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Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Identification of peptide coatings that enhance diffusive transport of nanoparticles through the tumor
Rashmi P Mohanty1, Xinquan Liu, Jae Y Kim
1Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, USA. dghosh@austin.utexas.edu.
Abstract:
In solid tumors, increasing drug penetration promotes their regression and improves the therapeutic index of compounds. However, the heterogeneous extracellular matrix (ECM) acts as a steric and interaction barrier that hinders effective transport of therapeutics, including nanomedicines. Specifically, the interactions between the ECM and surface physicochemical properties of nanomedicines (e.g. charge, hydrophobicity) affect their diffusion and penetration. To address the challenges using existing surface chemistries, we used peptide-presenting phage libraries as a high-throughput approach to screen and identify peptides as coatings with desired physicochemical properties that improve diffusive transport through the tumor microenvironment. Through iterative screening against the ECM and identification by next-generation DNA sequencing and analysis, we selected individual clones and quantify their transport by diffusion assays. Here, we identified a net-neutral charge, hydrophilic peptide P4 that facilitates significantly higher diffusive transport of phage than negative control through in vitro tumor ECM. Through alanine mutagenesis, we confirmed that the hydrophilicity, charge, and spatial ordering impact diffusive transport. The P4 phage clone exhibited almost 200-fold improved uptake in ex vivo pancreatic tumor xenografts compared to the negative control. Nanoparticles coated with P4 exhibited ∼40-fold improvement in diffusivity in pancreatic tumor tissues, and P4-coated particles demonstrated less hindered diffusivity through the ECM compared to functionalized control particles. By leveraging the power of molecular diversity using phage display, we can greatly expand the chemical space of surface chemistries that can improve the transport of nanomedicines through the complex tumor microenvironment to ultimately improve their efficacy.
Insights
Researchers identified a novel peptide coating (P4) that significantly enhances nanomedicine penetration through the tumor extracellular matrix (ECM). This peptide improves drug delivery and therapeutic efficacy in solid tumors by overcoming transport barriers.
Area of Science:
- Biomedical Engineering
- Materials Science
- Oncology
Background:
- Solid tumors present significant challenges for drug delivery due to their dense extracellular matrix (ECM), which hinders therapeutic transport.
- The physicochemical properties of nanomedicines, such as charge and hydrophobicity, critically influence their diffusion and penetration within the tumor microenvironment.
- Existing surface chemistries often fail to adequately address the barriers posed by the heterogeneous ECM.
Purpose of the Study:
- To identify novel peptide coatings that enhance nanomedicine transport through the tumor ECM.
- To leverage high-throughput screening methods for discovering peptides with optimized surface properties for improved drug diffusion.
- To evaluate the efficacy of these peptide-coated nanomedicines in preclinical tumor models.
Main Methods:
- Utilized peptide-presenting phage libraries for high-throughput screening of peptides against tumor ECM.
- Employed next-generation DNA sequencing for clone identification and quantification.
- Conducted in vitro and ex vivo diffusion assays to measure transport efficiency of phage and nanoparticles.
- Performed alanine mutagenesis to confirm the role of peptide properties in diffusion.
Main Results:
- Identified a net-neutral charge, hydrophilic peptide (P4) that significantly enhanced phage diffusion through in vitro tumor ECM.
- P4 phage clone showed a ~200-fold improved uptake in ex vivo pancreatic tumor xenografts compared to controls.
- P4-coated nanoparticles demonstrated a ~40-fold improvement in diffusivity in pancreatic tumor tissues.
- Confirmed that peptide hydrophilicity, charge, and spatial ordering are critical for enhanced diffusive transport.
Conclusions:
- Phage display is a powerful tool for discovering peptides that improve nanomedicine transport in the tumor microenvironment.
- The identified P4 peptide coating effectively enhances nanomedicine penetration by overcoming ECM barriers.
- This approach holds promise for developing more effective nanomedicine-based cancer therapies by improving drug delivery and efficacy.
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