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Amphotericin B conjugated to a discrete PEG (dPEG®) linker with a free amine have higher water solubility and lower toxicity than the parent compound.

Amphotericin B+dPEG®: Water-Soluble, Less Toxic, Potent

Amphotericin B conjugated to a discrete PEG (dPEG®) linker with a free amine have higher water solubility and lower toxicity than the parent compound.
Amphotericin B conjugated to a discrete PEG (dPEG®) linker with a free amine has higher water solubility and lower toxicity than the parent compound. Image used by permission from J. Med. Chem. (2016), 59, 1197-1206, copyright 2016, American Chemical Society.

 

About Amphotericin B

Structure of Amphotericin B. Used with permission from J. Med. Chem. (2016), 59, 1197-1206, copyright 2016, American Chemical Society.
Figure 1: Structure of Amphotericin B. Image used by permission from J. Med. Chem. (2016), 59, 1197-1206, copyright 2016, American Chemical Society.

Amphotericin B (Figure 1) is the "gold standard" treatment for systemic fungal infections and diseases caused by the parasite Leishmania. Sometimes it is the only effective treatment because drug resistance renders other treatments useless. Systemic fungal infections are an increasingly serious, widespread problem in medicine. Patients with weakened or suppressed immune systems (caused by HIV/AIDS, diabetes, organ transplants, some cancer treatments) are especially at risk. An estimated 1.5-2 million people die each year from systemic fungal infections (1). Despite its "gold standard" label, Amphotericin B has several well-known difficulties.

A polyene macrolide antifungal drug, Amphotericin B was first discovered in 1953 from the fermentation culture of the bacterium Streptomyces nodosus. It entered the pharmaceutical market in 1958 (2)(3)(4). Nearly insoluble in water, the drug is not absorbed from the human gastrointestinal tract and must be administered intravenously. Amphotericin B was first formulated as a suspension in sodium deoxycholate solution called Fungizone-Squibb (2)(7). Novel, less toxic lipid formulations have been developed recently (5)(6)(7), but these formulations cost more and require high doses to be effective, thus limiting their use (4)(7).

This drug is also toxic. Its side effects are well known, serious, and sometimes fatal (7)(8). Common side effects from taking this drug include high fever coupled with shaking chills ("shake and bake"), headache, kidney problems, low blood pressure, nausea, vomiting, unusual bruising or bleeding, and irregular heartbeat. Anaphylactic shock sometimes occurs with this drug. A 1997 report from the Center for Drug Evaluation and Research, a division of the United States Food and Drug Administration, stated that the toxicity of Amphotericin B was 1.5 mg/Kg in rats. Other reports reach similar conclusions (4)(5)(6)(7)(8).

Since its discovery, numerous researchers have attempted to modify the properties of Amphotericin B to make it more water-soluble, less toxic, or both. PEGylation is one obvious strategy for improving the water solubility of a water-insoluble drug. Greenwald, et al. (9), and Sedlak, et al. (10)(11) created PEGylated prodrug versions of the drug, but these constructs used large, dispersed, polymeric PEGs that are heterogeneous in size and, hence, difficult to characterize.

 

A Different Approach to Water-Soluble Amphotericin B

In a paper published in January 2016 in the Journal of Medicinal Chemistry, Assaf Halperin, Yana Shadkchan, Evgeni Pisarevsky, Alex Szpilman, Hani Sandovsky, Nir Osherov, and Itai Benhar, from Tel-Aviv University and the Israel Institute of Technology chose to work with short PEG chains of defined length and molecular weight. Specifically, they chose to create a stable amide bond on the mycosamine ring and expose a free amine at the opposite end of the linker. After testing PEG linkers with 4, 8, and 44 ethylene oxide units, they settled on the PEG8 linker, because it offered significant improvement in water solubility with little loss in efficacy. By contrast, the PEG4 linker improved water solubility, but less well than the PEG8 and PEG44 linkers. The PEG44 linker improved water solubility greatly, but the derivative's efficacy dropped thirty-fold compared to the parent drug.

