Targeted Nanoparticles for Glioblastoma Theranostics

Abstract

Targeted nanoparticles are provided which facilitate detection of and therapy for glioblastoma multiforme (GBM). The nanoparticles may be used to target other forms of cancer as well, such as pancreatic, colorectal, and breast. The nanoparticles may provide optical contrast for pre-operative diagnostic imaging and intraoperative navigation using surface-enhanced Raman scattering techniques. Moreover, the nanoparticles may inhibit tumoral growth, block tumoral blood flow, and decrease metastatic spread of GBM. The nanoparticles may further reduce the inflammatory response, which is essential to the growth of the glioma and can be harmful to the patient. The nanoparticle may comprise a biologically inert substance, a biocompatible polymer, an optical-acoustic reporter, and a glioblastoma specific receptor ligand conjugated to the biocompatible polymer. For instance, in some embodiments, the biologically inert substance may be a gold or silica nanoshell, the biocompatible polymer may be polyethylene glycol, the optical-acoustic reporter may be prussian blue, and the glioblastoma specific receptor ligand may be aprepitant.

Claims

1. A nanoparticle comprising: a biologically inert substance, wherein the biologically inert substance is a nanoshell; a biocompatible polymer; an optical-acoustic reporter; and a glioblastoma specific receptor ligand conjugated to the biocompatible polymer.

2. The nanoparticle of claim 1, wherein the nanoshell is comprised of gold or silica.

3. The nanoparticle of claim 1, wherein the biocompatible polymer is polyethylene glycol.

4. The nanoparticle of claim 1, wherein the optical-acoustic reporter is prussian blue.

5. The nanoparticle of claim 1, wherein the glioblastoma specific receptor ligand is a neurokinin-1 receptor antagonist.

6. The nanoparticle of claim 5, wherein the neurokinin-1 receptor antagonist is aprepitant.

7. A pharmaceutical composition comprising: a plurality of nanoparticles, wherein each nanoparticle comprises: a biocompatible polymer; an optical-acoustic reporter; and a glioblastoma specific receptor ligand conjugated to the biocompatible polymer.

8. The pharmaceutical composition of claim 7, wherein the composition is administered orally.

9. The pharmaceutical composition of claim 7, wherein the plurality of nanoparticles comprise gold nanoshells.

10. The pharmaceutical composition of claim 7, wherein the plurality of nanoparticles comprise silica nanoshells.

11. The pharmaceutical composition of claim 7, wherein the biocompatible polymer is polyethylene glycol.

12. The pharmaceutical composition of claim 7, wherein the optical-acoustic reporter is prussian blue.

13. The pharmaceutical composition of claim 7, wherein the glioblastoma specific receptor ligand is a neurokinin-1 receptor antagonist.

14. The pharmaceutical composition of claim 13, wherein the neurokinin-1 receptor antagonist is aprepitant.

15. A nanoparticle comprising: a nanoshell, wherein the nanoshell comprises gold or silica; polyethylene glycol an optical-acoustic reporter; and a glioblastoma specific receptor ligand conjugated to the polyethylene glycol.

16. The nanoparticle of claim 15, wherein the optical-acoustic reporter is prussian blue.

17. The nanoparticle of claim 15, wherein the glioblastoma specific receptor ligand is a neurokinin-1 receptor antagonist.

18. The nanoparticle of claim 17, wherein the neurokinin-1 receptor antagonist is aprepitant.

Description

DETAILED DESCRIPTION

[0034] Having summarized various aspects of the present disclosure, reference will now be made in detail to various embodiments of the present invention. While the disclosure will comprise specific details, there is no intent to limit it to the embodiment or embodiments disclosed herein. Rather, the intent is to cover all alternatives, modifications and equivalents included within the spirit and scope of the disclosure as defined by the appended claims.

[0035] Briefly described, one embodiment, among others, is a nanoparticle that comprises a biologically inert substance, a biocompatible polymer, an optical-acoustic reporter, and a glioblastoma specific receptor ligand. The glioblastoma specific receptor ligand may be conjugated to the biocompatible polymer. The nanoparticle may be administered orally. In other embodiments, the nanoparticle may be intravenously delivered.

