Dataset Information

Ligand-decorated click polypeptide derived nanoparticles for targeted drug delivery applications.

ABSTRACT: A ligand decorated, synthetic polypeptide block copolymer platform with environment-responsive capabilities was designed. We evaluated the potential of this system to function as a polymersome for targeted-delivery of a systemic chemotherapy to tumors. Our system employed click chemistry to provide a pH-responsive polypeptide block that drives nanoparticle assembly, and a ligand (folic acid) conjugated PEG block that targets folate-receptor over-expressing cancer cells. These nanocarriers were found to encapsulate a high loading of conventional chemotherapeutics (e.g. doxorubicin at physiological pH) and release the active therapeutic at lysosomal pH upon cellular uptake. The presence of folic acid on the nanoparticle surface facilitated their active accumulation in folate-receptor-overexpressing cancer cells (KB), compared to untargeted carriers. Folate-targeted nanoparticles loaded with doxorubicin also showed enhanced tumor accumulation in folate-receptor positive KB xenografts, resulting in the suppression of tumor growth in an in vivo hind flank xenograft mouse model.

SUBMITTER: Quadir MA

PROVIDER: S-EPMC5641973 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Ligand-decorated click polypeptide derived nanoparticles for targeted drug delivery applications.

Quadir Mohiuddin A MA Morton Stephen W SW Mensah Lawrence B LB Shopsowitz Kevin K Dobbelaar Jeroen J Effenberger Nicole N Hammond Paula T PT

Nanomedicine : nanotechnology, biology, and medicine 20170302 5

A ligand decorated, synthetic polypeptide block copolymer platform with environment-responsive capabilities was designed. We evaluated the potential of this system to function as a polymersome for targeted-delivery of a systemic chemotherapy to tumors. Our system employed click chemistry to provide a pH-responsive polypeptide block that drives nanoparticle assembly, and a ligand (folic acid) conjugated PEG block that targets folate-receptor over-expressing cancer cells. These nanocarriers were f ...[more]

PMID: 28263813

Similar Datasets

Project description:Rationale: The availability of therapeutics to treat pregnancy complications is severely lacking, mainly due to the risk of harm to the fetus. In placental malaria, Plasmodium falciparum-infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) on the surfaces of trophoblasts. Based on this principle, we have developed a method for targeted delivery of payloads to the placenta using a synthetic placental CSA-binding peptide (plCSA-BP) derived from VAR2CSA, a CSA-binding protein expressed on IEs. Methods: A biotinylated plCSA-BP was used to examine the specificity of plCSA-BP binding to mouse and human placental tissue in tissue sections in vitro. Different nanoparticles, including plCSA-BP-conjugated nanoparticles loaded with indocyanine green (plCSA-INPs) or methotrexate (plCSA-MNPs), were administered intravenously to pregnant mice to test their efficiency at drug delivery to the placenta in vivo. The tissue distribution and localization of the plCSA-INPs were monitored in live animals using an IVIS imaging system. The effect of plCSA-MNPs on fetal and placental development and pregnancy outcome were examined using a small-animal high-frequency ultrasound (HFUS) imaging system, and the concentrations of methotrexate in fetal and placental tissues were measured using high-performance liquid chromatography (HPLC). Results: plCSA-BP binds specifically to trophoblasts and not to other cell types in the placenta or to CSA-expressing cells in other tissues. Moreover, we found that intravenously administered plCSA-INPs accumulate in the mouse placenta, and ex vivo analysis of the fetuses and placentas confirmed placenta-specific delivery of these nanoparticles. We also demonstrate successful delivery of methotrexate specifically to placental cells by plCSA-BP-conjugated nanoparticles, resulting in dramatic impairment of placental and fetal development. Importantly, plCSA-MNPs treatment had no apparent adverse effects on maternal tissues. Conclusion: These results demonstrate that plCSA-BP-guided nanoparticles could be used for the targeted delivery of payloads to the placenta and serve as a novel placenta-specific drug delivery option.

Project description:BackgroundCancerous state is a highly stimulated environment of metabolically active cells. The cells under these conditions over express selective receptors for assimilation of factors essential for growth and transformation. Such receptors would serve as potential targets for the specific ligand mediated transport of pharmaceutically active molecules. The present study demonstrates the specificity and efficacy of protein nanoparticle of apotransferrin for targeted delivery of doxorubicin.Methodology/principal findingsApotransferrin nanoparticles were developed by sol-oil chemistry. A comparative analysis of efficiency of drug delivery in conjugated and non-conjugated forms of doxorubicin to apotransferrin nanoparticle is presented. The spherical shaped apotransferrin nanoparticles (nano) have diameters of 25-50 etam, which increase to 60-80 etam upon direct loading of drug (direct-nano), and showed further increase in dimension (75-95 etam) in conjugated nanoparticles (conj-nano). The competitive experiments with the transferrin receptor specific antibody showed the entry of both conj-nano and direct-nano into the cells through transferrin receptor mediated endocytosis. Results of various studies conducted clearly establish the superiority of the direct-nano over conj-nano viz. (a) localization studies showed complete release of drug very early, even as early as 30 min after treatment, with the drug localizing in the target organelle (nucleus) (b) pharmacokinetic studies showed enhanced drug concentrations, in circulation with sustainable half-life (c) the studies also demonstrated efficient drug delivery, and an enhanced inhibition of proliferation in cancer cells. Tissue distribution analysis showed intravenous administration of direct nano lead to higher drug localization in liver, and blood as compared to relatively lesser localization in heart, kidney and spleen. Experiments using rat cancer model confirmed the efficacy of the formulation in regression of hepatocellular carcinoma with negligible toxicity to kidney and liver.ConclusionsThe present study thus demonstrates that the direct-nano is highly efficacious in delivery of drug in a target specific manner with lower toxicity to heart, liver and kidney.

Dataset Information

Ligand-decorated click polypeptide derived nanoparticles for targeted drug delivery applications.

Publications

Ligand-decorated click polypeptide derived nanoparticles for targeted drug delivery applications.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets