Self-assembled 20-nm 64Cu-micelles enhance accumulation in rat glioblastoma

Abstract

There is an urgent need to develop nanocarriers for the treatment of glioblastoma multiforme (GBM). Using co-registered positron emission tomography (PET) and magnetic resonance (MR) images, here we performed systematic studies to investigate how a nanocarrier’s size affects the pharmacokinetics and biodistribution in rodents with a GBM xenograft. In particular, highly stable, long-circulating three-helix micelles (3HM), based on a coiled-coil protein tertiary structure, were evaluated as an alternative to larger nanocarriers. While the circulation half-life of the 3HM was similar to 110-nm PEGylated liposomes (t1/2 = 15.5 and 16.5 h, respectively), the 20-nm micelles greatly enhanced accumulation within a U87MG xenograft in nu/nu rats after intravenous injection. After accounting for tumor blood volume, the extravasated nanoparticles were quantified from the PET images, yielding ~0.77 %ID/cc for the micelles and 0.45 %ID/cc for the liposomes. For GBM lesions with a volume greater than 100 mm3, 3HM accumulation was enhanced both within the detectable tumor and in the surrounding brain parenchyma. Further, the nanoparticle accumulation was shown to extend to the margins of the GBM xenograft. In summary, 3HM provides an attractive nanovehicle for carrying treatment to GBM.

Glia to glioma: A wrathful journey

“…Gradually, successive interplay of differentiation and de-differentiation aid the transformation of radial astrocytic stem cells into neuron of hippocampal region via respective transformation to type 1 to type 2 to type 3 neural stem cells, while the ependymal cells lining the region of cerebrospinal fluid are under the crucial influence of various growth factors and their intricate signaling system such as Notch, Wnt, TGF-β, BMP, etc [61,62] . Periventricular adult NSC has been characterized to express a high level of GFAP-positive astrocytes, which along with combined loss of tumor suppressors p16 and p19 (causing increased expression of eGFr) and loss of p53 (causing over-expression of oncogenes such as c-myc) clearly indicate the de-differentiated property of astrocytes to give origin to GBM [63][64][65] . Parallel to these modifications, the formation of type C progenitor cells from SvZ, which later become restricted to neuroblast and oligodendrocyte precursor cells (OPC), seem to inculcate a number of genetic alterations to manifest initial gliomagenesis [66,67] .…”

Responsive hybrid (poly)peptide–polymer conjugates

“…99, 190–193 Shu et al explored coiled-coil helix bundle forming peptides in which hydrophobic PS was conjugated onto the N-terminus. 99 These conjugates were able to form micelles ca.…”

“…192 This 3-helix amphiphile was labeled with 64 Cu and demonstrated a superior ability to accumulate in glioblastoma within a rat model, as compared to a PEGylated liposome. 193 The size, stability, blood circulation half-life and ability to be used for imaging or carrying a drug payload, shows the versatility of this 3-helix amphiphile and its potential in drug delivery systems.…”

“…Many have shown utility in multiple cancer cell lines, including, breast, 192 colon, 204 and cervical, 222,223 as well as in animal models. 192,193,206 …”

ParamagneticGd2O3Nanoparticle-Based Targeting Theranostic Agent for C6 Rat Glioma Cell

“…Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor in the central nervous system (CNS) [30][31][32]. The most widely used GBM cell lines in neurobiological research are C6 cell line cloned from a chemically induced rat GBM and immortalized glial cells of rat brain which is both astrocytic and oligodendrocytic [33][34][35].…”