Background Reading

Compounds need to possess balanced hydrophilicity and hydrophobicity to be efficiently absorbed from oral dosing or safely administered by i.v. injection. Unfortunately, the majority of the potent anticancer compounds in the development pipeline suffer from limited water solubility, and using conventional pharmaceutical formulations to improve the solubility is challenging, resulting in termination of many potent compounds in early development. Moreover, these highly cytotoxic agents often lack selectivity in drug biodistribution and cell killing, inducing severe side effects.

In the drug delivery field, nanomedicine is often referred to as assembling a drug into a pharmaceutical vehicle that is in the nanometer size range (10-200 nm) for improved physiochemical properties (i.e. increased solubility, stability and dissolution), pharmacokinetics, or tissue selectivity (i.e. inflamed tissue and cancer).  These nanoparticles encompass liposomes, micelles, polymeric nanoparticles, dendrimers, and macromolecules. Nanomedicine is particularly attractive for tumor diagnosis and therapy owing to its unique feature termed as enhanced permeability and retention (EPR) effect: nanoparticles selectively extravasate into a tumor through its leaky vasculature, while sparing the normal tissues with a rigid capillary structure.  Small molecule drugs, on the other hand, permeate into both normal and cancerous tissues with no selectivity, inducing significant side effects. Additionally, tumor targeted drug delivery can be enhanced by conjugating a targeting ligand (i.e. antibody) onto nanoparticles that recognizes a surface receptor on tumor cells, resulting in improved efficacy.  The tremendous promise of nanomedicine in non-invasive tumor imaging, early detection and drug delivery is evidenced with many products in clinical use and trials (Clinical Pharmacology & Therapeutics 2014).

Although nanoparticles can be employed to improve water solubility and tissue selectivity of anticancer compounds, there are several biological barriers to their delivery (Fig). Nanoparticles injected intravenously must evade reticuloendothelial (RES) and renal clearance, and remain stable in plasma during systemic circulation, such that a sufficient dose of the nanoparticle and drug can interact with tumor physiology. Once particles successfully extravasate into the tumor compartment, the particles must travel through the stroma against high interstitial fluid pressure (IFP) gradients, and ultimately interact with the target cells or release the drug payload for pharmacological effect. Therefore, nanoparticle formulations must be carefully designed to overcome these barriers to achieve significant therapeutic activity.

Figure. The three phases of drug delivery by nanoparticles.

The Li lab has developed several drug delivery technologies to overcome these barriers:

Lipid-based Delivery Systems

• Active Loading of Insoluble or Membrane Impermeable Drugs into Liposomal Core
• Solid Lipid Nanoparticles
• Targeting Ligand for Cell- and Tissue-Specific Delivery of Liposomes
• Microfluidic Technologies to Fabricate Nano- and Microparticles
• Sustained Local Drug Release
• Heat-activated Cytotoxic Thermosensitive Liposomes
  • Multifunctional Thermosensitive Liposomes for Noninvasive Measurements of Real-time Drug Delivery
  • Noninvasive Imaging of Therapeutic Biomarker for Thermosensitive Liposomal Therapy

Polymer-based Delivery Systems

• Cellax System for Docetaxel
  • P-gp & Overcoming Multidrug Resistance (MDR)
  • Tumor Microenvironment & Antistromal Activity
• Celludo System for Podophyllotoxin

Overcoming Multidrug Resistance (MDR)

• Preventing Pgp Overexpression with Cellax

Tumor Microenvironment

• Cellax System for Targeted Delivery