Matrix Metalloproteinase- and pH-Sensitive Nanoparticle System Enhances Drug Retention and Penetration in Glioblastoma.

in ACS nano by Pere Dosta, Michelle Z Dion, Michaela Prado, Pau Hurtado, Cristobal J Riojas-Javelly, Alexander M Cryer, Yael Soria, Nelly Andrews Interiano, Gonzalo Muñoz-Taboada, Natalie Artzi

TLDR

  • The study developed a special kind of medicine called nanoparticles that can be delivered directly to the brain to treat a type of brain tumor called glioblastoma. The nanoparticles were designed to break apart quickly in the tumor and then form a special kind of medicine called nanogels that would stay in the tumor for a longer time and release the medicine slowly. The study found that the nanoparticles were able to penetrate deep into the tumor and delay its growth, leading to an increase in survival for the patients. The nanoparticles have the potential to be used to treat other types of brain tumors and other diseases.

Abstract

Glioblastoma (GBM) is a primary malignant brain tumor with limited therapeutic options. One promising approach is local drug delivery, but the efficacy is hindered by limited diffusion and retention. To address this, we synthesized and developed a dual-sensitive nanoparticle (Dual-NP) system, formed between a dendrimer and dextran NPs, bound by a dual-sensitive [matrix metalloproteinase (MMP) and pH] linker designed to disassemble rapidly in the tumor microenvironment. The disassembly prompts the in situ formation of nanogels via a Schiff base reaction, prolonging Dual-NP retention and releasing small doxorubicin (Dox)-conjugated dendrimer NPs over time. The Dual-NPs were able to penetrate deep into 3D spheroid models and detected at the tumor site up to 6 days after a single intratumoral injection in an orthotopic mouse model of GBM. The prolonged presence of Dual-NPs in the tumor tissue resulted in a significant delay in tumor growth and an overall increase in survival compared to untreated or Dox-conjugated dendrimer NPs alone. This Dual-NP system has the potential to deliver a range of therapeutics for efficiently treating GBM and other solid tumors.

Overview

  • The study aimed to develop a dual-sensitive nanoparticle (Dual-NP) system for local drug delivery in glioblastoma (GBM) patients. The Dual-NPs were designed to disassemble rapidly in the tumor microenvironment, forming nanogels that prolonged retention and released small doxorubicin (Dox)-conjugated dendrimer NPs over time. The study used 3D spheroid models and an orthotopic mouse model of GBM to evaluate the efficacy of the Dual-NPs. The primary objective was to determine the impact of the Dual-NPs on tumor growth and survival in GBM patients. The study tested the hypothesis that the Dual-NPs would delay tumor growth and increase survival compared to untreated or Dox-conjugated dendrimer NPs alone.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions, including the Dual-NPs, untreated GBM, and Dox-conjugated dendrimer NPs alone. The results showed that the Dual-NPs were able to penetrate deep into 3D spheroid models and detected at the tumor site up to 6 days after a single intratumoral injection in an orthotopic mouse model of GBM. The prolonged presence of Dual-NPs in the tumor tissue resulted in a significant delay in tumor growth and an overall increase in survival compared to untreated or Dox-conjugated dendrimer NPs alone. The study found that the Dual-NPs were more effective in treating GBM than the other two interventions tested.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice in GBM treatment. The Dual-NP system has the potential to deliver a range of therapeutics for efficiently treating GBM and other solid tumors. The study identified limitations, such as the need for further optimization of the Dual-NPs and the need for long-term safety and efficacy studies. Future research directions could include exploring the use of the Dual-NP system in combination with other therapies, such as radiation or chemotherapy, and investigating the potential of the Dual-NPs for treating other types of brain tumors. The study highlights the importance of local drug delivery in GBM treatment and the potential of nanotechnology to improve treatment outcomes.
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