 

Synthetic scheme used by Halperin, et al., to create the two PEGylated derivatives of Amphotericin B. Image used with permission from J. Med. Chem. (2016), 59, 1197-1206, copyright 2016, American Chemical Society.
Figure 2: Synthetic scheme used by Halperin, et al., to create the two PEGylated derivatives of Amphotericin B. Image used by permission from J. Med. Chem. (2016), 59, 1197-1206, copyright 2016, American Chemical Society.

For the construction of two different PEGylated derivatives, the research group used Quanta BioDesign's Fmoc-N-amido-dPEG®8-NHS ester, product number 10995, purchased from our German distributor, Iris Biotech, GmbH. (Click here for a complete list of our distributors.) The authors stated the reason for their choice in this way:

This approach creates a well-defined medium-molecular-weight product that can be easily separated and characterized by NMR and other common techniques .... The short and specific synthesis and well-defined structural nature of the antifungal conjugate is expected to be an advantage in clinical approval as well. (4, page 1201).

After the dPEG® was conjugated to Amphotericin B, the Fmoc protecting group was removed, exposing the free amine on the dPEG® linker. The synthetic scheme used by the authors is shown in Figure 2.

 

Amphotericin B-dPEG®8 Derivatives Show Promise as Clinical Replacements for the Parent Compound

In testing, both dPEG®ylated derivatives (AB1, the free acid; AM2, the methyl ester; see Figure 3) increased dramatically in water solubility, decreased considerably in toxicity, and maintained (with only a moderate decrease) efficacy.

The solubility of Amphotericin B in water is less than 1 µg/mL (<0.001 mg/mL). The AM2 derivative's water solubility increased to 700 µg/mL (0.7 mg/mL), while AB1 increased to 5,500 µg/mL (5.5 mg/mL). Previous efforts to make useful PEGylated derivatives of Amphotericin B used carbamate linkages between the drug and the PEG. These linkages hydrolyzed readily in phosphate-buffered saline (PBS). By contrast, neither AB1 nor AM2 showed any hydrolysis in PBS after 4 hours, and both hydrolyzed less than 1% after 24 hours in PBS, demonstrating that they are stable. Furthermore, pharmacokinetic studies of AM2 in mice showed no free Amphotericin B after 24 hours, indicating that the derivatives are stable.

Structures of the dPEG®8-amine derivatives of Amphotericin B. Image used by permission from J. Med. Chem. (2016), 59, 1197-1206, copyright 2016, American Chemical Society.
Figure 3: Structures of the dPEG®8-amine derivatives of Amphotericin B. Image used by permission from J. Med. Chem. (2016), 59, 1197-1206, copyright 2016, American Chemical Society.

The authors tested the toxicity of AB1 and AM2 against the parent drug in three ways. First, they evaluated nonspecific toxicity of all three compounds by suspending fresh human red blood cells (hRBCs) in PBS and measuring lysis of the cells (hemolysis) in the presence of Amphotericin B or the derivatives. Second, they assayed the viability of mouse embryonic fibroblast cells using an MTT assay (for a detailed, technical discussion of the MTT assay plus procedures for conducting the assay, click here). Third, they measured the LD50 of the three compounds by intravenous injection in mice.

In the first test, Amphotericin B was highly toxic as expected. AB1 was less toxic to hRBCs than the parent compound, while AM2 caused very little hemolysis and thus demonstrated little non-specific toxicity.

MTT Assay comparing Amphotericin B to the AB1 and AM2 derivatives.
Figure 4: MTT Assay comparing Amphotericin B to the AB1 and AM2 derivatives. A color version of this image is at the beginning of this post. AM1 (should be AB1) and AM2 are the derivatives shown in Figure 3. AMB is Amphotericin B (see Figure 1 for structure). Image used by permission from J. Med. Chem. (2016), 59, 1197-1206, copyright 2016, American Chemical Society.

