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Pharmaceutics
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Pegylation in Drug Delivery Applications
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Pegylation in Drug Delivery Applications

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (30 July 2022) | Viewed by 16095

Special Issue Editor

Prof. Dr. Carlota O. Rangel-Yagui

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Guest Editor
Department of Pharmaceutical and Biochemical Technology University of São Paulo, São Paulo, Brazil
Interests: pegylation of protein drugs; nanobiotechnology; self-aggregated nanostructures for drug delivery; polymersomes; polymeric micelles; PEG-based nanostructures; protein purification
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pegylation in the pharmaceutical field is understood as the covalent or non-covalent attachment of PEG (polyethylene glycol) chains to a functional molecules or delivery systems, such as nanoparticles. This strategy is very effective in improving pharmacokinetics and reducing toxicity; it has become the main approach to overcome the limitations of biological drugs and to increase the efficiency of drug delivery in general. Pegylation might result in higher solubility in water, decreased renal clearance, lower aggregation, opsonization and phagocytosis, as well as protection against in vivo degradation. Overall, it may prolong systemic circulation time. Today, several pegylated drugs and nanostructures are approved and, in spite of recent concerns regarding the immunogenicity of PEG, no alternative polymer has proven to be better in reducing protein drugs immunogenicity. In this issue, we will explore the versatility of this technology in improving drug delivery, including the principles and peculiarities of different applications, as well as novel trends.

Prof. Dr. Carlota O. Rangel Yagui
Guest Editor

Manuscript Submission Information

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Keywords

  • pegylated nanoparticles for drug delivery
  • pegylation of protein drugs
  • pegylation of small molecule drugs
  • pegylated liposomes for drug delivery
  • pegylation of therapeutic antibodies
  • pegylation and immunogenicity
  • novel pegylation reactions for the delivery of drugs
  • pegylation and drug pharmacokinetics

Published Papers (6 papers)

