PEGylated Proteins as Cancer Therapeutics

Morpurgo, Margherita; Pasut, Gianfranco; Veronese, Francesco M.

doi:10.1142/9781860948039_0005

Cited by 3 publications

(2 citation statements)

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“…The issues affecting drug delivery devices is underscored by the lack of nanocarriers approved by the FDA. The short list of polymers approved for cancer therapy in the U.S. includes Gliadel © , a poly(anhydride) implantable wafer approved for glioblastoma, [9] and a number of PEGylated proteins [10] with Zinostatin stimalmer © (SMANCS) approved in Japan [11]. The first two of these therapeutics are not considered nanomedicines because Gliadel © is not a nanocarrier and PEGylated proteins are nanosized prior to PEGylation.…”

Section: Small Molecule Drugs Vs Nanomedicinesmentioning

confidence: 99%

Cancer nanomedicines: So many papers and so few drugs!

Venditto

Szoka

2013

Advanced Drug Delivery Reviews

480

327

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This review identifies a timeline to nanomedicine anticancer drug approval using the business model of inventors, innovators and imitators. By evaluating the publication record of nanomedicine cancer therapeutics we identified a trend of very few publications prior to FDA approval. We first enumerated the publications related to cancer involving polymers, liposomes or monoclonal antibodies and determined the number of citations per publication as well as the number of published clinical trials amongst the publications. Combining these data with the development of specific nanomedicines, we are able to identify an invention phase consisting of seminal papers in basic science necessary for the development of a specific nanomedicine. The innovation phase includes the first report, the development and the clinical trials involving that nanomedicine. Finally, the imitation phase begins after approval when others ride the wave of success by using the same formulation for new drugs or using the same drug to validate other nanomedicines. We then focused our analysis on nanomedicines containing camptothecin derivatives, which are not yet approved including two polymers considered innovations and one liposomal formulation in the imitation phase. The conclusion that may be drawn from the analysis of the camptothecins is that approved drugs reformulated in polymeric and liposomal cancer nanomedicines have a more difficult time navigating through the approval process than the parent molecule. This is probably due to the fact that for most currently approved drugs, reformulating them in a nanocarrier provides a small increase in performance that large pharmaceutical companies do not consider being worth the time, effort and expense of development. It also appears that drug carriers have a more difficult path through the clinic than monoclonal antibodies. The added complexity of nanocarriers also deters their use to deliver new molecular entities. Thus, the new drug candidates that might be most improved by drug delivery in nanocarriers are not formulated in this fashion.

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Section: Small Molecule Drugs Vs Nanomedicinesmentioning

confidence: 99%

Cancer nanomedicines: So many papers and so few drugs!

Venditto

Szoka

2013

Advanced Drug Delivery Reviews

480

327

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“…For example, in the case of proteins, an excessive amount can impair the biological activity; on the other hand, if the amount is too low, it may not be sufficient to improve the pharmacokinetic or pharmacodynamic properties of either proteins or nanoparticles or to prevent them from nonspecific interactions. Therefore, the amount of PEG, the size and shape of the polymer, as well as the chemistry of conjugation are all important variables that need to be optimized − .…”

Section: Introductionmentioning

confidence: 99%

Optimized Avidin Nucleic Acid Nanoassemblies by a Tailored PEGylation Strategy and Their Application as Molecular Amplifiers in Detection

Pignatto

Realdon²,

Morpurgo³

2010

Bioconjugate Chem.

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Avidin was recently found to display the ability to interact with high affinity with nucleic acids. In this work, we investigated how this property is affected by the protein modification with poly(ethylene glycol) (PEG). More precisely, we studied the influence of the size and geometry of the polymer and of the mode of anchorage to the protein surface. To this end, we synthesized five PEG derivatives capable of PEGylating avidin either through covalent attachment to its lysine primary amines or by exploiting its biotin binding pockets. Several differently PEGylated avidin derivatives were then obtained, which were later tested for their affinity for plasmid DNA by means of the electrophoretic mobility assay. The results show that covalent PEGylation reduces the affinity for DNA in a dose-dependent manner, whereas PEG anchoring through the biotin binding sites does not, even when bulky and high MW biotin-PEG derivatives are used. We then investigated how the size and molecular weight of the biotin-PEG affects the solubility and stability of avidin-nucleic acid nanoassemblies in physiological buffer. Among the biotin-PEG derivatives synthesized in this work, the branched forms were more efficient in protecting particle surface and preventing their aggregation. Full nanoparticle solubility was achieved by saturating 30% of the biotin binding sites with a 2 x 5 kDa branched derivative. the optimized avidin nucleic acid nanoassemblies (ANANAS) were employed in a model analytical test where they showed at least 40-fold higher efficiency than monomeric avidin in recognizing biotinylated surface immobilized IgGs. The results pave the way toward the application of this novel nanosystem in biomedicine.

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