Antibody‐mediated targeting of liposomes to red cells in vivo

Singhal, Arun; Gupta, C. M.

doi:10.1016/0014-5793(86)80632-9

Cited by 44 publications

(18 citation statements)

References 21 publications

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“…5 C and D). Previous work has shown that the plasma half-lives of liposomes and ovalbumin can be extended via fusion to anti-RBC antibodies (39) or peptides (40). Our molecule exhibited a similarly extended terminal plasma half-life, which was nearly twice as long in huGYPA transgenic mice compared with nontransgenic mice (28.3 h vs. 15.5 h) (Fig.…”

Section: Discussionmentioning

confidence: 49%

Targeted erythropoietin selectively stimulates red blood cell expansion in vivo

Burrill

Vernet

Collins

et al. 2016

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

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The design of cell-targeted protein therapeutics can be informed by natural protein-protein interactions that use cooperative physical contacts to achieve cell type specificity. Here we applied this approach in vivo to the anemia drug erythropoietin (EPO), to direct its activity to EPO receptors (EPO-Rs) on red blood cell (RBC) precursors and prevent interaction with EPO-Rs on nonerythroid cells, such as platelets. Our engineered EPO molecule was mutated to weaken its affinity for EPO-R, but its avidity for RBC precursors was rescued via tethering to an antibody fragment that specifically binds the human RBC marker glycophorin A (huGYPA). We systematically tested the impact of these engineering steps on in vivo markers of efficacy, side effects, and pharmacokinetics. huGYPA transgenic mice dosed with targeted EPO exhibited elevated RBC levels, with only minimal platelet effects. This in vivo selectivity depended on the weakening EPO mutation, fusion to the RBC-specific antibody, and expression of huGYPA. The terminal plasma half-life of targeted EPO was ∼28.3 h in transgenic mice vs. ∼15.5 h in nontransgenic mice, indicating that huGYPA on mature RBCs acted as a significant drug sink but did not inhibit efficacy. In a therapeutic context, our targeting approach may allow higher restorative doses of EPO without platelet-mediated side effects, and also may improve drug pharmacokinetics. These results demonstrate how rational drug design can improve in vivo specificity, with potential application to diverse protein therapeutics.protein engineering | drug targeting | platelet | scFv

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Section: Discussionmentioning

confidence: 49%

Targeted erythropoietin selectively stimulates red blood cell expansion in vivo

Burrill

Vernet

Collins

et al. 2016

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

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“…Given this scarcity of adequate antigens exposed on pRBCs, essential parameters that will be determinant in the capacity of iLPs to recognize and bind target cells are a careful selection of sufficiently specific antibodies, the way they are crosslinked to lipids, and their numbers on the liposome surface. Since RBCs have very poor endocytic processes [17], once iLPs are docked to them delivery of cargo into the cell has been proposed to occur through a membrane fusion process [7,10,18,19]. Nevertheless, considering the lack of strong evidence and the poor characterization of this fusion process using RBCs and pRBCs as targeted cells, alternative mechanisms of interaction should be considered.…”

Section: Introductionmentioning

confidence: 96%

“…Liposomal nanovectors bearing cell-specific antibodies on their surfaces (immunoliposomes, iLPs) have been widely considered as chemotherapeutic drug carriers due to their non-toxic and biodegradable character [6], but they have not progressed yet towards a working strategy for malaria therapeutics. Pioneering assays to treat Plasmodium berghei infections in mice focused on the encapsulation of the antimalarial drug chloroquine into liposomes (LPs) and iLPs functionalized with antibodies against RBCs and pRBCs [7][8][9]. Drug efficacy was significantly improved upon encapsulation, especially when targeted towards pRBCs, and after treatment with iLPs, mice exhibited lower parasitemias and longer survival times even with drug-resistant strains.…”

Section: Introductionmentioning

confidence: 99%

Immunoliposome-mediated drug delivery to Plasmodium -infected and non-infected red blood cells as a dual therapeutic/prophylactic antimalarial strategy

Moles

Urbán

Jiménez-Dı́az

et al. 2015

Journal of Controlled Release

112

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“…Studies have shown that the covalent attachment of antibodies to Ls specifically enhanced their binding to rat erythrocytes in vivo and reduced their uptake by the liver and therefore can be used to target antimalarials to erythrocytes [146,310,311]. MAb F10-bearing Ls containing CQ were produced and its efficacy was evaluated in mice infected with CQ-susceptible or CQ-resistant P. berghei [145].…”

Section: Malariamentioning

confidence: 99%

Antibody-Conjugated Nanoparticles for Therapeutic Applications

Cardoso

Peça²,

Roque³

2012

CMC

112

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Abstract:A great challenge to clinical development is the delivery of chemotherapeutic agents, known to cause severe toxic effects, directly to diseased sites which increase the therapeutic index whilst minimizing off-target side effects. Antibody-conjugated nanoparticles offer great opportunities to overcome these limitations in therapeutics. They combine the advantages given by the nanoparticles with the ability to bind to their target with high affinity and improve cell penetration given by the antibodies. This specialized vehicle, that can encapsulate several chemotherapeutic agents, can be engineered to possess the desirable properties, allowing overcoming the successive physiological conditions and to cross biological barriers and reach a specific tissue or cell. Moreover, antibody-conjugated nanoparticles have shown the ability to be internalized through receptor-mediated endocytosis and accumulate in cells without being recognized by the P-glycoprotein, one of the main mediators of multi-drug resistance, resulting in an increase in the intracellular concentration of drugs. Also, progress in antibody engineering has allowed the manipulation of the basic antibody structure for raising and tailoring specificity and functionality. This review explores recent developments on active drug targeting by nanoparticles functionalized with monoclonal antibodies (polymeric micelles, liposomes and polymeric nanoparticles) and summarizes the opportunities of these targeting strategies in the therapy of serious diseases (cancer, inflammatory diseases, infectious diseases, and thrombosis).

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Antibody‐mediated targeting of liposomes to red cells in vivo

Abstract: Drug targeting Liposome Cell‐specific antibody F(ab')2 fragment (Erythrocyte)

Cited by 44 publications

References 21 publications

Targeted erythropoietin selectively stimulates red blood cell expansion in vivo

Targeted erythropoietin selectively stimulates red blood cell expansion in vivo

Immunoliposome-mediated drug delivery to Plasmodium -infected and non-infected red blood cells as a dual therapeutic/prophylactic antimalarial strategy

Antibody-Conjugated Nanoparticles for Therapeutic Applications

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