Drug Delivery by an Enzyme‐Mediated Cyclization of a Lipid Prodrug with Unique Bilayer‐Formation Properties

Linderoth, Lars; Peters, Günther H.J.; Madsen, Robert; Andresen, Thomas Lars

doi:10.1002/ange.200805241

Cited by 21 publications

(12 citation statements)

References 24 publications

(6 reference statements)

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“…They further applied their discovery to create a lipid-capsaicin prodrug. The prodrug was able to form small unilamellar vesicle (SUV), and the SUV was stable in the bloodstream, but could specifically respond to PLA2 to release the covalently attached anticancer drug by PLA2-promoted intramolecular cyclization [99]. …”

Section: Enzymatic Activationmentioning

confidence: 99%

Stimuli-responsive nanoparticles for targeting the tumor microenvironment

Lane

Nie

2015

Journal of Controlled Release

297

161

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One of the most challenging and clinically important goals in nanomedicine is to deliver imaging and therapeutic agents to solid tumors. Here we discuss the recent design and development of stimuli-responsive smart nanoparticles for targeting the common attributes of solid tumors such as their acidic and hypoxic microenvironments. This class of stimuli-responsive nanoparticles is inactive during blood circulation and under normal physiological conditions, but is activated by acidic pH, enzymatic up-regulation, or hypoxia once they extravasate into the tumor microenvironment. The nanoparticles are often designed to first “navigate” the body’s vascular system, “dock” at the tumor sites, and then “activate” for action inside the tumor interstitial space. They combine the favorable biodistribution and pharmacokinetic properties of nanodelivery vehicles and the rapid diffusion and penetration properties of smaller drug cargos. By targeting the broad tumor habitats rather than tumor-specific receptors, this strategy has the potential to overcome the tumor heterogeneity problem and could be used to design diagnostic and therapeutic nanoparticles for a broad range of solid tumors.

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Section: Enzymatic Activationmentioning

confidence: 99%

Stimuli-responsive nanoparticles for targeting the tumor microenvironment

Lane

Nie

2015

Journal of Controlled Release

297

161

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“…Although the concept of Sn2 phospholipid prodrugs had never been considered for targeted drug delivery associated with CFDD, precedence for the formation of Sn2 phospholipid prodrugs was initially reported by David Thompson et al 37 in the context of triggered release mechanisms. Later Thomas Lars Andresen and colleagues [38][39][40][41][42][43][44][45][46][47][48] pursued an approach to deliver chemotherapeutics as Sn2 prodrugs via untargeted liposomes. They anticipated that increased liberation of phospholipases by cancers would trigger release of the compounds in the proximity of a tumor increasing the local drug bioavailability.…”

Section: Phospholipid Sn2 Prodrugs With Liposomesmentioning

confidence: 99%

Contact‐facilitated drug delivery with Sn2 lipase labile prodrugs optimize targeted lipid nanoparticle drug delivery

Pan

Pham

Weilbaecher

et al. 2015

WIREs Nanomed Nanobiotechnol

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Sn2 lipase labile phospholipid prodrugs in conjunction with contact-facilitated drug delivery offer an important advancement in Nanomedicine. Many drugs incorporated into nanosystems, targeted or not, are substantially lost during circulation to the target. However, favorably altering the pharmacokinetics and volume of distribution of systemic drug delivery can offer greater efficacy with lower toxicity, leading to new prolonged-release nanoexcipients. However, the concept of achieving Paul Erhlich's inspired vision of a ‘magic bullet’ to treat disease has been largely unrealized due to unstable nanomedicines, nanosystems achieving low drug delivery to target cells, poor intracellular bioavailability of endocytosed nanoparticle payloads, and the substantial biological barriers of extravascular particle penetration into pathological sites. As shown here, Sn2 phospholipid prodrugs in conjunction with contact-facilitated drug delivery prevent premature drug diffusional loss during circulation and increase target cell bioavailability. The Sn2 phospholipid prodrug approach applies equally well for vascular constrained lipid-encapsulated particles and micelles the size of proteins that penetrate through naturally fenestrated endothelium in the bone marrow or thin-walled venules of an inflamed microcirculation. At one time Nanomedicine was considered a ‘Grail Quest’ by its loyal opposition and even many in the field adsorbing the pains of a long-learning curve about human biology and particles. However, Nanomedicine with innovations like Sn2 phospholipid prodrugs has finally made ‘made the turn’ toward meaningful translational success.

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“…However, thioester hydrolysis by the enzyme occurred at a substantially lower rate than the catalytic hydrolysis of natural substrate (Balet et al, 1988; Reynolds et al, 1991). In addition, subsequent research indicated that the PLA 2 -catalyzed thioester hydrolysis is likely to proceed via a different reaction mechanism (Linderoth et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Activity-based targeting of secretory phospholipase A2 enzymes: A fatty-acid-binding-protein assisted approach

Keshavarz

Zelaya

Singh

et al. 2017

Chemistry and Physics of Lipids

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Syntheses and enzymological characterization of fluorogenic substrate probes targeting secretory phospholipase A2 (sPLA2) for detection and quantitative assays are presented. Three fluorogenic phosphatidylcholine analogs PC-1, PC-2, and PC-3 each containing the duo of 7-mercapto-4-methyl-coumarin fluorophore and 2,4-dinitroanaline quencher on either tail were synthesized from (R)-3-amino-1,2-propanediol and R-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol. These small reporter groups are advantageous in preserving natural membrane integrity. Phosphocholine was incorporated into the sn-3 position of the glycerol backbone. Acyl amino group at the sn-1 position in PC-1 and PC-2 is meant to block sPLA1. The sn-1 and sn-2 positions of the glycerol backbone in PC-1 have a quencher terminated 12-carbon chain and fluorophore terminated 11-carbon chain respectively. PC-2 has a quencher terminated 3-carbon chain at the sn-2 and chain terminating fluorescent reporter at the sn-1 positions. PC-3 resembles PC-1 except for an ester instead of amide at the sn-1 position, because of which it is more similar to natural phospholipids than PC-1. It was designed to elucidate the effect of replacing the ester group with amide by comparing its hydrolysis rate with that of PC-1. Design principles apply to synthesis of other labeled phospholipids. Enzymological characterization using bee-venom sPLA2 was performed by a fatty-acid-binding-protein fluorescence assay and by pH-Stat method in which the amount of fatty acid released by hydrolysis is given by the amount of base required to maintain a constant pH of 8.0. Hydrolytic activity toward PC-1 and PC-3 were each about 238 ± 25 μmol/mg/min and 537 μmol/mg/min on unmodified phospholipid. Ester to amide change did not affect hydrolysis rates. Activity toward PC-2 was about 45-μmol/mg/min. PC-1 and PC-3 show potential for targeted real-time spectrophotometric assay of sPLA2.

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Drug Delivery by an Enzyme‐Mediated Cyclization of a Lipid Prodrug with Unique Bilayer‐Formation Properties

Cited by 21 publications

References 24 publications

Stimuli-responsive nanoparticles for targeting the tumor microenvironment

Stimuli-responsive nanoparticles for targeting the tumor microenvironment

Contact‐facilitated drug delivery with Sn2 lipase labile prodrugs optimize targeted lipid nanoparticle drug delivery

Activity-based targeting of secretory phospholipase A2 enzymes: A fatty-acid-binding-protein assisted approach

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