Prodrug Delivery Using Dual-Targeting Nanoparticles To Treat Breast Cancer Brain Metastases

Abstract

Brain metastases from breast cancer are the most frequent brain metastasis in women, which are often difficult to be surgically removed due to the multifocal and infiltrative intracranial growth patterns. Cytotoxic drugs have potent anti-breast cancer properties. However, owing to the toxic side effects and the blood−brain barrier (BBB), these drugs cannot be fully and aggressively exploited with systemic administration and hence have very limited application for brain metastases. In this study, hyaluronidase-activated prodrug hyaluronic-doxorubicin (hDOX) was assembled by the BBB and metastatic breast cancer dual-targeting nanoparticles (NPs), which were constructed based on transcytosis-targeting peptide and hyaluronic acid co-modified poly(lactic-co-glycolic acid)-poly(ε-carbobenzoxy-Llysine). hDOX showed enzyme-recovered DNA insertion, selective cytotoxicity to metastatic breast cancer cells rather than astrocytes, and efficient loading into dual-targeting NPs. hDOX@NPs displayed the ability of dually targeting the BBB and metastatic breast cancer and significantly extended the median survival time of mice with intracranial metastatic breast cancer. Based on these improvements, this prodrug delivery tactic may serve as an important direction for drug therapy against brain metastases.

Ligand Chemistry in Antitumor Theranostic Nanoparticles

“…45 To be effective at both tumor extravasation and cancer cell uptake, some nanoparticles are equipped with transcytosistargeting peptides and cancer cell-targeting ligands to target both vasculature and cancer cells simultaneously. 46 Alternatively, there are also receptors overexpressed by both cancer cells and vasculature cells such as the glucose transporter (GLUT) receptor. Nanoparticles equipped with glucose as a targeting ligand exhibited improved performance in both vascular translocation and cancer cell uptake.…”

Nanoparticle drug delivery to target breast cancer brain metastasis: Current and future trends

“…To enhance the specificity of NPs to the BCBM tumor microenvironment (TME), Ju et al manufactured PLGA‐PLL‐based NP shells that were co‐functionalized with HA and transcytosis‐targeting peptide (TTP) 46 . These dual‐targeting NPs were proposed to efficiently cross the BBB via TTP‐mediated binding to heparin sulfate proteoglycans, followed by BCBM uptake through HA binding to CD44 expressed on BCBM cells.…”

“…Using nanoparticles modified to target PSMA and loaded with doxorubicin and lapatinib, the authors showed that the PSMA-targeted NPs had a 4.57-fold increase in tumor penetration compared to the unmodified NPs. Moreover, the median overall survival of mice treated with the PSMA-targeted NPs increased to 44 days vs 29 days for nontargeting NPs.To enhance the specificity of NPs to the BCBM tumor microenvironment (TME), Ju et al manufactured PLGA-PLL-based NP shells that were co-functionalized with HA and transcytosis-targeting peptide (TTP) 46. These dual-targeting NPs were proposed to efficiently cross the BBB via TTP-mediated binding to heparin sulfate proteoglycans, followed by BCBM uptake through HA binding to CD44 expressed on BCBM cells.…”

Recent advances in biomedical applications of bacterial outer membrane vesicles

“…The BBB strictly controls the material exchange between blood and brain, and hinders the delivery and accumulation of therapeutic drugs for intracranial diseases, making it difficult for brain-targeted drug therapies to achieve the expected effect. 120,121 In recent years, many nanotechnology-related studies have been devoted to the effective intracerebral delivery of therapeutic drugs for brain diseases, 122 such as the DDS based on low density lipoprotein receptor associated protein (LRP1) 123 and prostatespecific membrane antigen (PSMA) that can mediate endocytosis, 124 the DDS based on activating endothelial cell K ATP to promote BBB permeability, 125 the DDS that regulates endothelial Mfsd2a to antagonize its inhibition of transcytosis, 126,127 and the DDS that avoids basal LRP1 mediated brain clearance, etc. 128 However, the brain targeting efficiency is still not enough to achieve efficient treatment.…”