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Research

20 pages, 3525 KiB  
Article
PEG Conjugated Zein Nanoparticles for In Vivo Use
by Courtney van Ballegooie, Nicole Wretham, Tanya Ren, Ioana-Mihaela Popescu, Donald T. Yapp and Marcel B. Bally
Pharmaceutics 2022, 14(9), 1831; https://doi.org/10.3390/pharmaceutics14091831 - 31 Aug 2022
Cited by 2 | Viewed by 1668
Abstract
Zein can be utilized to form nanoscale particles for drug delivery applications. Despite the ease of synthesis, these particles often aggregate when exposed to physiologically relevant conditions (e.g., pH and salt concentrations). This instability has prevented their further development in applications requiring intravenous [...] Read more.
Zein can be utilized to form nanoscale particles for drug delivery applications. Despite the ease of synthesis, these particles often aggregate when exposed to physiologically relevant conditions (e.g., pH and salt concentrations). This instability has prevented their further development in applications requiring intravenous administration. To mitigate this colloidal instability, this research explored Zein nanoparticles (NP)s that were modified with polyethylene glycol (PEG) either through functionalized PEG pre- or post-NP formation. The results suggest that the pre-functionalization of the Zein using N-hydroxysuccinimide ester terminated PEG is the method of choice for synthesizing Zein NPs with conjugated PEG (Zein:PEG-Zein NPs). Zein:PEG-Zein NPs formed using this method displayed excellent stability in physiologically relevant conditions over 72 h and were stable at 4 °C for at least 3 months. When the NPs were cultured with cells for 72 h, no cytotoxicity or early signs of apoptosis were identified. Cellular uptake of the Zein:PEG-Zein NPs did not seem to be impacted by the amount of PEG incorporated in the NP but were concentration-, time-, and temperature-dependent. The lowest percent, stable Zein:PEG-Zein NP formulation (80% unmodified Zein and 20% PEG-modified Zein) induced no observable toxicity over 14 days in CD-1 mice dosed at 70 mg/kg via the tail vein. However, repeat dose pharmacokinetic (PK) studies demonstrated that following the first dose, the second dose caused health issues that required euthanasia shortly after administration. For those animals that survived, there was faster plasma elimination of the Zein:PEG-Zein NPs. Despite this, the Zein:PEG-Zein NPs represent a significantly improved formulation approach, one that displays a long circulation half-life and is suitable for single-use administration. Repeat dose applications will require additional methods to silence the immune response that is generated when using these NPs intravenously. Full article
(This article belongs to the Special Issue Pegylation in Drug Delivery Applications)
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18 pages, 6813 KiB  
Article
Peg-Grafted Liposomes for L-Asparaginase Encapsulation
by Marina de Souza Guimarães, Jorge Javier Muso Cachumba, Cecilia Zorzi Bueno, Karin Mariana Torres-Obreque, Grace Verónica Ruiz Lara, Gisele Monteiro, Leandro Ramos Souza Barbosa, Adalberto Pessoa, Jr. and Carlota de Oliveira Rangel-Yagui
Pharmaceutics 2022, 14(9), 1819; https://doi.org/10.3390/pharmaceutics14091819 - 29 Aug 2022
Cited by 8 | Viewed by 2321
Abstract
L-asparaginase (ASNase) is an important biological drug used to treat Acute Lymphoblastic Leukemia (ALL). It catalyzes the hydrolysis of L-asparagine (Asn) in the bloodstream and, since ALL cells cannot synthesize Asn, protein synthesis is impaired leading to apoptosis. Despite its therapeutic importance, ASNase [...] Read more.
L-asparaginase (ASNase) is an important biological drug used to treat Acute Lymphoblastic Leukemia (ALL). It catalyzes the hydrolysis of L-asparagine (Asn) in the bloodstream and, since ALL cells cannot synthesize Asn, protein synthesis is impaired leading to apoptosis. Despite its therapeutic importance, ASNase treatment is associated to side effects, mainly hypersensitivity and immunogenicity. Furthermore, degradation by plasma proteases and immunogenicity shortens the enzyme half-life. Encapsulation of ASNase in liposomes, nanostructures formed by the self-aggregation of phospholipids, is an attractive alternative to protect the enzyme from plasma proteases and enhance pharmacokinetics profile. In addition, PEGylation might prolong the in vivo circulation of liposomes owing to the spherical shielding conferred by the polyethylene (PEG) corona around the nanostructures. In this paper, ASNase was encapsulated in liposomal formulations composed by 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) containing or not different concentrations of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [methoxy (polyethylene glycol)-2000] (DSPE-PEG). Nanostructures of approximately 142–202 nm of diameter and polydispersity index (PDI) of 0.069 to 0.190 were obtained and the vesicular shape confirmed by Transmission Electron Microscopy (TEM and cryo-TEM). The encapsulation efficiency (%EE) varied from 10% to 16%. All formulations presented activity in contact with ASNase substrate, indicating the liposomes permeability to Asn and/or enzyme adsorption at the nanostructures’ surface; the highest activity was observed for DMPC/DSPE-PEG 10%. Finally, we investigated the activity against the Molt 4 leukemic cell line and found a lower IC50 for the DMPC/DSPE-PEG 10% formulation in comparison to the free enzyme, indicating our system could provide in vivo activity while protecting the enzyme from immune system recognition and proteases degradation. Full article
