The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles

126

119

Nanoparticles are currently being investigated in a number of human clinical trials. As information on how nanoparticles function in humans is difficult to obtain, animal studies that can be correlative to human behavior are needed to provide guidance for human clinical trials. Here, we report correlative studies on animals and humans for CRLX101, a 20-to 30-nm-diameter, multifunctional, polymeric nanoparticle containing camptothecin (CPT). CRLX101 is currently in phase 2 clinical trials, and human data from several of the clinical investigations are compared with results from multispecies animal studies. The pharmacokinetics of polymer-conjugated CPT (indicative of the CRLX101 nanoparticles) in mice, rats, dogs, and humans reveal that the area under the curve scales linearly with milligrams of CPT per square meter for all species. Plasma concentrations of unconjugated CPT released from CRLX101 in animals and humans are consistent with each other after accounting for differences in serum albumin binding of CPT. Urinary excretion of polymer-conjugated CPT occurs primarily within the initial 24 h after dosing in animals and humans. The urinary excretion dynamics of polymer-conjugated and unconjugated CPT appear similar between animals and humans. CRLX101 accumulates into solid tumors and releases CPT over a period of several days to give inhibition of its target in animal xenograft models of cancer and in the tumors of humans. Taken in total, the evidence provided from animal models on the CRLX101 mechanism of action suggests that the behavior of CRLX101 in animals is translatable to humans.nanomedicine | clinical translation | interspecies scaling | pharmacodynamics | Nanoparticles

Section: Discussionmentioning

confidence: 99%

Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

Eliasof

Lazarus

Peters

et al. 2013

126

119

“…Moreover, nanoparticle zeta potentials that are slightly negative to near-neutral are desirable, given that highly negatively and positively charged nanoparticles are known to (i) disrupt the BBB (11), (ii) facilitate formation of protein coronas that may mask or alter the function of the targeting ligand (12), and (iii) illicit unwanted immune responses and more rapid blood clearance via increased uptake through the mononuclear phagocyte system (13). Thus, we restricted our nanoparticles to have near-neutral zeta potentials (<−15 mV, as measured in 1.5 mM KCl).…”

mentioning

confidence: 99%

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

Wiley

Webster

Gale

et al. 2013

407

348

Receptor-mediated transcytosis across the blood-brain barrier (BBB) may be a useful way to transport therapeutics into the brain. Here we report that transferrin (Tf)-containing gold nanoparticles can reach the brain parenchyma from systemic administration in mice through a receptor-mediated transcytosis pathway. This transport is aided by tuning the nanoparticle avidity to Tf receptor (TfR), which is correlated with nanoparticle size and total amount of Tf decorating the nanoparticle surface. Nanoparticles of both 45 nm and 80 nm diameter reach the brain parenchyma, and their accumulation there (visualized by silver enhancement light microscopy in combination with transmission electron microscopy imaging) is observed to be dependent on Tf content (avidity); nanoparticles with large amounts of Tf remain strongly attached to brain endothelial cells, whereas those with less Tf are capable of both interacting with TfR on the luminal side of the BBB and detaching from TfR on the brain side of the BBB. The requirement of proper avidity for nanoparticles to reach the brain parenchyma is consistent with recent behavior observed with transcytosing antibodies that bind to TfR.E ffective delivery of therapeutics to the brain has remained elusive owing to many factors, including inadequate transport across the blood-brain barrier (BBB). Numerous multidisciplinary-based strategies for transporting therapeutic agents from the blood into the brain have been proposed (1), including the use of receptor-mediated transcytosis. Recently, Yu et al. (2) reported increased accumulation of antibodies to transferrin (Tf) receptor (TfR) in the brain parenchyma when the antibody affinity was reduced. In that work, antibodies with high TfR affinity bound strongly to and remained associated with TfRs in the BBB, whereas antibodies with lower TfR affinity allowed for their detachment from TfRs and subsequent release into the brain parenchyma. These results are consistent with a previous report of a low-affinity (nearly identical to Tf-TfR interaction strength) antibody that significantly accumulated in the brain parenchyma (3).Targeted nanoparticles are finding applications for the delivery of a wide variety of therapeutic agents, and several have already reached the clinical testing stage in humans (4, 5). For example, in a Phase I clinical trial, a Tf-containing nanoparticle was used to deliver siRNA to cancer patients and shown to deliver functional siRNA to melanoma tumors in a dose-dependent manner (6). The results demonstrate that Tf-containing nanoparticles can be administered safely to humans.It is well known that the avidity and receptor selectivity of targeted nanoparticles can be tuned by the choice of targeting ligand and its number density; multivalent nanoparticles can engage multiple cell surface receptors simultaneously (7,8). When an individual targeting ligand is conjugated to a nanoparticle, the affinity of the ligand to the receptor is reduced. However, if the receptor density is such that multiple targeting ligands on...

“…Charge has a major effect on the transport behavior of nanoparticles in vivo and in vitro (20). A high surface charge, either positive or negative, tends to trigger nonspecific uptake of the particles by macrophages and results in more accumulation of the particles in the liver than in the targeting region after systemic administration.…”

Section: Significancementioning

confidence: 99%

Quantum dot/antibody conjugates for in vivo cytometric imaging in mice

Han¹,

Niemeyer

Huang

et al. 2015

114

Multiplexed, phenotypic, intravital cytometric imaging requires novel fluorophore conjugates that have an appropriate size for long circulation and diffusion and show virtually no nonspecific binding to cells/serum while binding to cells of interest with high specificity. In addition, these conjugates must be stable and maintain a high quantum yield in the in vivo environments. Here, we show that this can be achieved using compact (∼15 nm in hydrodynamic diameter) and biocompatible quantum dot (QD) -Ab conjugates. We developed these conjugates by coupling whole mAbs to QDs coated with norbornene-displaying polyimidazole ligands using tetrazine–norbornene cycloaddition. Our QD immunoconstructs were used for in vivo single-cell labeling in bone marrow. The intravital imaging studies using a chronic calvarial bone window showed that our QD-Ab conjugates diffuse into the entire bone marrow and efficiently label single cells belonging to rare populations of hematopoietic stem and progenitor cells (Sca1+c-Kit+ cells). This in vivo cytometric technique may be useful in a wide range of structural and functional imaging to study the interactions between cells and between a cell and its environment in intact and diseased tissues.