The MTT assay (see Figure 4) showed dramatic differences between Amphotericin B and the derivatives. The MTT assay measures the half-maximal inhibitory concentration, also known as the IC50 (see also here), of a compound against cells in culture. In the assay, AB1 was forty times less toxic to the mouse embryonic fibroblasts than Amphotericin B, while AM2 was at least 600 times less toxic.

The in vivo toxicity testing showed dramatically different results among Amphotericin B, AB1, and AM2. The LD50 of Amphotericin B was 1.1 mg/Kg. Mice injected with twice the LD50 died instantly. By contrast, AB1 was not toxic to mice at the maximum injected dose of 22 mg/Kg, and AM2 was not toxic to mice at the maximum injected dose of 42 mg/Kg.

Efficacy (a measure of the potency of antifungal activity) was assessed both in vitro and in vivo. Both AB1 and AM2 retained activity against a broad spectrum of fungi but were 2-16 times less potent than Amphotericin B. When the length of time needed to kill all fungal cells was measured, AM2 eliminated all fungi in vitro within 2 hours, similar to Amphotericin B. In in vivo testing, Amphotericin B at 1 mg/Kg (near the LD50) cured 10 of 12 mice of fungal infection, compared to AM2, which achieved the same result using 3.5 mg/Kg. AM2, though, cured all mice of fungal infections at a dose of 7 mg/Kg, something that non-PEGylated parent drug could not do, because it was too toxic.

Interestingly, AM2 had a shorter serum half-life than Amphotericin B. This result seems odd at first glance because PEGylation is one of the primary means by which the serum half-life of therapeutic agents is extended. The reason for the difference is that Amphotericin B binds serum proteins, which lengthens the drug's serum half-life. Testing revealed that AM2 does not bind strongly to serum proteins. This allows it to be removed much more quickly from the body.

AB1 and AM2 both show promise as clinical antifungal agents. The increased water solubility and lower toxicity compared to Amphotericin B are important, but it is also important that the efficacy of the derivatives is not greatly diminished from the parent compound. The discrete PEGylation (dPEG®) reagent simplifies analysis of the products, and the specific dPEG® reagent chosen, PN10995, is ideal for conjugating the Amphotericin B derivatives to other molecules after removal of the Fmoc group protecting the terminal amine.

This work also highlights the remarkable power of a relatively small dPEG® linker. Many research groups tend to think that large, dispersed PEGs are the solution to their water solubility problems. This research shows that a dPEG®8 linker imparts significant water solubility and reduces toxicity, with only a modest impact on efficacy. This is truly important for understanding the power and ability of discrete PEGylation.

 

References

  1. Denning, D. W.; Bromley, M. J. Infectious disease: how to bolster the antifungal pipeline. Science (27 March 2015), 347(6229). 1414-1416.
  1. Dutcher, James D. The discovery and development of Amphotericin B. Dis. Chest (October 1968), 54(supplement 1), 40-42.
  1. Gallis, Harry A.; Drew, Richard H.; and Pickard, William W. Amphotericin B: 30 years of clinical experience. Clin. Infect. Dis. (1990), 12(2), 308-329.
  1. Halperin, Assaf; Shadkchan, Yana; Pisarevsky, Evgeni; Szpilman, Alex M.; Sandovsky, Hani; Osherov, Nir; and Benhar, Itai. Novel water-soluble Amphotericin B-PEG conjugates with low toxicity and potent in vivo efficacy. J. Med. Chem. (2016), 59, 1197-1206.
  1. Larabi, M.; Pages, N.; Pons, F.; Appel, M.; Gulik, A.; Schlatter, J.; Bouvet, S.; and Barrat, G. Study of the toxicity of a new lipid complex formulation of amphotericin B. J. Antimicrob. Chemother. (2004), 53, 81-88.
  1. Souza, L. C.; Campa, A. Pharmacological parameters of intravenously administered amphotericin B in rats: comparison of the conventional formulation with amphotericin B associated with a triglyceride-rich emulsion. J. Antimicrob. Chemother. (July 1999) 44(1): 77-84.
  1. Hamill, Richard J. Amphotericin B Formulations: A Comparative Review of Efficacy and Toxicity. Drugs (2013), 73: 919-934
  1. Laniado-Laborín, Rafael; and Cabrales-Vargas, Maria Noemí. Amphotericin B: side effects and toxicity. Rev Iberoam Micol. (2009) 26(4):223–227.

