Advanced Drug Delivery Systems Lecture 4

Advanced Drug Delivery Systems

• Site Directed Drug Targeting (Lecture 4): Focuses on drug carriers for targeted delivery.

Carriers for Drug Targeting

• Soluble macromolecular carrier systems: These systems exist.
• Colloidal/Nano-carrier systems: These systems exist.
  • Lipid-based systems: Includes liposomes, solid-lipid nanoparticles, non-emulsions, and others.
  • Polymer-based systems:
    • Dendrimers: Derived from the Greek word "dendron" meaning "tree". Have a tree-like branched architecture. Their size ranges between 1-100nm. Can include functional groups in 3 parts to modulate solubility, permeability, and thermal stability. Design can include passive targeting with PEG coats and active targeting with ligands like folic acid. Dendrimers under preclinical studies are made of:
      • Polyamidoamine (PAMAM) dendrimers: Hydrophilic, biocompatible, and non-immunogenic.
      • Poly-propyleneimine (PPI) dendrimers: Contain alkyl and tertiary amine groups.
      • Poly-L-lysine (PLL) dendrimers: Have positively charged primary amine terminal groups.
    • Polymeric micelles: Nano-sized particles made of polymer chains. Formed by self-assembly in liquid through hydrophobic or ion pair interactions between polymer segments. Each chain is amphiphilic (hydrophobic core and hydrophilic outer segment). Size is 5nm to 100nm and they have narrow particle distribution. Hydrophilic components (mainly PEG) form the outer shell and provide stealth character for passive targeting. Hydrophobic component includes Polyaspartate, polylactide, or polycaprolactone. More stable and have low critical micellar concentrations compared to surfactant micelles. Targeting groups can be added to the surface. Drug solubilised within the core.
  • Solid polymeric nanoparticles: Prepared using natural or synthetic polymers. Commonly, biodegradable synthetic polymers such as poly(lactide-co-glycolide) (PLGA), polylactic acid (PLA), and polycaprolactone (PCL) are used. Polysaccharides like chitosan are also used. In the body, copolymers of polylactic and glycolic acid undergo hydrolysis into glycolic and lactic acid, which are removed by the body via the citric acid cycle. Used for passive targeting of drugs to tumour sites via the EPR effect. PEG-PLGA copolymers are used as stealth nanoparticles to prolong circulation time. Active targeting with targeting ligands is also studied.

Formulations of Some Drug Targeting Delivery Systems

• Polymeric micellar formulations:
  • Paclitaxel-incorporating micelles (NK105): Contain block copolymers with PEG and polyaspartate. The MW is 20kDa with PEG at 12kDa. Paclitaxel is physically entrapped (23%w/w) in the core via hydrophobic interactions. In animal studies, slower clearance from the plasma with increased half-life (5x longer) was seen, along with a 2-3 fold increase in PTX concentration at the tumour site.
  • Cisplatin-incorporating micelles (NC-6004): Contains PEG-poly(sodium-L-glutamate) block copolymer. PEG forms the outer hydrophilic shell. The hydrophobic core contains cisplatin complexed with the PGA component. Overall MW is 18kDa with 12kDa PEG contribution. Size is 30nm. Improved circulation time and tumour targeting, reducing side effects.

Stimuli-Responsive Nano-carrier Systems (Smart DDS)

• Ideal Drug Delivery Systems: Release the required amount of drug at the target site. Efficient drug release strategies are needed for targeted cells, tissues, or organs, such as on-demand processes (on/off switching) providing tailored release profiles. On-demand drug-delivery is possible through design of stimulus-responsive systems.
• Internal stimuli: Triggered drug release from systems based on pH changes, enzymes, redox potential, and solute concentrations. pH responsive systems, for example take advantage of pH variations existing across organs.
• External stimuli: Triggered drug release from systems based on temperature change, magnetic fields, ultrasound, and electric fields.
  • Thermoresponsive systems: Retain drug load at body temperature (~37°C) and rapidly release it at target site (~40-42°C). Systems include liposomes, polymer micelles, or nanoparticles.
  • Magnetically responsive systems: Magnetic guidance and drug release under permanent magnetic fields can occur; temperature increase in an alternating magnetic field; magnetic resonance imaging (MRI) development for associated therapy and diagnostics. Examples include core-shell nanoparticles made of magnetite (Fe3O4) coated with silica or polymer, or magnetoliposomes with Fe3O4 nanocrystals encapsulated within liposomes. Continuous magnetic fields can trigger drug delivery in ferrogel systems made of Pluronic F127 micelles encapsulating super magnetic iron oxide nanoparticles. Alternating magnetic fields increase heat and may lead to hyperthermia for tumour treatment.
• Examples/details (Liposomes): Conventional and PEGylated liposomes. These can be adapted for theranostic or ligand-targeted uses to provide advanced drug delivery.