(This article belongs to the Special Issue Pegylation in Drug Delivery Applications)
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15 pages, 2682 KiB  
Article
Formulation of Amphotericin B in PEGylated Liposomes for Improved Treatment of Cutaneous Leishmaniasis by Parenteral and Oral Routes
by Guilherme S. Ramos, Virgínia M. R. Vallejos, Gabriel S. M. Borges, Raquel M. Almeida, Izabela M. Alves, Marta M. G. Aguiar, Christian Fernandes, Pedro P. G. Guimarães, Ricardo T. Fujiwara, Philippe M. Loiseau, Lucas A. M. Ferreira and Frédéric Frézard
Pharmaceutics 2022, 14(5), 989; https://doi.org/10.3390/pharmaceutics14050989 - 05 May 2022
Cited by 14 | Viewed by 3011
Abstract
Liposomal amphotericin B (AmB) or AmBisome® is the most effective and safe therapeutic agent for visceral leishmaniasis (VL), but its clinical efficacy is limited in cutaneous leishmaniasis (CL) and HIV/VL co-infection. The aim of this work was to develop a formulation of [...] Read more.
Liposomal amphotericin B (AmB) or AmBisome® is the most effective and safe therapeutic agent for visceral leishmaniasis (VL), but its clinical efficacy is limited in cutaneous leishmaniasis (CL) and HIV/VL co-infection. The aim of this work was to develop a formulation of AmB in PEGylated liposomes and compare its efficacy to AmBisome® in a murine model of CL. Formulations of AmB in conventional and PEGylated liposomes were characterized for particle size and morphology, drug encapsulation efficiency and aggregation state. Those were compared to AmBisome® in Leishmania amazonensis-infected BALB/c mice for their effects on the lesion size growth and parasite load. The conventional and PEGylated formulations showed vesicles with 100–130 nm diameter and low polydispersity, incorporating more than 95% of AmB under the non-aggregated form. Following parenteral administration in the murine model of CL, the PEGylated formulation of AmB significantly reduced the lesion size growth and parasite load, in comparison to control groups, in contrast to conventional liposomal AmB. The PEGylated formulation of AmB was also effective when given by oral route on a 2-day regimen. This work reports for the first time that PEGylated liposomal AmB can improve the treatment of experimental cutaneous leishmaniasis by both parenteral and oral routes. Full article
(This article belongs to the Special Issue Pegylation in Drug Delivery Applications)
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13 pages, 3187 KiB  
Article
PEGylated versus Non-PEGylated pH-Sensitive Liposomes: New Insights from a Comparative Antitumor Activity Study
by Shirleide Santos Nunes, Juliana de Oliveira Silva, Renata Salgado Fernandes, Sued Eustaquio Mendes Miranda, Elaine Amaral Leite, Marcelo Alexandre de Farias, Rodrigo Villares Portugal, Geovanni Dantas Cassali, Danyelle M. Townsend, Mônica Cristina Oliveira and André Luís Branco de Barros
Pharmaceutics 2022, 14(2), 272; https://doi.org/10.3390/pharmaceutics14020272 - 24 Jan 2022
Cited by 15 | Viewed by 2809
Abstract
PEGylated liposomes are largely studied as long-circulating drug delivery systems. Nevertheless, the addition of PEG can result in reduced interactions between liposomes and cells, hindering liposomal internalization into target cells. The presence of PEG on the surface of pH-sensitive liposomes is not advantageous [...] Read more.
PEGylated liposomes are largely studied as long-circulating drug delivery systems. Nevertheless, the addition of PEG can result in reduced interactions between liposomes and cells, hindering liposomal internalization into target cells. The presence of PEG on the surface of pH-sensitive liposomes is not advantageous in terms of biodistribution and tumor uptake, raising the question of whether the indiscriminate use of PEG benefits the formulation. In this study, two doxorubicin-loaded pH-sensitive liposomal formulations, PEGylated (Lip2000-DOX) or non-PEGylated (Lip-DOX), were prepared and characterized. Overall, the PEGylated and non-PEGylated liposomes showed no differences in size or morphology in Cryo-TEM image analysis. Specifically, DLS analysis showed a mean diameter of 140 nm, PDI lower than 0.2, and zeta potential close to neutrality. Both formulations showed an EP higher than 90%. With respect to drug delivery, Lip-DOX had better cellular uptake than Lip2000-DOX, suggesting that the presence of PEG reduced the amount of intracellular DOX accumulation. The antitumor activities of free-DOX and both liposomal formulations were evaluated in 4T1 breast tumor-bearing BALB/c mice. The results showed that Lip-DOX was more effective in controlling tumor growth than other groups, inhibiting tumor growth by 60.4%. Histological lung analysis confirmed that none of the animals in the Lip-DOX group had metastatic foci. These results support that pH-sensitive liposomes have interesting antitumor properties and may produce important outcomes without PEG. Full article