Do you have questions or comments about this post? Please leave a comment below. Also, be sure and check out our list of related products below.

 

Related Products

PN10994, Fmoc-N-amido-dPEG®4-NHS ester

PN10995, Fmoc-N-amido-dPEG®8-NHS ester

PN10996, Fmoc-N-amido-dPEG®12-NHS ester

Click here to learn why TFP esters are superior to NHS esters.

PN11000, Fmoc-N-amido-dPEG®4-TFP ester

PN11005, Fmoc-N-amido-dPEG®8-TFP ester

PN11006, Fmoc-N-amido-dPEG®12-TFP ester

PN11007, Fmoc-N-amido-dPEG®24-TFP ester

PN11008, Fmoc-N-amido-dPEG®36-TFP ester

PN10033, Fmoc-N-amido-dPEG®3-acid

PN10213, Fmoc-N-amido-dPEG®4-acid

PN10053, Fmoc-N-amido-dPEG®5-acid

PN10063, Fmoc-N-amido-dPEG®6-acid

PN10273, Fmoc-N-amido-dPEG®8-acid

PN10283, Fmoc-N-amido-dPEG®12-acid

PN10313, Fmoc-N-amido-dPEG®24-acid

PN10903, Fmoc-N-amido-dPEG®36-acid

PN11301, Fmoc-N-amido-dPEG®24-amido-dPEG®24-acid

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Chart showing the analgesic activities of various galanin analogues used in a formalin pain assay.

PEGylated Galanin Shows Enhanced Analgesic Effects in PNS

Galanin is a naturally occurring neuropeptide in the human body that facilitates communication between cells to balance a myriad of physiological functions. Neuropeptides are biosynthesized molecules used by the human body for everything from neurogenesis to cell communication.  Galanin’s main receptor sites reside in the central nervous system (CNS), and it normally crosses the blood brain barrier; however, the peripheral nervous system (PNS) also reacts directly to galanin and its receptors in sites of pain mediation.1 Galanin’s role as a pain inhibitor is a peripheral one, which means that, as a drug, its analgesic role would be secondary.  Peripheral effects of peptides are overshadowed by their effectiveness in carrying out primary functions and limiting concentration in low receptor site areas. Peripheral roles of neuropeptides can play just as important of a role as the primary roles in regulating changes in the nervous system.

 

Structure of the galanin neuropeptide found in humans. The peptide sequence is GWTLNSAGYLLGPHAVGNHRSFSDKNGLTS
Figure 1: Structure of the galanin neuropeptide found in humans. The peptide sequence is GWTLNSAGYLLGPHAVGNHRSFSDKNGLTS

 

Common methods of altering drug permeability include lipidization, counterionization, poly-disperse PEGylation, carrier protein conjugation, and many more. The modification is a means to justify an end, in this case the efficacy of the drug. A research team from the University of Utah’s College of Pharmacology and Toxicology and NeuroAdjuvants, Inc., in Salt Lake City studied PEGylation of galanin in response to their research done on other methods of alteration to the neuropeptide. Results of previous research by the group showed increased penetration across the blood brain barrier by galanin. The analgesic properties of galanin are restricted when allowed to permeate unrestricted from blood to brain. The group hypothesized that “dPEGylation will restrict penetration of the neuropeptide analogues into the brain, while their activities in the PNS would be retained”2.

