Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles

Our plain-English summary of Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles, by A.H. Colby, R. Liu, M.D. Schulz, et al (Scientific Reports, 2016).

The study

• Authors: A.H. Colby, R. Liu, M.D. Schulz, R.F. Padera, Y.L. Colson, M.W. Grinstaff
• Journal: Scientific Reports
• Published: 2016;6:18720
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of peritoneal cancers, including mesothelioma, ovarian, and pancreatic cancer, which regularly employ regimens of intravenous and/or intraperitoneal chemotherapy (e.g., gemcitabine, cisplatin, pemetrexed, and paclitaxel) with limited results. Here, we show that a "two-step" nanoparticle (NP) delivery system may address this limitation. This two-step approach involves the separate administration of NP and drug where, first, the NP localizes to tumor. Second, subsequent administration of drug then rapidly concentrates into the NP already stationed within the target tissue. This two-step method results in a greater than 5-fold increase in intratumoral drug concentrations compared to conventional "drug-alone" administration. These results suggest that this unique two-step delivery may provide a novel method for increasing drug concentrations in target tissues.

In plain English

This laboratory and animal study tested a "two-step" way of delivering the cancer drug paclitaxel to mesothelioma tumors. It did not study asbestos exposure. The authors first gave tiny pH-responsive particles (expansile nanoparticles, eNPs) containing no drug, then gave paclitaxel separately, so the drug could collect in particles already in the tumor. In a laboratory test, paclitaxel concentrated in swollen particles at more than four times its level in the surrounding liquid. Human mesothelioma cells (MSTO-211H) pre-treated with eNPs took up nearly 5 times more labeled paclitaxel than cells pre-treated with media or comparison PLGA particles. In female nude mice with these human tumors in the abdomen, average tumor paclitaxel was 2,341 ng/g after eNP pre-treatment (n = 21), versus 439 ng/g after saline (n = 14) and 487 ng/g after PLGA particles (n = 13). Drug packed inside the particles delivered about 50-fold more than the two-step method. No toxic effects were observed, but the dose was chosen to be well tolerated, so toxicity differences could not be judged. The authors called the design a proof of concept.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiments and animal experiment in a mouse model of peritoneal mesothelioma
• Who was studied: A human mesothelioma cell line (MSTO-211H) grown in the laboratory, and female athymic nude mice aged 6 to 8 weeks injected with these tumor cells in the abdomen. There were 3 eNP and 3 saline mice in the imaging study. In the measurement study there were 21 eNP, 14 saline, 13 PLGA-NP and 10 Pax-eNP tumor measurements.
• Exposure: No asbestos exposure was studied. On day 11 after tumor cell injection, mice received drug-free eNPs (0.3 mL of 20 μg/mL), drug-free PLGA nanoparticles, or saline into the abdomen. On day 13 they received 10 mg/kg paclitaxel. A comparison group received paclitaxel-loaded eNPs (Pax-eNPs). Tumors were collected on day 16.
• Main results:
  • In a dialysis experiment, paclitaxel concentrated in the swollen gel particles at a ratio of more than 4 to 1 compared with the surrounding liquid.
  • In MSTO-211H mesothelioma cells, uptake of labeled paclitaxel was nearly 5 times greater in cells pre-treated with eNPs than in cells pre-treated with media or PLGA-NPs.
  • In the mouse imaging study, labeled eNPs and labeled paclitaxel were seen together in tumor nodules in eNP pre-treated mice. Neither signal was visible in saline pre-treated mice.
  • Average tumor paclitaxel concentration (mean plus or minus standard error) was 2,341 plus or minus 335 ng/g in eNP pre-treated mice (n = 21). It was 439 plus or minus 125 ng/g in saline pre-treated mice (n = 14) and 487 plus or minus 45 ng/g in PLGA-NP pre-treated mice (n = 13). The eNP group differed significantly from both (P less than 0.05). The PLGA-NP and saline groups did not differ significantly.
  • Paclitaxel-loaded eNPs (Pax-eNPs) delivered about 50-fold more drug to tumor than eNPs plus paclitaxel, and about 250-fold more than saline plus paclitaxel or PLGA-NPs plus paclitaxel.
  • The authors observed no toxic or adverse effects during the study.
• The authors' conclusion: The authors concluded that this initial design was a proof of concept, giving more than a 5-fold increase in tumor paclitaxel concentration compared with giving paclitaxel alone.
• Limitations the authors state:
  • Drug and particle doses were chosen to be well tolerated, so no toxicity, and no difference in toxicity between paclitaxel alone and eNPs plus paclitaxel, could be detected.
  • The tumor drug measurement was a bulk measurement, so it could not show whether the particles concentrated the drug inside or outside the cells.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Chemotherapy, Gemcitabine, Cisplatin, Pemetrexed (Alimta).

Related studies

• Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma — R. Liu, A.H. Colby, et al. (2016)
• Extracellular vesicles isolated from adipose tissue-derived mesenchymal stromal cells as carriers for Paclitaxel delivery — A. Marcianti, E. Spampinato, et al. (2025)
• Paclitaxel-loaded expansile nanoparticles in a multimodal treatment model of malignant mesothelioma — M.D. Schulz, K.A. Zubris, et al. (2011)
• Paclitaxel-loaded expansile nanoparticles enhance chemotherapeutic drug delivery in mesothelioma 3-dimensional multicellular spheroids — H. Lei, S.C. Hofferberth, et al. (2015)
• Curcumin loaded PLGA-poloxamer blend nanoparticles induce cell cycle arrest in mesothelioma cells — L. Mayol, C. Serri, et al. (2015)
• Nanoparticle drug-delivery systems for peritoneal cancers: a case study of the design, characterization and development of the expansile nanoparticle — A.H. Colby, N.H. Oberlies, et al. (2017)

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