Polyelectrolyte Multilayers for Sequential MultiDrug Delivery

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Polyelectrolyte Multilayers for Sequential
Multi-Drug Delivery Helen F. Chuang, Mara L.
McDonald, and Renee C. Smith, Chemical
Engineering, MIT Paula T. Hammond, Professor,
Chemical Engineering, MIT SBE ICBN 2006
Preliminary Data
Future Directions
Concept
Ongoing and Upcoming Research
Single Drug Incorporation and Release
In vitro Response to Antimicrobial Films

• Assess efficacy against biofilms.
• Incorporation of small-molecule drugs through
  complexing agents.
• Incorporation of biologic drugs based on
  peptides, proteins, and nucleic acids.
• Synthesize and characterize poly(ß-amino esters)
  and polyphosphazenes to extend release timescale.
• Mechanical testing.
• In vivo evaluation.

Antimicrobial films incorporating gentamicin were
constructed with dosage tuning control.

• 10 of primary arthroplasty fail.
• Common causes Aseptic loosening and infection
• Competing technologies Bacterin,
• Spire Biomedical, and Implant Sciences.
• Envisioned solution by LbL coating
• - Wear-resist base layer (PAA/PAH)n
• - Degradable layers sequentially delivering
• Antibiotics (e.g. gentamycin, tobramycin)
• Osteoinductive and angiogenic factors (e.g.
  BMP-2, bFGF)
• - Advantage over existing technology
• Higher efficacy, more therapeutically
  versatile, lower cost, more conformal, and more
  scalable than ion bombardment.

Antimicrobial efficacy of these films were
validated with standard liquid macrodilution and
Kirby-Bauer disk diffusion assays of
Staphylococcus aureus.
Build-up of (Poly 1/PS)20 films
Degradable LbL multilayers for sequential,
controlled release of multiple therapeutic agents.
Protein Encapsulation

• Criteria Biocompatible
• Biodegradable
• Preserves drug efficacy
• Controllable, sustained release
• Stable in storage

• Enzymes have been incorporated with
• 100 retention of biological activity.
• Extended release of over a month.
• Controls over release rate via choice of
  polymers.

Dual Drug Incorporation and Release
Insertion of a crosslinked (PAA/PAH)1 spacer
layer resulted in sequential delivery of
polysaccharides heparin and dextran.
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Other Applications

• Intraocular Lens (IOL)
• Sequential elutions of pain killer and
  anti-inflammatory to address complications from a
  cataract surgery.
• Drug-Eluting Stent (DES)
• A completely biodegradable coating to elute
  antithrombotic agents.
• Self-Scheduling Vaccines
• Eliminates the need for multiple injections.
• Coated Seeds
• Can elute their own schedules of fertilizers and
  pesticides, eliminating the time, expense, and
  negative environmental impact of large-scale
  spraying.
• .

Biocompatibility with Mammalian Cultures
Confirmed non-toxicity towards - NIH 3T3 (by
Lynn et al.) murine embryonic fibroblast-
MC3T3 murine osteoblast - F32 murine
lymphoid - Cos-7 simian kidney By MTT and cell
proliferation assays.
In vitro Response to Heparin-loaded Films
Advantages of LbL Drug Delivery
(Poly 1/Hep)n films were co-incubated with liquid
cultures of F32 cells, an engineered murine
lymphoid line. We demonstrated that (1) heparin
was released in its active form, (2) Poly 1 was
not cytotoxic to F32, and (3) in vitro dosage of
heparin from films can be easily controlled by
film size or film thickness.

• ? Disruptive feature delivery of multiple
  distinct agents sequentially from a single
  coating, each with an independently tunable
  delivery profile.
• ? Process is very scalable.
• ? Spatial and temporal flexibility.
• Spatial can coat surfaces of any size,
  geometry, and degree of roughness, i.e.
  conformality
• Temporal can tune durations of drug release
  and of delays between sequential drugs.
• ? Simple and inexpensive to fabricate.
• ? Mild aqueous fabrication protocol making it
  ideal for delivery of proteins and other biologic
  drugs that are sensitive to other polymeric
  encapsulation procedures.

Acknowledgements Dr. Robert S. Langer, MIT Dr.
David M. Lynn, UWI Madison Dr. Myron Spector,
Harvard Medical School Dr. David Berry, Harvard
Medical School Kris C. Wood, Christopher R.
Loose, Aliac Carter, Matt Clancy, and Jenny Yeh,
MIT Deshpande Center for Innovation,
MIT Department of Defense for NDSEG
Fellowship NSF for Fellowship Lucent Technologies
for BLGR Fellowship
Expanded Library of Polymers
FE film equivalent amount of heparin, with
associated amount of Poly 1
Drug potentiation - Promotes F32 cell uptake of
heparin - Imparts bateriocidal capacity to
otherwise biocompatible polyanions such as
dextran, alginate, and heparin.