Structure and dynamics of drug carriers and their interaction with cellular receptors: Focus on serum transferrin

Luck, Ashley N.; Mason, Anne B.

doi:10.1016/j.addr.2012.11.001

Cited by 36 publications

(37 citation statements)

References 51 publications

(84 reference statements)

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“…Published reports and we confirmed that antibody against TfR also induced TfR endocytosis followed by transport to lysosomal compartments [15,16]. This cellular uptake pathway and overexpression on tumor cells make TfR one of the most exploited target spots in tumor targeted therapy [17][18][19]. Our previous studies demonstrated antibody against TfR could recognize tumor cells with high efficiency in vitro and 131 I-TfR Ab displayed a feature of specific accumulation in tumor tissue in vivo [20,21].…”

Section: Introductionsupporting

confidence: 80%

Establishment of a hTfR mAb-functionalized HPPS theranostic nanoplatform

Guo

et al. 2020

Nanotheranostics

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Rational: Many efforts have been made to develop ligand-directed nanotheranostics in cancer management which could afford both therapeutic and diagnostic functions as well as tumor-tailored targeting. Theranostic nanoplatform targeting transferrin receptor (TfR) is an effective system for favorable delivery of diagnostic and therapeutic agents to malignancy site. Methods: To enable amalgamation of therapy and diagnosis to many TfR + tumor, hTfR (human TfR) monoclonal antibody (mAb)-functionalized HPPS nanoparticle (HPPS-mAb) was prepared with hTfR mAb on the shell and with fluorophore DiR-BOA in the core. The targeting specificity was investigated in vitro by immunostaining and in vivo using a double-tumor-engrafted mouse model. HPPS-mAb/siRNA effect on HepG2 cells was determined by RT-PCR and western blot. Results: HPPS-mAb could specifically target cancer cells through TfR and achieve tumor accumulation at an early valuable time node, thus efficiently delivering therapeutic survivin siRNA into TfR + HepG2 cells and mediating cell apoptosis. DiR-BOA can act as an imaging tool to diagnose cancer. Conclusions: Our studies provide a promising TfR mAb-directed theranostic nanoplatform candidate in tumor molecular imaging and in TfR targeted tumor therapy.

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Section: Introductionsupporting

confidence: 80%

Establishment of a hTfR mAb-functionalized HPPS theranostic nanoplatform

Guo

et al. 2020

Nanotheranostics

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“…P values for all potential pairwise comparisons are given in SI Appendix, Table S2. complex is known to undergo significant conformational changes after the pH change (24). It is possible that continuous occupation of TfR by pH-independent, high-affinity Abs inhibits necessary conformational changes in the Tf-TfR complex, causing sorting to the lysosome.…”

Section: Discussionmentioning

confidence: 99%

Increased brain uptake of targeted nanoparticles by adding an acid-cleavable linkage between transferrin and the nanoparticle core