 

Figure 2: Octanol/Water Partition Coefficients (logD) of Galanin Analogues. Y axis: LogD=Log([peptide in octanol)/(peptide in water)]
Figure 2: Octanol/Water Partition Coefficients (logD) of Galanin Analogues. Y axis: LogD=Log([peptide in octanol)/(peptide in water)]
 

Figure 2 shows data for the availability of an altered galanin (Gal-B2) with a discrete PEG in solution between octane and water2. The data shows that the PEGylated Gal-B2 favors the aqueous phase instead, which hypothetically limits its permeability across the blood brain barrier.
The testing of the peptides was carried out by studying the effects both in vitro and in vivo testing methods. The in vitro method included testing the effectiveness of the peptide to bind to its receptor by measuring fluorescence in a competitive binding assay. After PEGylation the neuropeptides retained nanomolar affinities for their receptor sites2. The in vivo testing included formalin injections into the dermal layer of mice paws to trigger a pain response. The mouse’s response to the pain, quantified by licking the wound, was compared across a series of unmodified and modified peptides and a control.

 

Figure 3: Chart showing the analgesic activities of various galanin analogues used in a formalin pain assay.
Figure 3: Analgesic activities of various galanin analogues used in a formalin pain assay.

 

Figure 4: Table showing the anticonvulsant activity of various galanin analogues.
Figure 4: Anticonvulsant activity of various galanin analogues.

Figures 3 and 4 show some surprising results relative to the group's hypothesis. The PEGylated peptide retained similar analgesic activity as the unmodified peptide for acute pain (Figure 3, phase I), and was better than the unmodified peptide in controlling inflammatory pain (Figure 3, phase II). Figure 4 shows that the PEGylated peptides (Gal-B2-dPEG24 and Gal-R2-dPEG24) had reduced anticonvulsant protective effects when administered to mice via intracerebroventricular (icv) injections and had no anticonvulsant protective effects when administered via intraperitoneal (ip) injections. This is most clearly shown by comparing the area under the curve (AUC) of the unmodified Gal-B2 against the AUC of each modified peptide.

This research is significant in that it shows that PEGylation of a biologically active peptide can change both the biodistribution and bioactivity profile of the peptide. This gives promise for “further exploration of monodisperse oligoethyleneglycol residues toward more neuroactive peptides that mediate their actions in the central and peripheral nervous systems”2. As research into this field continues, access to high quality, diverse PEGylation reagents will be a cornerstone.

Our Role in This Research

In this research the role of discrete PEG was important, because polydisperse PEGylation forms a diverse array of peptides3. Quanta BioDesign's patented discrete PEG (dPEG®) technology produces PEGylation reagents that are single molecules, not an intractable mixture of different PEG linker lengths each with a different molecular weight. Using our m-dPEG®24-acid reagent to modify Gal-B2 through a lysine side chain resulted in specific single molecules (Gal-B2-dPEG24 and Gal-R2-dPEG24) that could be fully characterized.

An amide bond between the dPEG® and the peptide was the end goal and we offer myriad products with free acids, active esters, and amines to help create that bond. To create other types of linkages, we offer products with different functional groups, including hydrazides (to form hydrazone bonds), oxyamines (oxime bonds), aldehydes (secondary amines, oximes), thiols (disulfides), and many more. In addition to our linear dPEG® products, Quanta Biodesign also offers dPEG® reagents with multiple arms to better modify your small molecule, peptide, or protein without the cost of extra reaction sites.

 

References on Galanin and PEGylation:

1. Lang, R.; Gundlach, A. L.; Kofler, B. The galanin peptide family: receptor pharmacology, pleiotropic biological actions, and implications in health and disease. Pharmacol. Ther. 2007, 115, 177−207.

