(4aw) Nanocarriers for Controlled Delivery of Therapeutic Agents

Traditional drug formulation has relied on organic solvents
and non-ionic surfactants for compounds not soluble or bioavailable in aqueous
medium.  However, these techniques fail for many natural products and offer imperfect
solutions for others, e.g. the Taxol® formulation of paclitaxel is dose-limited
by the toxic excipient Cremophor EL.  Nanocarriers can overcome these
limitations and can be tailored to specific compounds while retaining biocompatibility
and safety.  Liposomal nanocarriers have found some clinical success, e.g. Ambisome®
formulation of amphotericin B, but are compatible with too few compounds for
broad application.  Micelles offer far more potential in terms of
biocompatibility, stability, ease of manufacture, and can be tailored to
efficiently nanoencapsulate a broad range of compounds.

My post-doctorial research has focused on the formulation of
difficult-to-formulate compounds using safe and biocompatible micelle-based nanocarriers. 
Rapamycin is a potent anti-tumor agent; however, poor solubility (< 2 μg/ml)
has prevented clinical development since its discovery over 25 years ago.   In
Glen Kwon's lab, we developed a biocompatible formulation using pegylated
phospholipids ? materials currently in clinical use with little adverse effects
(e.g. Ambisome®).  To overcome stability issues, tocopherol (Vitamin E) was
incorporated in the micelles to resist serum-induced destabilization.  The
resulting system demonstrated controlled release with a release half-life of 11
h under simulated in vivo conditions.  We are applying similar techniques
to other compounds that have proven difficult to formulate using traditional systems.

A separate thrust in my research has been the structural modification
of drugs to increase loading into nanocarriers.   Most efforts in the structural
modification of drugs have focused on improving the solubility of the drug,
e.g. the addition of sugars or polyethylene glycol chains.  While these
techniques may improve solubility, the resulting derivatives may still suffer
high toxicity, poor tumor delivery, and rapid clearance from the circulatory
system.  Micelles offer the advantages of sustained circulation, low
non-specific interaction, and high tumor accumulation ? collectively known as
the enhanced permeability and retention effect (EPR).  However, due to their
amphiphilic nature or distinct structure, many compounds may load poorly into
micelles.  Geldanamycin, a potent but poorly water soluble anti-tumor agent, was
derivatized using fatty acids via a labile ester bond.  The resulting
derivatives were extremely lipophilic but were well solubilized by micelles,
unlike the parent molecule.  Ester hydrolysis restores the active form of the
drugs upon release from the micelles. 

During my doctorial work, I focused on the development of
novel polymers for gene therapy with the same goal of creating biocompatible
and safe carriers.  Despite the success of viral carriers in the laboratory,
the progress to clinical use has been slow with too many devastating setbacks,
e.g. the development of insertional leukemogenesis by SCID children treated
using a murine leukemia virus.  In the long-term, non-viral techniques,
although comparably inefficient, will be the safer route.  In Daniel Pack's
lab, we developed several biodegradable polymeric gene carriers with the goals
of safety, biocompatibility, efficiency, and ease of manufacture.  Two of our
derivatives, a degradable cross-linked polyethylenimine and an acetylated polyethylenimine
derivative, are among some of the most efficient polymeric carriers reported to
date.   

In conclusion, my research will focus on the development of
novel nanocarriers for problem compounds, such as plasmid DNA and insoluble drug
candidates, with the goal of clinical formulation, thus keeping in mind the
necessity of biocompatibility, efficacy, and scalable facile synthesis.