Targeting of N-(2-Hydroxypropyl)Methacrylamide Copolymer-Doxorubicin Conjugate to the Hepatocyte Galactose-Receptor in Mice: Visualisation and Quantification by Gamma Scintigraphy as a Basis for Clinical Targeting Studies

Mv, Pimm; Ac, Perkins; Duncan, Ruth; Ulbrich, Karel

doi:10.3109/10611869308996068

Cited by 40 publications

(12 citation statements)

References 15 publications

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“…As can be clearly seen, 3D CT-FMT realistically depicted probe accumulation in liver, kidney and bladder. Both absolute (%ID) and relative (organs-to-organ) values were relatively well in line with those reported in the literature for radiolabeled polymeric nanomedicines 12,34,[36][37][38][39] . Furthermore, as for tumors ( Figure 5), also the time-dependent trends in liver, kidney and bladder accumulation were in line with previous studies, with liver remaining relatively constant over time, and kidney and bladder decreasing 12,34,36 .…”

Section: Non-invasive Optical Imaging Of Nanomedicine Biodistributionsupporting

confidence: 88%

“…Taking previous results obtained with regard to the biodistribution of radiolabeled HPMA-based polymeric drug carriers into account, 12,34,[36][37][38][39] however, also 3D FMT did not properly reflect tumor and healthy organ accumulation. As exemplified by the lower panels in Figure 2B, apart from significant accumulation in tumors and some residual signal that could be allocated to the heart (i.e.…”

Section: Resultsmentioning

confidence: 77%

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Noninvasive Optical Imaging of Nanomedicine Biodistribution

et al. 2012

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Nanomedicines are submicrometer-sized carrier materials designed to improve the biodistribution of i.v. administered (chemo-) therapeutic agents. In recent years, ever more efforts in the nanomedicine field have employed optical imaging (OI) techniques to monitor biodistribution and target site accumulation. Thus far, however, the longitudinal assessment of nanomedicine biodistribution using OI has been impossible, due to limited light penetration (in case of 2D fluorescence reflectance imaging; FRI), and to the inability to accurately allocate fluorescent signals to non-superficial organs (in case of 3D fluorescence molecular tomography; FMT). Using a combination of high-resolution micro-computed tomography (μCT) and FMT, we have here set out to establish a hybrid imaging protocol for non-invasively visualizing and quantifying the accumulation of near-infrared fluorophore-labeled nanomedicines in tissues other than superficial tumors. To this end, HPMA-based polymeric drug carriers were labeled with Dy750, their biodistribution and tumor accumulation were analyzed using FMT, and the resulting data sets were fused with anatomical μCT data sets in which several different physiologically relevant organs were pre-segmented. The robustness of 3D organ segmentation was validated, and the results obtained using 3D CT-FMT were compared to those obtained upon standard 3D FMT and 2D FRI. Our findings convincingly demonstrate that combining anatomical μCT with molecular FMT facilitates the non-invasive assessment of nanomedicine biodistribution. KeywordsNanomedicine; Drug targeting; Biodistribution; FMT; FRI; CT Nanomedicines aim to deliver drugs and imaging agents more efficiently and more specifically to pathological sites. A significant amount of evidence has been obtained over the years exemplifying the superiority of nanomedicine formulations over free drugs, both at the preclinical and at the clinical level. [1][2][3][4][5] Prototypic examples of nanomedicine formulations are liposomes, polymers, micelles and nanoparticles. These submicrometersized carrier materials are designed to modulate the pharmacokinetics and the biodistribution of conjugated or entrapped (chemo-) therapeutic drugs. Upon intravenous (i.v.)

