1. Silicon microparticles (injectable nanoparticle generator, iNPG) were loaded with a polymeric form of the chemotherapeutic doxorubicin (pDox); iNPG then released pDox nanoparticles (NPs) into tumor tissue that in turn delivered free doxorubicin (Dox) into tumor cells
2. Mice with metastatic lung tumors showed increased survival when treated with iNPG-pDox in comparison to other methods of Dox treatment.
Evidence Rating Level: 2 (Good)
Study Rundown: Chemotherapeutics need to overcome many biological obstacles in order to successfully kill tumor cells. These include specifically targeting tumors as opposed to healthy tissue, as well as entering, remaining and surviving within tumor cells. Here, researchers developed iNPG-pDox in order to address these challenges of chemotherapeutic delivery.
iNPG-pDox delivered Dox to tumor cells in two steps. First, iNPG-pDox accumulated in tumor tissue, where it released pDox NPs. Second, pDox NPs were taken up by tumor cells, where acidic pH promoted Dox release by dissolving the pH-sensitive linker between Dox and its associated polymer. iNPG-pDox was administered to mice with triple-negative breast cancer that metastasized to the lungs. Treatment resulted in lung Dox concentrations which were significantly elevated in comparison to those resulting from other Dox delivery methods. Further analysis showed iNPG specifically localizing in microvessels of the lung metastatic tumors. Mice treated with iNPG-pDox showed greater survival in comparison to mice given Dox via other delivery methods. The researchers then tested the potential therapy in a multidrug resistant (MDR) cell line, demonstrating decreased cell viability following pDox NP treatment in comparison to Dox alone. Mice inoculated with these MDR cells and treated with iNPG-pDox showed a greater reduction in tumor load as compared to treatment with free Dox.
Though this work included initial safety studies, further testing is warranted before considering clinical use of iNPG-pDox. Overall, this study presents a novel drug delivery technology which may circumvent many common challenges of chemotherapeutic drug delivery.
Click to read the study in Nature Biotechnology
Relevant Reading: Principles of nanoparticle design for overcoming biological barriers to drug delivery
In-Depth [animal study]: pDox was synthesized by conjugating poly(L-glutamic acid) to Dox via a pH-sensitive linker, causing Dox to be released at low pH within tumor cells. Nanopores within iNPG were loaded with pDox, which formed 30-80 nm pDox NPs at physiological pH.
A mouse model of metastatic MDA-MB-231 triple-negative breast cancer was used to test the efficacy of iNPG-pDox. Compared with pDox NPs or Dox alone, intraperitoneal administration of 6 mg/kg iNPG-pDox led to higher Dox concentrations in the lung and liver one week following administration (p<0.05, n=3). Concentrations of Dox in the heart were lower in the iNPG-pDox group (p<0.01), suggesting that iNPG-pDox may not carry the risk of cardiotoxicity posed by high doses of free Dox. Histological examination revealed preferential iNPG-pDox localization to lung tumor microvessels, and flow cytometry analysis showed a higher percentage of Dox-positive endothelial (p<0.05) and lung tumor cells (p<0.01) in the iNPG-pDox treatment group as compared to free Dox or liposome-encapsulated Dox (Doxil). Biweekly 6 mg/kg iNPG-pDox treatment also resulted in a median survival time of 233 days as compared to 84-124 days in other treatment groups (p<0.01 vs. free Dox, iNPG alone, or Doxil, n=10 mice per group).
Additional experiments considered the response of MDA-MB-231/MDR cells to iNPG-pDox treatment. Cell viability in vitro was greatly decreased when Dox was encapsulated in NPs as compared to equivalent concentrations of Dox alone. Furthermore, mice injected with the MDR cells showed decreased tumor growth when treated biweekly with 6 mg/kg iNPG-pDox as compared to Dox alone (p<0.05 at 2, 4 and 6 weeks, n=5).
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