Introduction to Targeted Drug Delivery
This unit focuses on the ultimate goal of advanced pharmaceutics: delivering the drug specifically to its site of action. It covers the concepts and approaches of targeted drug delivery, particularly active versus passive targeting. It provides an in-depth look at carrier systems, specifically vesicular carriers like Liposomes and Niosomes, and particulate carriers like Nanoparticles. Finally, it introduces the highly specific biological targeting achieved through Monoclonal Antibodies.
Syllabus & Topics
- 1Targeted Drug Delivery – Concepts & Advantages: Targeted Drug Delivery: A method delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. The goal is to maximize therapeutic efficacy and minimize systemic toxicity. Advantages: Significantly reduces side effects (especially crucial for highly toxic drugs like cancer chemotherapeutics which damage rapidly dividing healthy cells), increases drug efficacy by concentrating drug at the site of action, allows reduction in total dose, protects rapidly degrading drugs (like peptides/DNA). Disadvantages: Highly complex formulation processes, expensive manufacturing, stability issues of colloidal carriers, rapid clearance by the Reticuloendothelial System (RES).
- 2Approaches: Passive vs. Active Targeting: (1) Passive Targeting: Exploits the natural pathophysiological conditions of the disease site. EPR Effect (Enhanced Permeability and Retention effect): the physiological hallmark of solid tumors. Tumor blood vessels are leaky (large endothelial gaps), and tumors lack effective lymphatic drainage. Colloidal carriers (like liposomes/nanoparticles of 10-100 nm size) leak out of these vessels and accumulate in the tumor tissue simply due to their size. (2) Active Targeting: Occurs when a specific biological interaction dictates drug accumulation. It involves conjugating a ‘targeting moiety’ or ligand (e.g., an antibody, peptide, or folic acid) to the surface of the drug carrier. The ligand binds to specific receptors overexpressed on the target cells (e.g., cancer cell membranes), triggering receptor-mediated endocytosis to internalize the carrier.
- 3Liposomes: Liposomes are spherical, self-closed vesicular structures composed of one or more concentric lipid bilayers (primarily phospholipids and cholesterol) enclosing an aqueous core. Structure: Can encapsulate hydrophilic drugs in the central aqueous core, and lipophilic drugs within the hydrocarbon chains of the lipid bilayer. Classification based on size/lamellarity: SUV (Small Unilamellar Vesicles, 20-100nm), LUV (Large Unilamellar Vesicles, >100nm), MLV (Multilamellar Vesicles, >500nm – many concentric lipid rings, like an onion). Preparation Methods: Thin-film hydration method (Bangham method), Reverse-phase evaporation, Sonication, Solvent injection. Applications: Targeted cancer chemotherapy (e.g., Doxil – liposomal doxorubicin for Kaposi’s sarcoma/breast cancer), antifungal therapy (AmBisome – liposomal amphotericin B to reduce nephrotoxicity), gene delivery, vaccine adjuvants.
- 4Stealth Liposomes & RES Clearance: The Reticuloendothelial System (RES) (primarily macrophages in the liver and spleen) recognizes standard liposomes as foreign bodies entirely circulating in the blood and rapidly phagocytoses them, clearing them from the blood before they can reach the target (e.g., a tumor). Stealth Liposomes (Long-circulating liposomes): Liposomes whose surface is modified (PEGylated) by attaching Polyethylene Glycol (PEG) chains. The PEG creates a hydrophilic ‘steric shield’ around the liposome, preventing the adsorption of opsonins (blood proteins that signal macrophages). Thus, stealth liposomes evade the RES, drastically increasing circulation half-life and allowing time for the EPR effect to work (accumulation in tumors).