2. Zhang L, Klein BD, Metcalf CS, Smith MD, McDougle DR, Lee HK, White HS, Bulaj G. Incorporation of monodisperse oligoethyleneglycol amino acids into anticonvulsant analogues of galanin and neuropeptide Y provides peripherally acting analgesics. Mol. Pharm. (2013), 10(2): 574-85

3. Gaberc-Porekar, V.; Zore, I.; Podobnik, B.; Menart, V. Obstacles and pitfalls in the PEGylation of therapeutic proteins. Curr. Opin. Drug Discovery Dev. 2008, 11, 242−50.

 

Example Linear, Amine-Reactive dPEG® Products (also available as NHS esters and 2,3,5,6-tetrafluorophenyl esters)

m-dPEG®2-acid

m-dPEG®4-acid

m-dPEG®12-acid

m-dPEG®24-acid (used in this study to modify galanin)

m-dPEG®37-acid

m-dPEG®48-CO(CH2)3-acid

 

Example Branched Amine-Reactive dPEG® Products (also available as NHS esters and 2,3,5,6-tetrafluorophenyl esters)

Carboxyl-dPEG®₄-(m-dPEG®₄)₃

Carboxyl-dPEG®₄ -(m-dPEG®₈)₃

Carboxyl-dPEG®₄-(m-dPEG®₁₁)₃

 

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Organophosphorus Hydrolase Pharmacokinetics and Immunogenicity are Improved by Branched dPEG®

Organophosphorus hydrolase  (OPH,EC 8.1.3.1), also known as Aryldialkylphosphatase, is a remarkably stable homodimeric enzyme that can detoxify organophosphate compounds. Organophosphate compounds are the basis of numerous pesticides (e.g., malathion) and chemical warfare weapons (e.g., sarin, VX). Organophosphates act by blocking the action of the enzyme acetylcholinesterase. Overuse and misuse of organophosphate pesticides are major causes of acute pesticide poisoning and death. See also here.

Boris N. Novikov and colleagues with the Department of Biochemistry and Biophysics at Texas A&M University, reported in the Journal of Controlled Release on the effects of modifying organophosphorus hydrolase (often abbreviated OPH) with linear and branched PEG derivatives. The group chose these PEG reagents because conjugates altered by PEGs see “their immunogenicity is reduced and the renal excretion is slowed considerably, leading to prolonged half-life, reduced side effects and increased treatment efficiency,” C.S. Fishburn, The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics, J. Pharm. Sci. 97 (2008) 4167–4183.

 

 dPEG® Reagents Modifying Organophosphorus Hydrolase

PEG derived conjugates, specifically discrete linear and branched PEGs, were used to help generate data on the biochemical, biophysical, and pharmacological properties or organophosphorus hydrolase. The discrete PEGs chosen were all terminated with a methoxy group at one end of the PEG linker and functionalized with an NHS ester on the other end of the linker to react with surface-accessible lysine residues, forming an amide bond between the PEG linker and organophosphorus hydrolase. The linear, discrete PEGs had spacing lengths of 16.4Å (PEG4), 30.8Å (PEG8), and 44.9Å (PEG12), while the branched, discrete PEG chosen is shown in Figure 1, below. All of the PEG linkers used were made by Quanta BioDesign Ltd. and purchased through Quanta BioDesign distributor Thermo Scientific (formerly Pierce).

 

PN10401, NHS-dPEG®-(m-dPEG®12)3, used to modify organophosphorus hydrolase

Figure 1: The branched discrete PEG used in this research to modify organophosphorus hydrolase.

 

Attaching the PEG linkers altered the biophysical properties of organophosphorus hydrolase. Specifically, the catalytic functionality (kcat) decreased for all PEGylated species, but the enzyme retained substantial activity of 30% - 60% depending on substrate. Moreover, the substrate affinities of the modified enzymes increased (thus, kM decreased), which meant that the overall catalytic efficiencies of the unmodified and modified enzymes were comparatively close.