[0036] In certain embodiments, the biologically inert substance may comprise a nanoshell. Further, the nanoshell may be formed of gold or silica. In embodiments where the nanoshell comprises gold, the gold may be inert and may be safe for use in biomedical applications. Silica may also be inert. In some embodiments, the nanoshell may be spherical in shape and consist of a dielectric core covered by a thin metallic shell. Also, the nanoshell may be characterized by a low toxicity profile and therefore, may be safe for use in humans. Moreover, the nanoshell may provide flexibility as to which molecules may be conjugated thereto.

[0037] In other embodiments, the biologically inert substance may comprise other shapes as well. For instance, the biologically inert substance may comprise a nanorod, a nanostar, a nanotube, a nanocube, a nanosphere, a nanocapsular particle, or other nanomaterials. Indeed, a person of ordinary skill in the art will recognize that the biologically inert substance may comprise numerous other structures.

[0038] The nanoshell may be transported across the blood-brain barrier, thereby permitting therapeutic drugs to be delivered to diseased areas of the brain. The nanoshell may further act as a contrast agent for diagnostic imaging. More particularly, the nanoshell may allow for greater visualization of GBM for diagnostic MRI and CT. Additionally, the nanoshell may increase the Raman scattering signal using SERS, which, in turn, may permit highly sensitive detection of microscopic portions of a tumor. In application, intraoperative SERS probes, scanners, or other implements may be used to detect the boundaries of a tumor during surgical resection.

[0039] Moreover, the nanoshell may increase the effective dose of radiation applied to a tumor, peritumoral stroma, and peritumoral vessels. During radiotherapy, the nanoshell may cause radiation from within the tumor. Thus, the nanoshell may improve the therapeutic window by allowing lower radiation doses to normal brain tissue while increasing the effective dose to diseased cells.

[0040] In certain embodiments, the biocompatible polymer may be polyethylene glycol (PEG). PEG may be an inert, coiled polymer comprised of repeating ethylene ether units with dynamic conformations. In other embodiments, the biocompatible polymer may comprise polyalkylene glycol. A person of ordinary skill in the art will appreciate that many other biocompatible polymers may be used in accordance with this invention. For instance, the biocompatible polymer may comprise polyethylene, polyvinyl alcohols, polyhydroxyacids, polycarbonate, polyanhydrides, polyesters, polypropylfumerates, polyamines, polycaprolactones, polyamides, polyacetals, polyethers, polycyanoacrylates, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polyureas, polystyrenes, or combinations thereof.

[0041] The biocompatible polymer may prolong the circulation half-life of the nanoparticle in vivo. Indeed, the biocompatible polymer may reduce accumulation of the nanoparticle in the reticuloendothelial system (RES). In this way, the biocompatible polymer may mitigate concerns about nanoparticle toxicity, which often arises due to accumulation in the RES. The biocompatible polymer may also decrease association of the nanoparticle to non-targeted serum and tissue proteins, thereby resulting in stealth behavior.

[0042] In some embodiments, the optical-acoustic reporter may be prussian blue. Prussian blue may be a cyanide-bridged coordination polymer dye characterized by a strong and sharp single vibrational peak at 2156 cm(1) throughout the whole Raman spectrum. Prussian blue may provide a SERS tag that may associate with and effectively label diseased tissue. Specifically, prussian blue may facilitate the use of Raman spectroscopy, which may be used for intraoperative differentiation of brain tumor from normal brain tissue. Use of prussian blue and Raman spectroscopy may be nondestructive, non-invasive, and may provide information about the molecular composition and structure of GBM. Through this application, the optical-acoustic reporter may provide high sensitivity and specificity of detection and may also reduce false positive signals, leading to less resection of normal brain tissue. Together with the nanoshell, the optical-acoustic reporter may enhance the SERS signal, allowing use of intraoperative SERS probes, scanners, or other implements for neurosurgical intraoperative navigation. One of ordinary skill in the art will recognize that other optical-acoustic reporters may be implemented in accordance with this invention. For instance, the optical-acoustic reporter may comprise galodium chelate, superparamagnetic iron oxide, and hematoxylin-eosin.

