Dopamine Delivery via pH‐Sensitive Nanoparticles for Tumor Blood Vessel Normalization and an Improved Effect of Cancer Chemotherapeutic Drugs

Abstract

Tumor blood vessels have been reported to be abnormal in both structure and function compared with those in normal tissues, leading to a hostile microenvironment and inadequate antitumor drug delivery. Dopamine, a chemical messenger, is proven to inhibit angiogenesis and improve tumor vessel normalization. Here, a mesoporous silicon nanoparticle (MSN) is constructed that is responsive to the weakly acidic pH of the tumor extracellular matrix for steady delivery and tumor‐localized release of dopamine. Then MSNs are functionalized with amine conjugated phenylboronicacid molecules, and dopamine is loaded by reacting with phenylboronic acid. In a weakly acidic environment, MSNs intelligently release dopamine due to the hydrolysis of boronic‐ester bond between dopamine and phenylboronic acid, resulting in an evident inhibition of vascular endothelial cell migration and tubule formation. It is shown that loading of dopamine into the functional MSNs significantly prolong the circulatory half‐life of this small molecule. After intravenous injection to tumor bearing mice, this nanoformulation induce tumor blood vessel normalization, thereby improving the antitumor chemotherapeutic efficacy of doxorubicin. This study demonstrates that the pH‐responsive MSN offers great potential for delivery of dopamine in vivo and the normalization of tumor vessels by dopamine can provide an auxiliary treatment for cancer chemotherapeutic drugs.

Nanoparticle Surface Functionalization: How to Improve Biocompatibility and Cellular Internalization

“…In vivo experiments confirmed the results obtained in vitro, showing that the DOX-loaded NPs inhibited the growth of tumor more efficiently compared to free drug and also reduced side-effects (Men et al, 2020). Another example of pH-sensitive NPs is reported by Taleb et al (2019). In this work, mesoporous silicon nanoparticles were functionalized with amine conjugated phenylboronic acid linked to dopamine with a pH-sensitive covalent bond.…”

Recent advances of nanotechnology-based tumor vessel-targeting strategies

“…DA can up-regulate angiopoietin-1 (Ang1, a factor that can promote vascular pericyte recruitment and vascular maturation) in pericytes, and also can inhibit VEGF. Taleb [ 72 ] used MSNs with amine groups (NH 2 ) as the carrier, and modified with phenylboronic acid (PBA) by conjugation. and DA was loaded into NPs by reacting with PBA.…”

Anti-Cancer Nanomedicines: A Revolution of Tumor Immunotherapy

“…Some pure inorganic nanoparticles, including gold or silver nanoparticles, can modulate tumor blood vessels ( 58 , 59 ). Moreover, many reagents ( 60 ) and siRNAs ( 61 ) targeting blood vessels can be loaded into nanoparticles to retain vascular normalization ( 62 ). In addition, the remodeling of blood vessels increases the enrichment and infiltration of anti-tumor drugs and GrzB + effector T cells in tumors, which sensitize tumor to immunotherapy ( 63 , 64 ).…”