 

Organophosphorus Hydrolase PEGylation Altered Pharmacokinetics and Immunogenicity

In animal testing, unmodified organophosphorus hydrolase had a circulated half-life of 0.86 hr and a mean residence time of 1.1 hr. PEGylation of the enzyme even with the smallest PEG (PEG4) increased the circulated half-life and mean residence time of the modified enzyme compared to the unmodified enzyme. PEGylation with the large branched PEG (Figure 1, above) resulted in a dramatically longer circulated half-life (32.5 hr) and mean residence time (46.7 hr). See Figure 2, below.

 

Figure 2: Amount of circulating organophosphorus hydrolase (unmodified vs PEGylated) remaining in bloodstream over time
Figure 2: Amount of circulating enzyme (unmodified vs PEGylated) remaining in bloodstream over time

 

Moreover, injection of unmodified organophosphorus  hydrolase into test animals caused formation of antibodies to the enzyme. Injection of the PEG-modified enzymes into test animals slightly reduced, but did not prevent, formation of antibodies to organophosphorus hydrolase. The differences in antibody formation between the linear PEG4, PEG8, and PEG12 were not statistically significant. By contrast, though, antibodies formed to the enzyme modified with the branched PEG12 (Figure 1) were significantly less compared to the unmodified enzyme. See Figure 3, below.

 

Figure 3: Antibodies formed to organophosphorus hydrolase, comparing unmodified and PEGylated enzyme
Figure 3: Antibodies formed to organophosphorus hydrolase, comparing unmodified and PEGylated enzyme

 

In their conclusions, Novikov, et al., observed,

“The ability of the PEG modifications to both prolong the residence time in the vascular system and to lower immunogenicity of the conjugates was shown to be directly correlated with mass of the attached polymer, with maximal effect achieved with the branched PEG12 ....”

They then suggested that “... it is reasonable to expect an enhanced circulatory residence of the bacterial enzyme (OPH) conjugated with PEG12 in ... humans.”

 

Quanta BioDesign’s Role in dPEG® Research and Manufacturing

Quanta BioDesign, Ltd. is the developer and leading innovator and manufacturer of discrete PEGylation reagents. We look constantly for new collaborations and opportunities for custom synthesis in creating new dPEG® products. Our customers’ ideas drive the creation of many new products and have given us many popular products. We scientists and Quanta BioDesign are committed to developing new dPEG® constructs for all types of applications including diagnostic, therapeutic, theranostic, and nanotechnology uses. All ideas are welcomed, and we look forward to helping your research by providing the PEGylation reagents necessary for your research and manufacturing needs, whether you need milligrams or multiple kilograms.

For information about any of the PEGylation reagents we make, custom synthesis, or to order products visit us at www.QuantaBioDesign.com.

 

References:

B.N. Novikov, et al., Improved pharmacokinetics and immunogenicity profile of organophosphorus hydrolase by chemical modification with polyethylene glycol, J. Control. Release (2010), doi:10.1016/j.jconrel.2010.06.003

C.S. Fishburn, The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics, J. Pharm. Sci. 97 (2008) 4167–4183

 

 Additional dPEG® PEGylation Reagents

Carboxyl-dPEG®₄-(m-dPEG®₄)₃

Carboxyl-dPEG®₄-(m-dPEG®₁₁)₃

Carboxyl-dPEG®₄-(m-dPEG®₂₄)₃

Carboxyl-dPEG®₄-(m-dPEG®₁₂)₃

Carboxyl-dPEG®₄ -(m-dPEG®₈)₃

NHS-dPEG®₄-( m-dPEG®₁₂)₃-ester

 

Adam Fulkert, B.S. – Received his B.S. in Chemistry from The Ohio State University in the autumn of 2011. Adam is a Process Development Chemist involved in process development and scale-up activities.

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