Advanced Drug Delivery Systems: Principles and Applications

Posted on Mar 21, 2025 in Biotechnology

Basic Concepts in Drug Delivery

Drug delivery refers to methods used to administer pharmaceutical compounds for therapeutic effects. The goal is to enhance bioavailability, improve efficacy, enable targeted release, and optimize administration routes. Drug names include chemical (precise structure), generic (officially recognized), trade (brand-specific), and street names. Delivery strategies include passive targeting (e.g., liposomes accumulate in tumors via Enhanced Permeability and Retention (EPR)) and active targeting (e.g., ligands direct drugs to specific cells).

Administration routes impact absorption and elimination:

  • Oral: Convenient but with potentially low absorption.
  • Parenteral: Rapid but requires needles.
  • Transdermal: Continuous but limited to lipophilic drugs.
  • Pulmonary: Fast but with complex lung interactions.
  • Nasal: Bypasses first-pass metabolism but has absorption limits.

Absorption depends on molecular weight, lipid solubility, ionization, and stability. Pharmacokinetics (PK) describes absorption, distribution, metabolism, and excretion, while pharmacodynamics (PD) focuses on drug effects. Drug release can be immediate, sustained, or zero-order. Barriers include physical (cell membranes, Blood-Brain Barrier (BBB)), metabolic (enzymatic degradation), and efflux pumps. Controlled drug delivery optimizes therapy by reducing side effects and improving targeting.

Drug Modification Strategies

Drug modification enhances solubility, stability, and bioavailability. Strategies include prodrugs (inactive forms converted into active drugs), PEGylation (attaching polyethylene glycol (PEG) to improve solubility and circulation), nanocarriers (liposomes, micelles, polymeric nanoparticles), and antibody-drug conjugates (ADCs for targeted therapy).

Methods to improve solubility include salt formation, nanocrystals, cyclodextrins, and pH adjustment. Stability is improved by encapsulation, chemical modifications, freeze-drying, and biodegradable coatings. Drug targeting strategies involve passive targeting (EPR effect) and active targeting (ligands direct drugs to specific cells). Examples of modified drugs include PEGylated interferon (extended half-life), liposomal doxorubicin (reduced toxicity), and trastuzumab emtansine (HER2-targeted chemotherapy). Challenges include high costs, regulatory hurdles, and unpredictable metabolism. Future advancements focus on smart delivery, gene therapy, and AI-driven drug design.

Polymer-Drug Conjugates

Polymer-drug conjugates enhance drug solubility, targeting, and controlled release while reducing toxicity. Components include polymers (natural: dextran, chitosan; synthetic: PEG, poly(lactic-co-glycolic acid) (PLGA)), linkers (pH-sensitive, enzyme-cleavable, redox-sensitive), and active drugs (chemotherapeutics, antibiotics, anti-inflammatories). Covalent attachment forms stable conjugates via amide bonds or thiol-maleimide coupling, while non-covalent interactions use hydrophobic or electrostatic forces.

Drug release occurs via:

  • pH sensitivity: Tumor targeting.
  • Enzyme cleavage: Matrix metalloproteinase (MMP)-sensitive PEG-doxorubicin.
  • Redox sensitivity: Glutathione-triggered paclitaxel release.
  • Diffusion: PLGA implants.

Applications include cancer therapy (EPR effect), anti-inflammatory treatments, antibiotic delivery, and gene therapy. Challenges include toxicity, manufacturing complexity, and non-target accumulation. Future directions involve smart responsive polymers and hybrid delivery systems.

Controlled Drug Delivery Systems

Controlled drug delivery regulates drug release to enhance efficacy and reduce side effects. Compared to conventional delivery, it maintains stable plasma levels, reduces dosing frequency, and improves patient compliance.

Delivery mechanisms include:

  • Diffusion-controlled: Reservoir and matrix systems.
  • Chemically controlled: Biodegradable implants, hydrolysis-based release.
  • Osmotically controlled: Pressure-driven OROS® tablets.
  • Stimuli-responsive: pH, temperature, magnetic field.

Polymers used include biodegradable (PLGA, chitosan) for implants and non-biodegradable (PEG, ethylene-vinyl acetate (EVA)) for transdermal patches. Applications span oral (pH-sensitive coatings), transdermal (nicotine patches), injectable/implantable (chemotherapy implants), ocular (intraocular implants), and pulmonary (microsphere-based inhalers). Challenges include high costs, immune responses, and polymer degradation control. Future trends include smart drug delivery, 3D-printed tablets, gene-based systems, and nanotechnology integration.

Microparticles and Nanoparticles for Drug Delivery

Nanotechnology involves materials at the nanoscale (1-100 nm), while microparticles range from 1-1000 µm. Nanoparticles are ideal for passing biological barriers, whereas microparticles work well for inhalation therapy. Advantages of microparticles include easy formulation, better lung retention, and slow drug release over weeks. Nanoparticles can enter cells, travel through capillaries, and avoid immune detection for targeted therapy.