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Section: Non-invasive Optical Imaging Of Nanomedicine Biodistributionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 77%

Noninvasive Optical Imaging of Nanomedicine Biodistribution

et al. 2012

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“…Previous studies have shown that attachment of galactose or NAG facilitates hepatocyte targeting of a variety of uncharged, watersoluble polymers (36)(37)(38). We attached NAG to the polymersiRNA backbone through a CDM linkage to determine whether we could target the siRNA polyconjugate to liver hepatocytes after simple i.v.…”

Section: Resultsmentioning

confidence: 99%

Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes

Rozema

Lewis

Wakefield

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

619

624

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Achieving efficient in vivo delivery of siRNA to the appropriate target cell would be a major advance in the use of RNAi in gene function studies and as a therapeutic modality. Hepatocytes, the key parenchymal cells of the liver, are a particularly attractive target cell type for siRNA delivery given their central role in several infectious and metabolic disorders. We have developed a vehicle for the delivery of siRNA to hepatocytes both in vitro and in vivo, which we have named siRNA Dynamic PolyConjugates. Key features of the Dynamic PolyConjugate technology include a membrane-active polymer, the ability to reversibly mask the activity of this polymer until it reaches the acidic environment of endosomes, and the ability to target this modified polymer and its siRNA cargo specifically to hepatocytes in vivo after simple, low-pressure i.v. injection. Using this delivery technology, we demonstrate effective knockdown of two endogenous genes in mouse liver: apolipoprotein B (apoB) and peroxisome proliferator-activated receptor alpha (ppara). Knockdown of apoB resulted in clear phenotypic changes that included a significant reduction in serum cholesterol and increased fat accumulation in the liver, consistent with the known functions of apoB. Knockdown of ppara also resulted in a phenotype consistent with its known function, although with less penetrance than observed in apoB knockdown mice. Analyses of serum liver enzyme and cytokine levels in treated mice indicated that the siRNA Dynamic PolyConjugate was nontoxic and well tolerated.pH labile bonds ͉ nonviral siRNA delivery ͉ siRNA-polymer conjugates ͉ endosomolytic polymers

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“…[71] Preclinical studies have shown that this conjugate, referred to as PK2, delivers doxorubicin preferentially to the liver. [272][273][274] In an- other approach, the (6-maleimidocaproyl)hydrazone derivative of doxorubicin was coupled to a thiolated form of lactosaminated human albumin (L-HSA) ( Figure 26). [70,82,275] The resulting conjugate L-HSA-DOXO achieved very efficient targeting of the drug to the livers of treated mice, with doxorubicin concentrations reaching levels 7-20-fold higher than those raised in extrahepatic tissues.…”

Section: Receptor Targetingmentioning

confidence: 99%

Prodrug Strategies in Anticancer Chemotherapy

Kratz¹,

Müller²,

Ryppa³

et al. 2008

ChemMedChem

438

425

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The majority of clinically approved anticancer drugs are characterized by a narrow therapeutic window that results mainly from a high systemic toxicity of the drugs in combination with an evident lack of tumor selectivity. Besides the development of suitable galenic formulations such as liposomes or micelles, several promising prodrug approaches have been followed in the last decades with the aim of improving chemotherapy. In this review we elucidate the two main concepts that underlie the design of most anticancer prodrugs: drug targeting and controlled release of the drug at the tumor site. Consequently, active and passive targeting using tumor-specific ligands or macromolecular carriers are discussed as well as release strategies that are based on tumor-specific characteristics such as low pH or the expression of tumor-associated enzymes. Furthermore, other strategies such as ADEPT (antibody-directed enzyme prodrug therapy) and the design of self-eliminating structures are introduced. Chemical realization of prodrug approaches is illustrated by drug candidates that have or may have clinical importance.

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Targeting of N-(2-Hydroxypropyl)Methacrylamide Copolymer-Doxorubicin Conjugate to the Hepatocyte Galactose-Receptor in Mice: Visualisation and Quantification by Gamma Scintigraphy as a Basis for Clinical Targeting Studies

Cited by 40 publications

References 15 publications

Noninvasive Optical Imaging of Nanomedicine Biodistribution

Noninvasive Optical Imaging of Nanomedicine Biodistribution

Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes

Prodrug Strategies in Anticancer Chemotherapy

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