Transferrin-Containing, Cyclodextrin Polymer-Based Particles for Tumor-Targeted Gene Delivery

Abstract

Transferrin is a well-studied ligand for tumor targeting due to upregulation of transferrin receptors in numerous cancer cell types. Here, we report the development of a transferrin-modified, cyclodextrin polymer-based gene delivery system. The delivery system is comprised of a nanoparticle (formed by condensation of a cyclodextrin polycation with nucleic acid) that is surface-modified to display poly(ethylene glycol) (PEG) for increasing stability in biological fluids and transferrin for targeting of cancer cells that express transferrin receptor. A transferrin-PEG-adamantane conjugate is synthesized for nanoparticle modification. The transferrin conjugate retains high receptor binding and self-assembles with the nanoparticles by adamantane (host) and particle surface cyclodextrin (guest) inclusion complex formation. At low transferrin modification, the particles remain stable in physiologic salt concentrations and transfect K562 leukemia cells with increased efficiency over untargeted particles. The increase in transfection is eliminated when transfections are conducted in the presence of excess free transferrin. The transferrin-modified nanoparticles are appropriate for use in the systemic delivery of nucleic acid therapeutics for metastatic cancer applications.

Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor

“…Tf was coupled to gold nanoparticles through an NHS-PEG 5k -OPSS linker, where the N-hydroxysuccinimide (NHS) ester reacts with Tf through primary amines on lysine groups [the preferred method of PEG coupling to Tf (19)] and orthopyridyl disulfide (OPSS) reacts with gold surfaces through gold-thiol dative bonding ( Fig. 1).…”

Targeted delivery of RNA-cleaving DNA enzyme (DNAzyme) to tumor tissue by transferrin-modified, cyclodextrin-based particles

“…32 CDP-Imid, AD-PEG 5000 , AD-gluglu-PEG-gal, and AD-PEG 3400 -Tf were synthesized following analogous protocols described previously. 18 Fluorescein-labeled transferrin (Tf-fluor) was prepared by conjugation of TUMOR-TARGETED NANOPARTICLES FOR DNAZYME DELIVERY 18 Polyplex Formulation and Characterization. Unmodified polyplexes were prepared by adding an equal volume of CDP-Imid (Fig.…”

“…17 These Tf-PEG-polyplexes have been shown to facilitate plasmid delivery and in vitro transgene expression via transferrin receptor-mediated endocytosis. 18 Joyce and coworkers used in vitro selection to obtain singlestranded DNA capable of catalytic cleavage of RNA. [19][20][21] These enzymatic DNAs (DNAzymes) have been successful in site-specific RNA cleavage in both in vitro and in vivo settings.…”

A review of RGD-functionalized nonviral gene delivery vectors for cancer therapy

“…One of the means being explored to achieve the improvement of transfection efficiency is targeted delivery, where therapeutic genes are delivered to selected cells of interest. A wide range of targeting ligands for cancer gene therapy have been incorporated into the nonviral vectors, including folate, 32 Asn-Gly-Arg (NGR) peptides, 33 RGD peptides, 13 transferrins 34,35 and antibodies. 36,37 Discussed below are the RGD-modified polymers, lipids and peptides that have been utilized as nonviral vectors for targeted delivery of genetic materials to achieve efficient cancer gene therapy, including antiangiogenic therapy.…”