Clark

Davis

2015

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

222

175

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Most therapeutic agents are excluded from entering the central nervous system by the blood-brain barrier (BBB). Receptor mediated transcytosis (RMT) is a common mechanism used by proteins, including transferrin (Tf), to traverse the BBB. Here, we prepared Tf-containing, 80-nm gold nanoparticles with an acid-cleavable linkage between the Tf and the nanoparticle core to facilitate nanoparticle RMT across the BBB. These nanoparticles are designed to bind to Tf receptors (TfRs) with high avidity on the blood side of the BBB, but separate from their multidentate Tf-TfR interactions upon acidification during the transcytosis process to allow release of the nanoparticle into the brain. These targeted nanoparticles show increased ability to cross an in vitro model of the BBB and, most important, enter the brain parenchyma of mice in greater amounts in vivo after systemic administration compared with similar highavidity nanoparticles containing noncleavable Tf. In addition, we investigated this design with nanoparticles containing high-affinity antibodies (Abs) to TfR. With the Abs, the addition of the acid-cleavable linkage provided no improvement to in vivo brain uptake for Ab-containing nanoparticles, and overall brain uptake was decreased for all Ab-containing nanoparticles compared with Tf-containing ones. These results are consistent with recent reports of high-affinity anti-TfR Abs trafficking to the lysosome within BBB endothelium. In contrast, high-avidity, Tf-containing nanoparticles with the acid-cleavable linkage avoid major endothelium retention by shedding surface Tf during their transcytosis.blood-brain barrier | transcytosis | therapeutic delivery | systemic administration | in vivo T he inability of drugs to cross the blood-brain barrier (BBB) is one of the major impairments to developing treatments for neurological diseases. This highly restrictive, physiologic barrier excludes 98% of small-molecule drugs and ∼100% of large-molecule drugs from reaching the central nervous system (CNS) from blood circulation (1). Many methods to bypass the BBB have been investigated, such as transient disruption of the BBB, inhibition of efflux pumps, or transport using endogenous transcytosis systems, including receptor-mediated transcytosis (2-4).Transferrin receptor (TfR) has been one of the primary targets investigated for receptor-mediated transcytosis across the BBB because of its high expression on BBB endothelium (5). Anti-TfR antibody-drug conjugates have received the most attention because of their ability to bind TfR with high affinity without interfering with endogenous transferrin (Tf) (6-8). Despite the perceived potential of anti-TfR antibody-drug conjugates, a BBB-permeable drug using this approach has yet to reach the clinic. Yu et al. showed that anti-TfR Abs enter the brain in greater numbers when their affinity to TfR is reduced (9). Follow-up work from the same group showed that highaffinity, bispecific anti-TfR Abs preferentially trafficked to the lysosome within BBB endothelium, rather than transcy...

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“…An example of a promising drug delivery system where opportunities to improve routing are frequently overlooked is transferrin (Tf), an 80 kDa iron glycoprotein whose primary function is the delivery of iron to cells. It is one of very few plasma proteins that gain cellular entry by the process of receptor-mediated endocytosis [5], a fact that has long attracted attention of the drug design community [6–9]. …”

Section: Introductionmentioning

confidence: 99%

Evaluation of Nonferrous Metals as Potential In Vivo Tracers of Transferrin-Based Therapeutics

Zhao

Wang

Nguyen

et al. 2015

J. Am. Soc. Mass Spectrom.

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Transferrin (Tf) is a promising candidate for targeted drug delivery. While development of such products is impossible without the ability to monitor biodistribution of Tf-drug conjugates in tissues and reliable measurements of their levels in blood and other biological fluids, the presence of very abundant endogenous Tf presents a significant impediment to such efforts. Several non-cognate metals have been evaluated in this work as possible tracers of exogenous transferrin in complex biological matrices using inductively coupled plasma mass spectrometry (ICP MS) as a detection tool. Placing Ni(II) on a His-tag of recombinant Tf resulted in formation of a marginally stable protein-metal complex, which readily transfers the metal to ubiquitous physiological scavengers, such as serum albumin. An alternative strategy targeted iron-binding pockets of Tf, where cognate Fe(III) was replaced metal ions known to bind this protein. Both Ga(III) and In(III) were evaluated, with the latter being vastly superior as a tracer (stronger binding to Tf unaffected by the presence of metal scavengers and the retained ability to associate with Tf receptor). Spiking serum with indium-loaded Tf followed by ICP MS detection demonstrated that protein quantities as low as 0.04 nM can be readily detected in animal blood. Combining laser ablation with ICP MS detection allows distribution of exogenous Tf to be mapped within animal tissue cross-sections with spatial resolution exceeding 100 μm. The method can be readily extended to a range of other therapeutics where metalloproteins are used as either carriers or payloads.

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Structure and dynamics of drug carriers and their interaction with cellular receptors: Focus on serum transferrin

Cited by 36 publications

References 51 publications

Establishment of a hTfR mAb-functionalized HPPS theranostic nanoplatform

Establishment of a hTfR mAb-functionalized HPPS theranostic nanoplatform

Increased brain uptake of targeted nanoparticles by adding an acid-cleavable linkage between transferrin and the nanoparticle core

Evaluation of Nonferrous Metals as Potential In Vivo Tracers of Transferrin-Based Therapeutics

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