- 5Niosomes: Niosomes are non-ionic surfactant-based microscopic vesicles, similar in structure to liposomes. Instead of phospholipids, they are formed by the self-assembly of non-ionic surfactants (like Spans or Tweens) and cholesterol in an aqueous medium. Advantages over liposomes: (1) Phospholipids are chemically unstable (prone to oxidation and hydrolysis) and expensive. Non-ionic surfactants are highly chemically stable, uncharged, and much cheaper. (2) Easier to handle and store. (3) Less stringent storage conditions. Disadvantages: Surfactant toxicity limits the dose compared to relatively biocompatible phospholipids. Applications: Similar to liposomes: targeted drug delivery, cosmetics (anti-aging creams), vaccine delivery, transdermal enhancement.
- 6Nanoparticles: Nanoparticles: Solid, colloidal particulate systems ranging in size from 10 nm to 1000 nm. The drug is dissolved, entrapped, encapsulated, or attached to a nanoparticle matrix. Two main types: Nanospheres (drug uniformly dispersed in the matrix) and Nanocapsules (drug confined to a cavity surrounded by a unique polymer membrane). Materials: Natural polymers (chitosan, gelatin), synthetic biodegradable polymers (PLGA, PLA). Solid Lipid Nanoparticles (SLNs): Instead of a polymer matrix, they use a solid lipid core (e.g., triglycerides, waxes) that is solid at body temperature. Advantages: High drug loading, excellent physical stability, controlled release, can cross the blood-brain barrier depending on surface modification. Preparation: Solvent evaporation, nanoprecipitation, salting out.
- 7Monoclonal Antibodies (mAbs): Monoclonal antibodies: Antibodies produced by identical immune cells that are all clones of a single parent cell. Concept: Because they are identical, they have absolute specificity for a single specific antigen (epitope). Production: Traditionally via Hybridoma technology (Kohler and Milstein) – fusing a specific antibody-producing B-cell with a myeloma (cancer) cell to create an immortal, antibody-producing hybrid cell. Applications in Targeted Delivery: (1) Direct therapeutic action (e.g., Trastuzumab/Herceptin binds to HER2 receptors on breast cancer cells, blocking growth). (2) Antibody-Drug Conjugates (ADCs): A highly toxic drug is chemically linked to a mAb. The mAb targets the cancer cell receptor, the whole ADC is internalized, and the toxic drug is released inside the cell, killing it specifically (e.g., Trastuzumab emtansine/Kadcyla).
Learning Objectives
Exam Prep Questions
Q1. What is the EPR effect in tumor targeting?
EPR stands for Enhanced Permeability and Retention effect. It’s the basis for passive targeting in tumors. Tumor blood vessels grow rapidly and abnormally, leaving wide gaps (fenestrations) between endothelial cells (Enhanced Permeability). Furthermore, solid tumors lack effective lymphatic drainage (Enhanced Retention). Therefore, nanoscale drug carriers (like liposomes or nanoparticles, 10–100 nm) injected into the blood easily leak out through the gaps into the tumor tissue and stay there, selectively accumulating without needing specific targeting ligands.
Q2. Why does Amphotericin B benefit so much from liposomal formulation?
Conventional Amphotericin B is a highly effective antifungal but is notorious for its severe nephrotoxicity (kidney damage). When formulated into liposomes (AmBisome), the drug is firmly held within the lipid bilayer. The liposomes are too large to filter through the glomerulus of the kidney, thus diverting the drug away from the kidneys and dramatically reducing nephrotoxicity, while still delivering the drug to fungal infection sites via macrophage uptake.
Q3. What is the fundamental structural difference between Liposomes and Solid Lipid Nanoparticles (SLNs)?
A liposome is a vesicular system comprising an outer lipid bilayer membrane enclosing an inner aqueous core (like a water balloon). It can carry both water-soluble drugs (in the core) and lipid-soluble drugs (in the membrane).
An SLN is a solid particulate system made of a solid lipid core matrix (solid at room and body temperature). The drug is homogeneously dispersed throughout this solid lipid matrix. SLNs offer better physical stability and controlled release compared to the fluid bilayer of liposomes.