The polyethyleneglycol dilemma: advantage and disadvantage of PEGylation of liposomes for systemic genes and nucleic acids delivery to tumors.
01 Jun 2013-Biological & Pharmaceutical Bulletin (The Pharmaceutical Society of Japan)-Vol. 36, Iss: 6, pp 892-899
TL;DR: The development and applications of MEND are described, various strategies for overcoming the PEG dilemma based on the manipulation of both pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release are discussed and pH- sensitive liposomes using pH-sensitive lipids are described.
Abstract: Gene and nucleic acid therapy is expected to play a major role in the next generation of agents for cancer treatment. We have recently developed a multifunctional envelope-type nano device (MEND) for use as a novel nonviral gene delivery system. The modification of polyethyleneglycol (PEG), i.e., PEGylation, is a useful method for achieving a longer circulation time for the delivery of MEND to a tumor via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity of the delivery system. For successful nucleic acid delivery for cancer treatment, the crucial problem associated with the use of PEG, i.e., the "PEG dilemma" must be resolved. In this review, we describe the development and applications of MEND and discuss various strategies for overcoming the PEG dilemma based on the manipulation of both pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release. To increase cellular uptake, target ligands including proteins, peptides, antibodies and aptamers that recognize molecules specifically expressed on tumors are first introduced. Second, cleavable PEG systems are described. The cleavage of PEG from carriers was achieved in response to the intracellular environment as well as the tumor microenvironment, which improvs cellular uptake and endosomal escape. Then, endosomal fusogenic peptides are discussed. Finally, pH-sensitive liposomes using pH-sensitive lipids are described.
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TL;DR: The history of the development of PEGylated nanoparticle formulations for systemic administration is described, including how factors such as PEG molecular weight, PEG surface density, nanoparticle core properties, and repeated administration impact circulation time.
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Cites background from "The polyethyleneglycol dilemma: adv..."
...However, PEGylation often compromises the ability of NPs to escape endosomes, which is a required step prior to entering the cell cytoplasm [186]....
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...The “stealth” property endowed by NP PEGylation that minimizes undesired phagocytic clearance can also interfere with the ability of NP to interact with and be internalized by target cells [186, 187]....
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Abstract: Polymeric micelles are demonstrating high potential as nanomedicines capable of controlling the distribution and function of loaded bioactive agents in the body, effectively overcoming biological barriers, and various formulations are engaged in intensive preclinical and clinical testing. This Review focuses on polymeric micelles assembled through multimolecular interactions between block copolymers and the loaded drugs, proteins, or nucleic acids as translationable nanomedicines. The aspects involved in the design of successful micellar carriers are described in detail on the basis of the type of polymer/payload interaction, as well as the interplay of micelles with the biological interface, emphasizing on the chemistry and engineering of the block copolymers. By shaping these features, polymeric micelles have been propitious for delivering a wide range of therapeutics through effective sensing of targets in the body and adjustment of their properties in response to particular stimuli, modulating the act...
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Cites background from "The polyethyleneglycol dilemma: adv..."
...Acid labile bond cleavage for PEG-detachment Despite the success of ‘stealth’ systems in achieving stability and long-circulation, the major drawbacks of these nanocarriers are poor cellular uptake and slow drug release from endosomes [50, 51], resulting in low bioavailability in the target and compromised drug efficacy [52, 53], known as the PEG dilemma....
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TL;DR: A State-of-the-art use of PEG in therapeutic applications, its clinical status and commercial use is summarized, and toxicities related to different PEG grades and related impurities are discussed in this review.
Abstract: Introduction: Polyethylene glycol (PEG) is a polymer of choice in drug delivery systems. This USFDA-approved polymer is popular due to its tunable properties and well-established safety profile: prime requisites considered during the selection of any excipient in formulation development.Areas covered: The unique properties and applications of PEG have been discussed at length in the existing literature. However, a proper guidance on selection of PEG grade to cater to one’s purpose is lacking. This article provides preliminary guidelines to formulators on selection of appropriate PEG grade, typically based on its physico-chemical properties and role-based functional application in pharmaceuticals. It should be noted that the aim article is not to deep dive in each application area.Expert opinion: Guidance on PEG application and grade of choice is lacking in the available literature. The authors have discussed and provided guidance to formulators on the appropriate PEG grade selection for particular...
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...between them is requisite to maintain efficacy.[103]...
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