Dendritic Block Copolymer Micelles as New Targeted Drug Delivery Systems

Summary

Principal Investigator: Paula Hammond
Affiliation: Massachusetts Institute of Technology
Country: USA
Abstract: A barrier to the effective delivery of cancer chemotherapy drugs is the transport of the toxic drug to specific tumor cells, ensuring high uptake of drug by cancer cells while avoiding noncancerous ones. One means of accomplishing this method is the use of ligand groups added to the exterior of a nano-scale drug carrier;however, much is not understood about maximizing these ligand interactions to achieve orders of magnitude improvements in efficacy and reduced side effects. The primary objective of this work is the synthesis of new amphiphilic linear-dendritic block copolymers that self-assemble in the solution state to generate stable micelles with highly branched, dense dendritic groups in the exterior shell. Due to the unique nature of the dendritic outer block, these micelles will act as vessels with a highly tunable 3D presentation of ligand, enabling the creation of delivery nanoparticles with homo- or heterogeneous surfaces that enable cluster presentation of ligand. Biological studies of cellular interactions with ligands indicate that not only the valency but spatial factors such as branching mode and the localized clustering of groups are important in influencing binding and downstream signaling processes. This important aspect of targeting may have potentially significant impact on all kinds of nanoparticle delivery systems, from liposomes to inorganic nanoparticles. If this capability can be transferred to drug delivery vehicles, it may greatly impact efficacy and specificity of targeted delivery. Preliminary findings with the proposed systems suggest that ligand clustering can lead to significantly higher micelle cellular uptake compared to homogeneous distribution of ligand. The first specific aim is the synthetic optimization of a linear-dendritic diblock copolymer series generated in the Hammond group, consisting of a biocompatible linear polypeptide hydrophobic block and a hydrophilic polyester dendron to which targeting ligands will be conjugated via PEG linkers. Linear backbone modification, direct drug conjugation and photocrosslinkable groups within the hydrophobic core will be investigated to enhance drug loading and sustained release of drug. Micelle stability and drug release studies will be performed to determine release characteristics of each system under physiological and endosomal conditions. Results of these studies will be used to guide further synthesis of the copolymer and to ultimately select the most promising copolymer systems for further study. The second specific aim of this work is to examine the role of valency and ligand clustering through the use of mixed micelle clusters to significantly enhance efficacy in the delivery of cytotoxic drugs in vitro, with specific emphasis on peptide sequence, LyP-1, discovered using phage display methods, which exhibits a highly specific recognition to p32 surface receptors on a subset of tumor cells and tumor lymphatic cells including breast carcinomas. This system will be of particular therapeutic and clinical relevance, and will be used to address the universality of impact of valency and clustering in ligand presentation by extending the concept to different receptor types. Results of this Aim will be compared with recently obtained results from folate targeted micelles to determine differences in the significance of clustering. In the third specific aim, the best micellar-drug nanoparticle formulations from this analysis will be evaluated using an in vivo animal model. These studies will focus on both folate and LyP-1 as specific tumor ligands with potential clinical interest, with a focus on pharmacokinetics, biodistribution as a function of time, organ specificity, accumulation of drug carriers, intratumor uptake, and tumor inhibition as well as cytotoxicity.
Funding Period: 2009-09-01 - 2011-08-31
more information: NIH RePORT