[0043] As mentioned previously, the glioblastoma specific receptor ligand may be conjugated to the biocompatible polymer. In certain embodiments, the glioblastoma specific receptor ligand may be a neurokinin-1 receptor (NK1R) antagonist. More specifically, the NK1R antagonist may target NK1R in GBM and peritumoral vessels and may competitively inhibit SP and HK-1 binding to the NK1R. This competitive inhibition of the SP/NK1R system may, in turn, block the effects of both SP and HK-1 and may decrease angiogenesis and the inflammatory response mediated by the NK1R. The NK1R antagonist may block the breakdown of glycogen in glioblastoma cells and since cancer cells require a high level of glucose, proliferation of such cells may be inhibited. Additionally, the NK1R antagonist may prevent the migration of glioblastoma cells by blocking changes in cellular shape mediated by SP, including blebbing. The NK1R antagonist may even induce the death of glioblastoma cells by apoptosis.

[0044] In other embodiments, the NK1R antagonist may also exert an anti-tumor action against cancer stem cells by inhibiting the pathways associated with hypoxia-mediated maintenance of glioblastoma stem cells. Moreover, due to the high density of NK1R in GBM, the NK1R antagonist may target the NK1R in GBM and peritumoral vessels to facilitate visualization of the tumor for diagnostic imaging. For example, the NK1R antagonist binding to the NK1R in GBM may result in a gradient of enhancement on MRI and a density gradient on CT imaging.

[0045] In some embodiments, the NK1R antagonist may be aprepitant. Aprepitant may be lipid soluble and may readily cross the blood-brain barrier, allowing for high concentrations to be reached in the central nervous system. Aprepitant may be well-tolerated and safe for human consumption. Further, aprepitant may treat cancer chemotherapy induced nausea and vomiting.

[0046] According to certain embodiments of this invention, the pharmaceutical composition may comprise a plurality of nanoparticles. Each of the plurality of nanoparticles may comprise a biocompatible polymer, an optical-acoustic reporter, and a glioblastoma specific receptor ligand conjugated to the biocompatible polymer.

[0047] It should be emphasized that the above-described embodiments are merely examples of possible implementations. Many variations and modifications may be made to the above-described embodiments without departing from the principles of the present disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims.

[0048] Moreover, embodiments and limitations disclosed herein are not dedicated to the public under the doctrine of dedication if the embodiments and/or limitations: (1) are not expressly claimed in the claims; and (2) are or are potentially equivalents of express elements and/or limitations in the claims under the doctrine of equivalents.

CONCLUSIONS, RAMIFICATIONS, AND SCOPE

[0049] While certain embodiments of the invention have been illustrated and described, various modifications are contemplated and can be made without departing from the spirit and scope of the invention. For example, the glioblastoma specific receptor ligand may bind other types of receptors other than the NK1R. In this manner, the nanoparticle may target and treat other types of cancer, such as pancreatic, colorectal, or breast cancer. Accordingly, it is intended that the invention not be limited, except as by the appended claim(s).

[0050] The teachings disclosed herein may be applied to other systems, and may not necessarily be limited to any described herein. The elements and acts of the various embodiments described above can be combined to provide further embodiments. All of the above patents and applications and other references, including any that may be listed in accompanying filing papers, are incorporated herein by reference. Aspects of the invention can be modified, if necessary, to employ the systems, functions and concepts of the various references described above to provide yet further embodiments of the invention.

[0051] Particular terminology used when describing certain features or aspects of the invention should not be taken to imply that the terminology is being refined herein to be restricted to any specific characteristics, features, or aspects of the targeted nanoparticles for glioblastoma theranostics with which that terminology is associated. In general, the terms used in the following claims should not be constructed to limit the targeted nanoparticles for glioblastoma theranostics to the specific embodiments disclosed in the specification unless the above description section explicitly define such terms. Accordingly, the actual scope encompasses not only the disclosed embodiments, but also all equivalent ways of practicing or implementing the disclosed system, method and apparatus. The above description of embodiments of the targeted nanoparticles for glioblastoma theranostics is not intended to be exhaustive or limited to the precise form disclosed above or to a particular field of usage.

[0052] While specific embodiments of, and examples for, the method, system, and apparatus are described above for illustrative purposes, various equivalent modifications are possible for which those skilled in the relevant art will recognize.

[0053] While certain aspects of the method and system disclosed are presented below in particular claim forms, various aspects of the method, system, and apparatus are contemplated in any number of claim forms. Thus, the inventor reserves the right to add additional claims after filing the application to pursue such additional claim forms for other aspects of the targeted nanoparticles for glioblastoma theranostics.