Cell-Penetrating Peptide-Modified Gold Nanoparticles for the Delivery of Doxorubicin to Brain Metastatic Breast Cancer

Abstract

As therapies continue to increase the lifespan of patients with breast cancer, the incidence of brain metastases has steadily increased, affecting a significant number of patients with metastatic disease. However, a major barrier toward treating these lesions is the inability of therapeutics to penetrate into the central nervous system and accumulate within intracranial tumor sites. In this study, we designed a cell-penetrating gold nanoparticle platform to increase drug delivery to brain metastatic breast cancer cells. TAT peptide-modified gold nanoparticles carrying doxorubicin led to improved cytotoxicity toward two brain metastatic breast cancer cell lines with a decrease in the IC50 of at least 80% compared to free drug. Intravenous administration of these particles led to extensive accumulation of particles throughout diffuse intracranial metastatic microsatellites with cleaved caspase-3 activity corresponding to tumor foci. Furthermore, intratumoral administration of these particles improved survival in an intracranial MDA-MB-231-Br xenograft mouse model. Our results demonstrate the promising application of gold nanoparticles for improving drug delivery in the context of brain metastatic breast cancer.

Autocatalytic Delivery of Brain Tumor–Targeting, Size‐Shrinkable Nanoparticles for Treatment of Breast Cancer Brain Metastases

“…Chemotherapy, which has been a major driving force to improve clinical management of most cancers, plays a limited role in BCBMs treatment, largely because of the lack of approaches to overcoming the BBB 4,5. To address this challenge, targeted delivery approaches using various tumor targeting ligands, including HA,6 TAT,7 iRGD,8 polysorbate 80,1b and chlorotoxin,9 have been explored but have had limited success. Consistently, we found that the simple ligand‐mediated delivery approach is insufficient for systemic delivery of NPs to the brain and further improved delivery of NPs to BCBMs could be achieved through integration of intelligent responsiveness and BBB penetration (Figures 3–5).…”

“…To improve drug delivery to tumors, a common approach has been engineering nanocarriers through conjugation of ligands that recognize “receptor” molecules expressed on cancer cells, such as hyaluronic acid (HA),6 TAT,7 iRGD,8 polysorbate 80,1b and chlorotoxin,9 which have been tested for BCBMs. Despite their potential, this approach has shown to be limited by various factors, including the lack of molecules that is specifically expressed on the surface of all cancer cells but not normal tissues 10.…”

Nanoparticles as Theranostic Vehicles in Experimental and Clinical Applications—Focus on Prostate and Breast Cancer

“…Gold NPs (AuNPs) in the form of nano-cages, -spheres, -beacons, -stars, -shells, -seeds, -sheets, or nanorods is being evaluated in many different settings, for example, for both PCa and BC (Figure 2) [8,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141]. By changing the AuNPs’ shape, size, or surface characteristics it is possible to fine-tune their properties in order to maximize their applicability as a tool for cancer diagnosis, photo-dynamic/thermal therapy, therapy-drug carrier, radiotherapy drug enhancer, targeted gene therapy, or as a combined theranostic nanovehicle [142,143,144,145,146,147,148,149,150,151,152,153,154,155].…”

<p>Improving Cell Penetration of Gold Nanorods by Using an Amphipathic Arginine Rich Peptide</p>

“…In this regard, some studies have reported the use of CPPs on the surface of nanoparticles for brain drug delivery, 30,31 eg, the use of gold nanoparticles functionalized with the cell-penetrating peptide TAT, to increase doxorubicin delivery to brain metastatic breast cancer cells. 32 One kind of CPP is the arginine sequence of peptides as oligoarginines. However, there are few studies related to the functionalization of GNRs with oligoarginines.…”