(This article belongs to the Special Issue Pegylation in Drug Delivery Applications)
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15 pages, 1768 KiB  
Article
Therapeutic Potential of Injectable Nano-Mupirocin Liposomes for Infections Involving Multidrug-Resistant Bacteria
by Ahuva Cern, Yaelle Bavli, Atara Hod, Daniel Zilbersheid, Shazad Mushtaq, Ayelet Michael-Gayego, Dinorah Barasch, Yael Feinstein Rotkopf, Allon E. Moses, David M. Livermore and Yechezkel Barenholz
Pharmaceutics 2021, 13(12), 2186; https://doi.org/10.3390/pharmaceutics13122186 - 17 Dec 2021
Cited by 5 | Viewed by 2979
Abstract
Antibiotic resistance is a global health threat. There are a few antibiotics under development, and even fewer with new modes of action and no cross-resistance to established antibiotics. Accordingly, reformulation of old antibiotics to overcome resistance is attractive. Nano-mupirocin is a PEGylated nano-liposomal [...] Read more.
Antibiotic resistance is a global health threat. There are a few antibiotics under development, and even fewer with new modes of action and no cross-resistance to established antibiotics. Accordingly, reformulation of old antibiotics to overcome resistance is attractive. Nano-mupirocin is a PEGylated nano-liposomal formulation of mupirocin, potentially enabling parenteral use in deep infections, as previously demonstrated in several animal models. Here, we describe extensive in vitro profiling of mupirocin and Nano-mupirocin and correlate the resulting MIC data with the pharmacokinetic profiles seen for Nano-mupirocin in a rat model. Nano-mupirocin showed no cross-resistance with other antibiotics and retained full activity against vancomycin-, daptomycin-, linezolid- and methicillin- resistant Staphylococcus aureus, against vancomycin-resistant Enterococcus faecium, and cephalosporin-resistant Neisseria gonorrhoeae. Following Nano-mupirocin injection to rats, plasma levels greatly exceeded relevant MICs for >24 h, and a biodistribution study in mice showed that mupirocin concentrations in vaginal secretions greatly exceeded the MIC90 for N. gonorrhoeae (0.03 µg/mL) for >24 h. In summary, Nano-mupirocin has excellent potential for treatment of several infection types involving multiresistant bacteria. It has the concomitant benefits from utilizing an established antibiotic and liposomes of the same size and lipid composition as Doxil®, an anticancer drug product now used for the treatment of over 700,000 patients globally. Full article
(This article belongs to the Special Issue Pegylation in Drug Delivery Applications)
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12 pages, 2492 KiB  
Article
PEGylated Liposomes Remotely Loaded with the Combination of Doxorubicin, Quinine, and Indocyanine Green Enable Successful Treatment of Multidrug-Resistant Tumors
by Emma Grabarnick (Portnoy), Alexander V. Andriyanov, Hadas Han, Sara Eyal and Yechezkel Barenholz
Pharmaceutics 2021, 13(12), 2181; https://doi.org/10.3390/pharmaceutics13122181 - 17 Dec 2021
Cited by 13 | Viewed by 2419
Abstract
Multidrug resistance (MDR) of cancer cells remains a major obstacle to favorable outcomes of treatment with many drugs, including doxorubicin. Most of the clinical trials failed to demonstrate the benefit of the drug efflux transporter P-glycoprotein (P-gp) inhibitors to circumvent P-gp-mediated drug resistance [...] Read more.
Multidrug resistance (MDR) of cancer cells remains a major obstacle to favorable outcomes of treatment with many drugs, including doxorubicin. Most of the clinical trials failed to demonstrate the benefit of the drug efflux transporter P-glycoprotein (P-gp) inhibitors to circumvent P-gp-mediated drug resistance in vivo. The present study explored the therapeutic potential of combined treatment with liposomal doxorubicin, P-gp inhibitor quinine, and the photodynamic therapy (PDT) using indocyanine green (ICG) in the adenocarcinoma drug-resistant tumor model. Liposomes were actively co-remotely loaded with doxorubicin and quinine, and ICG was passively adsorbed. The liposomes were characterized by differential scanning calorimetry (DSC) and cryogenic transmission microscopy (Cryo-TEM). We found that quinine impaired the crystalline structure of doxorubicin. In vitro, treatment with single agents themselves was insufficient to inhibit the growth of HT-29 MDR1 cells. However, pegylated liposomal doxorubicin and quinine (PLDQ) significantly diminished HT-29 MDR1 cell survival. Furthermore, survival inhibition intensified by the addition of ICG to the PLDQ (ICG + PLDQ). In vivo, ICG + PLDQ significantly decreased tumor growth when combined with tumor irradiation with NIR light (** p < 0.01). ICG + PLDQ + irradiation was superior to single treatments or combinational treatments without irradiation. These findings suggest that ICG + PLDQ can overcome P-gp-mediated MDR in cancer cells. Full article
(This article belongs to the Special Issue Pegylation in Drug Delivery Applications)
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