Functional Biomaterials: Multifunctional Nanoparticles as Controlled Release Platforms

Controlled release technology is indispensable for the repair and regeneration of healthy tissues as well as the treatment of diseases. Uncontrolled presentation of morphogens elicits undesirable inflammatory responses from healthy tissues. Similarly, the burst release of anticancer drugs not only leads to severe toxic effects on the healthy tissues but also induces drug resistance in the target cells. We have created several types of block copolymer nanoparticles containing distinct compartments suitable for the sequestration of hydrophobic, anti–cancer drugs as well as hydrophilic, morphogenic factors.

Hyaluronic acid based microgels (1 or 10 μm) were produced via inverse emulsion polymerization. When covalently conjugated with heparin or heparan sulfate–bearing perlecan domain I (PlnDI), the microgels effectively sequester and modulate the release of various heparin binding growth factors. Particularly, bone morphogenetic protein 2 (BMP2)–loaded, PlnDI–conjugated HA microgels stimulate chondrogenic differentiation and robust production of cartilage specific ECM both in vitro and in vivo.

Polymeric NPs with an average diameter of ~70 nm have been assembled from an amphiphilic block copolymer (ECT) of poly(ethylene glycol) (PEG) and poly(ε–caprolactone) (PCL) bearing pendant cyclic ketals. We demonstrated that doxorubicin (DOX)–loaded ECT NPs modified with targeting ligands against CD19 can be delivered to leukemic cells in a CD19–specific manner. Leukemic mice treated with CD19 targeting DOX NPs survived significantly longer and manifested a higher degree of agility, indicating reduced apparent systemic toxicity during treatment compared to mice treated with free DOX. Separately, crosslinkable block copolymer micelles (xBCM) with an average diameter of ~20 nm containing a rubbery, hydrophobic core and chemically addressable hydrophilic shell were assembled from an amphiphilic block copolymer consisting of poly(acrylic acid) (PAA) partially modified with 2 hydroxyethyl acrylate (HEA), and poly(n–butyl acryclate) (PnBA). xBCMs were employed as drug depots and the microscopic crosslinkers for the preparation of mechano–responsive HA hydrogels with anti–inflammatory properties. Amphiphilic multiblock copolymers, (PS–PAA)n, containing alternating blocks of PAA and poly(styrene) were synthesized via ATRP, followed by step growth, Click coupling. These polymers were assembled into discrete NPs with a relatively low critical micelle concentration and polydispersity. Replacing the PS block with an elastin–derived peptide, (VPGVG)2 (VG2), has led to the production of hybrid multiblock copolymer [PAA-VG2]n. These hybrid copolymers self–assemble into NPs of 250–270 nm when the PAA block is deprotonated. These hybrid multiblock copolymers are potentially useful as pH–responsive drug delivery vehicles, with the possibility of drug loading through concerted H-bonds and hydrophobic interactions.

Collaborators:

  • Ayyappan K. Rajasekaran, Nemours Center for Childhood Cancer Research

Selected Publications:

  1. Krishnan, V.; Xu, X.; Kelly, D; Snook, A.; Waldman, S. A.; Mason, R. W.; Jia, X.; Rajasekaran, A. K.* "CD19–Targeted Nanodelivery of Doxorubicin Enhances Therapeutic Efficacy in B–cell Acute Lymphoblastic Leukemia", Mol. Pharm., 2015, 12, 2101–2111.
  2. Xiao, L.; Tong, Z.; Chen, Y.; Pochan, D. J.; Sabanayagam, C. R.; Jia, X.* "Hyaluronic Acid–Based Hydrogels Containing Covalently Integrated Drug Depots: Implication for Controlling Inflammation in Mechanically Stressed Tissues" Biomacromolecules, 2013, 14, 3808–3819.
  3. Krishnan, V.; Xu, X.; Barwe, S. P.; Yang, X.; Czymmek, K.; Waldman, S. A.; Mason, R. W.; Jia, X.; Rajasekaran, A. K.* "Dexamethasone–Loaded Block Copolymer Nanoparticles Induce Leukemia Cell Death and Enhances Therapeutic Efficacy: A Novel Application in Pediatric Nanomedicine", Mol. Pharm., 2013, 10, 2199–2210.
  4. Greene, A. C.; Zhu, J.; Pochan, D. J.; Jia, X.*; Kiick, K. L.* "Poly(Acrylic Acid–b–Styrene) Amphiphilic Multiblock Copolymers as Building Blocks for the Assembly of Discrete Nanoparticles", Macromolecules, 2011, 44, 1942–1951.
  5. Grieshaber, S. E.; Paik, B. A.; Bai, S.; Kiick, K. L.; Jia, X.* "Nanoparticle Formation from Hybrid, Multiblock Copolymers of Poly(acrylic acid) and a VPGVG Peptide" Soft Matter, 2012, 9, 1589–1599.
  6. Jha, A. K.; Yang, W.; Kirn-Safarn, C. B.; Farach–Carson, M. C.; Jia, X.* "Perlecan Domain I–Conjugated, Hyaluronic Acid-Based Hydrogel Particles for Enhanced Chondrogenic Differentiation via BMP–2 Release", Biomaterials, 2009, 30, 6964–6974.