Top Publications

  1. pmc Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment
    Zhou J Deng
    Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Rm 76 553, Cambridge, Massachusetts 02139, United States
    ACS Nano 7:9571-84. 2013
  2. pmc Crosslinked linear polyethylenimine enhances delivery of DNA to the cytoplasm
    Daniel K Bonner
    Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue Rm 66 350, Cambridge, MA 02139, USA
    J Control Release 167:101-7. 2013
  3. pmc Enhanced stability of polymeric micelles based on postfunctionalized poly(ethylene glycol)-b-poly(γ-propargyl L-glutamate): the substituent effect
    Xiaoyong Zhao
    Department of Chemical Engineering, Massachusetts Institute of Technology and Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts 02139, USA
    Biomacromolecules 13:1315-22. 2012
  4. pmc Self-assembled RNA interference microsponges for efficient siRNA delivery
    Jong Bum Lee
    Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Nat Mater 11:316-22. 2012
  5. pmc Intracellular trafficking of polyamidoamine-poly(ethylene glycol) block copolymers in DNA delivery
    Daniel K Bonner
    Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
    Bioconjug Chem 22:1519-25. 2011
  6. pmc Controlling in vivo stability and biodistribution in electrostatically assembled nanoparticles for systemic delivery
    Zhiyong Poon
    The Koch Institute for Integrative Cancer Research at MIT, Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
    Nano Lett 11:2096-103. 2011
  7. pmc Layer-by-layer nanoparticles with a pH-sheddable layer for in vivo targeting of tumor hypoxia
    Zhiyong Poon
    The Koch Institute for Integrative Cancer Research at MIT, Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
    ACS Nano 5:4284-92. 2011
  8. pmc Highly stable, ligand-clustered "patchy" micelle nanocarriers for systemic tumor targeting
    Zhiyong Poon
    Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
    Nanomedicine 7:201-9. 2011

Detail Information

Publications10

  1. pmc Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment
    Zhou J Deng
    Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Rm 76 553, Cambridge, Massachusetts 02139, United States
    ACS Nano 7:9571-84. 2013
    ....
  2. pmc Crosslinked linear polyethylenimine enhances delivery of DNA to the cytoplasm
    Daniel K Bonner
    Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue Rm 66 350, Cambridge, MA 02139, USA
    J Control Release 167:101-7. 2013
    ....
  3. pmc Enhanced stability of polymeric micelles based on postfunctionalized poly(ethylene glycol)-b-poly(γ-propargyl L-glutamate): the substituent effect
    Xiaoyong Zhao
    Department of Chemical Engineering, Massachusetts Institute of Technology and Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts 02139, USA
    Biomacromolecules 13:1315-22. 2012
    ..The present work demonstrated that the PEG-b-PPLG can be a uniform block copolymer platform toward development of polymeric micelle delivery systems for different drugs through the facile modification of the PPLG block...
  4. pmc Self-assembled RNA interference microsponges for efficient siRNA delivery
    Jong Bum Lee
    Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Nat Mater 11:316-22. 2012
    ..More than half a million copies of siRNA can be delivered to a cell with the uptake of a single RNAi-microsponge. The approach could lead to novel therapeutic routes for siRNA delivery...
  5. pmc Intracellular trafficking of polyamidoamine-poly(ethylene glycol) block copolymers in DNA delivery
    Daniel K Bonner
    Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
    Bioconjug Chem 22:1519-25. 2011
    ..Nuclear entry is demonstrated to be the most significant barrier to more efficient delivery and will be addressed in future versions of the system...
  6. pmc Controlling in vivo stability and biodistribution in electrostatically assembled nanoparticles for systemic delivery
    Zhiyong Poon
    The Koch Institute for Integrative Cancer Research at MIT, Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
    Nano Lett 11:2096-103. 2011
    ....
  7. pmc Layer-by-layer nanoparticles with a pH-sheddable layer for in vivo targeting of tumor hypoxia
    Zhiyong Poon
    The Koch Institute for Integrative Cancer Research at MIT, Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
    ACS Nano 5:4284-92. 2011
    ..We further demonstrate that this concept for tumor targeting is potentially valid for a broad range of cancers, with applicability for therapies that target hypoxic tumor tissue...
  8. pmc Highly stable, ligand-clustered "patchy" micelle nanocarriers for systemic tumor targeting
    Zhiyong Poon
    Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
    Nanomedicine 7:201-9. 2011
    ..We also demonstrate a fourfold increase in efficacy of paclitaxel when delivered in the targeted nanoparticle systems, while significantly decreasing in vivo toxicity of the chemotherapy treatment...