optimizes magnetic platelet labeling and provides details of particle pathways in platelets.

Minibody-indocyanine green based activatable optical imaging probes: the role of short polyethylene glycol linkers.

Minibodies show rapider blood clearance than IgGs due to smaller size that improves target-to-background ratio (TBR) in in vivo imaging. Additionally, the ability to activate an optical probe after binding to the target greatly improves the TBR. An optical imaging probe based on a minibody against prostate-specific membrane antigen (PSMA-MB) and conjugated with an activatable fluorophore, indocyanine green (ICG), was designed to fluoresce only after binding to cell-surface PSMA. To further reduce background signal, short polyethylene glycol (PEG) linkers were employed to improve the covalent bonding ratio of ICG. New PSMA-MBs conjugated with bifunctional ICG derivatives specifically visualized PSMA-positive tumor xenografts in mice bearing both PSMA-positive and -negative tumors within 6 h postinjection. The addition of short PEG linkers significantly improved TBRs; however, it did not significantly alter the biodistribution. Thus, minibody-ICG conjugates could be a good alternative to IgG-ICG in the optical cancer imaging for further clinical applications.

Short PEG-Linkers Improve the Performance of Targeted, Activatable Monoclonal Antibody-Indocyanine Green Optical Imaging Probes

The ability to switch optical imaging probes from the quenched (off) to the active state (on) has greatly improved target to background ratios. The optimal activation efficiency of an optical probe depends on complete quenching before activation and complete dequenching after activation. For instance, monoclonal antibody-indocyanine green (mAb-ICG) conjugates, which are promising agents for clinical translation, are normally quenched, but can be activated when bound to a cell surface receptor and internalized. However, the small fraction of commonly used ICG derivative (ICG-Sulfo-OSu) can bind noncovalently to its mAb and is, thus, gradually released from the mAb leading to relatively high background signal especially in the liver and the abdomen. In this study, we re-engineered a mAb-ICG conjugate, (Panitumumab-ICG) using bifunctional ICG derivatives (ICG-PEG4-Sulfo-OSu and ICG-PEG8-Sulfo-OSu) with short polyethylene glycol (PEG) linkers. Higher covalent binding (70-86%) was observed using the bifunctional ICG with short PEG linkers resulting in less in vivo noncovalent dissociation. Panitumumab-ICG conjugates with short PEG linkers were able to detect human epidermal growth factor receptor 1 (EGFR)-positive tumors with high tumor-to-background ratios (15.8 and 6.9 for EGFR positive tumor-to-negative tumor and tumor-to-liver ratios, respectively, at 3 d postinjection).

Chlorotoxin Labeled Magnetic Nanovectors for Targeted Gene Delivery to Glioma

Glioma accounts for 80% of brain tumors and currently remains one of the most lethal forms of cancers. Gene therapy could potentially improve the dismal prognosis of patients with glioma, but this treatment modality has not yet reached the bedside from the laboratory due to the lack of safe and effective gene delivery vehicles. In this study we investigate targeted gene delivery to C6 glioma cells in a xenograft mouse model using chlorotoxin (CTX) labeled nanoparticles. The developed nanovector consists of an iron oxide nanoparticle core, coated with a copolymer of chitosan, polyethylene glycol (PEG), and polyethylenimine (PEI). Green fluorescent protein (GFP) encoding DNA was bound to these nanoparticles, and CTX was then attached using a short PEG linker. Nanoparticles without CTX were also prepared as a control. Mice bearing C6 xenograft tumors were injected intravenously with the DNA-bound nanoparticles. Nanoparticle accumulation in the tumor site was monitored using magnetic resonance imaging and analyzed by histology, and GFP gene expression was monitored through Xenogen IVIS fluorescence imaging and confocal fluorescence microscopy. Interestingly, the CTX did not affect the accumulation of nanoparticles at the tumor site but specifically enhanced their uptake into cancer cells as evidenced by higher gene expression. These results indicate that this targeted gene delivery system may potentially improve treatment outcome of gene therapy for glioma and other deadly cancers.

Solid‐supported and pegylated H–Pro–Pro–Asp–NHR as catalysts for asymmetric aldol reactions

H-Pro-Pro-Asp-NH2 is a highly active and selective catalyst for asymmetric aldol reactions. Here, the versatility of H-Pro-Pro-Asp-NH2 has been further improved by immobilization on a solid support and functionalization with a short polyethylene glycol linker at the C-terminus. The development, synthesis, and the catalytic properties in aldol reactions of H-Pro-Pro-Asp-resin and H-Pro-Pro-Asp-Ahx-NH(CH2CH2O)3CH3 are described. For the solid-supported catalyst, TentaGel with a loading of 0.1-0.2 mmol g(-1) proved to be the optimal support. The solid-supported catalyst can be recycled at least three times without a significant drop in the catalytic activity or selectivity. Using the pegylated catalyst H-Pro-Pro-Asp-Ahx-NH(CH2CH2O)3CH3, only 0.5 mol % are necessary to obtain aldol products in up to 96% yield and 91% enantiomeric excess. In all cases, enantioselectivities are comparable to those obtained with the parent catalyst H-Pro-Pro-Asp-NH2. Thus, immobilization of H-Pro-Pro-Asp-NH2 on Tentagel as well as pegylation led to catalysts with selectivities comparable to the nonmodified catalyst, exhibiting additional distinct advantages such as facile reusability, ease of handling, higher solubility, and thereby greater versatility. handling, higher solubility, and thereby greater versatility.