Types include polymeric nanoparticles (PLGA, PLA, Chitosan), lipid-based nanoparticles (Liposomes), and dendrimers (branched polymers for high drug loading). Key design factors are delivery route, tissue interaction, release rate, and polymer biocompatibility. Nanoparticles can be synthesized through emulsion polymerization, solvent evaporation, nanoprecipitation, interfacial polymerization, emulsification-solvent evaporation, double emulsion (W/O/W), emulsion solvent diffusion, salting-out technique, desolvation, and PRINT method. Surfactants stabilize nanoparticles and reduce size; sonication creates nanoparticles, while vortex mixing forms microparticles. Liposomes can carry hydrophilic drugs in the core and hydrophobic drugs in the lipid layer. Hydrophilic drugs are added during hydration, and hydrophobic drugs are inserted into the lipid bilayer. Challenges include rapid clearance, toxicity risks, and aggregation. Overcoming these challenges involves PEGylation and steric stabilization. Applications include cancer therapy, gene therapy, vaccines, and targeted drug delivery.

Characterization of Nanoparticles

Characterization ensures stability, effectiveness, and proper function. Size and distribution are analyzed through dynamic light scattering (DLS), microscopy (transmission electron microscopy (TEM), scanning electron microscopy (SEM)), nanoparticle tracking analysis (NTA), tunable resistive pulse sensing (TRPS), and hyperspectral imaging. Surface charge and stability are measured using zeta potential and nanoparticle stability tests like turbidity changes, pH effects, and critical aggregation concentration. Drug loading and release are analyzed by measuring encapsulated and unencapsulated drug amounts, using centrifugation, dialysis, high-performance liquid chromatography (HPLC), and enzyme-linked immunosorbent assay (ELISA). Drug release mechanisms include diffusion, desorption, and polymer erosion. Surface characterization techniques include Auger Electron Spectroscopy (AES), X-ray Photoelectron Spectroscopy (XPS), Atomic Force Microscopy (AFM), and X-ray Diffraction (XRD). AES and XPS study surface composition, AFM maps surface topography, and XRD determines atomic structure.

In Vitro and In Vivo Studies of Nanoparticles

In vitro assays assess cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)/ 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), lactate dehydrogenase (LDH), Picogreen DNA, Live/Dead staining), apoptosis (ELISA, Western blot), oxidative stress (reactive oxygen species (ROS), lipid peroxidation), and autophagy (LC3-II protein). Hemocompatibility tests include hemolysis (hemoglobin release) and platelet aggregation assays (light transmission aggregometry, flow cytometry). Endotoxin contamination is detected via the Limulus Amebocyte Lysate (LAL) test.

In vivo studies assess biocompatibility (histology, liver enzyme levels), biodistribution (fluorescence imaging, magnetic resonance imaging (MRI), inductively coupled plasma mass spectrometry (ICP-MS)), and therapeutic efficacy (tumor volume reduction, survival studies). Tumor models include xenograft (non-native location), orthotopic (native site), and zebrafish models. Alternatives to animal testing include organ-on-a-chip and in silico models.

Pulmonary Drug Delivery

The respiratory tract enables gas exchange, air purification, and drug absorption. Pulmonary drug delivery methods include metered-dose inhalers (MDIs), dry powder inhalers (DPIs), nebulizers, and intratracheal instillation. Particle size affects deposition: >10 µm impact the throat, 5-10 µm reach the lungs, and 1-5 µm reach alveolar sacs. Ideal inhalers provide high lung deposition, slow aerosol velocity, and dose counters. pMDIs are portable but require coordination, DPIs avoid propellants but need inspiratory effort, and nebulizers allow deep lung penetration but are inefficient. Propellants (fluorinated hydrocarbons, nitrogen, CO2) enable aerosolization but may pose health risks. Challenges include immune system clearance, exhalation, and formulation constraints.

Transdermal Drug Delivery

Transdermal drug delivery (TDD) provides controlled drug release while bypassing first-pass metabolism. Skin barriers include the stratum corneum, dermis, and hypodermis. Drug delivery routes include transcellular, intercellular, and appendageal pathways. Patch types include reservoir (membrane-controlled), matrix (drug-dispersed), and drug-in-adhesive. Generations of TDD range from passive diffusion (1st-gen) to chemical enhancers and microneedles (3rd-gen) and smart patches (4th-gen). Enhancement methods include iontophoresis, ultrasound, electroporation, microneedles, and jet injection. Marketed products include nicotine, hormone, and pain relief patches. Challenges include skin irritation, low bioavailability, and limited drug compatibility.

Protein Delivery

Protein drugs degrade easily and have low bioavailability. Protein modifications (PEGylation, glycosylation) enhance stability. Delivery systems include polymeric nanoparticles, liposomes, hydrogels, and implants. Release mechanisms include diffusion, enzymatic degradation, and pH triggers. Delivery routes include injection (common), oral (low absorption), transdermal (microneedles), pulmonary (aerosols), and nasal (rapid uptake). Advances include iontophoresis, microneedle patches, and self-assembling biomaterials.

Stimuli-Responsive Drug Delivery

Smart drug delivery releases drugs in response to pH, temperature, enzymes, light, electricity, magnetism, ultrasound, or redox changes. pH-sensitive systems release drugs in acidic environments (tumors), temperature-responsive systems use lower critical solution temperature (LCST)/ upper critical solution temperature (UCST) polymers, enzyme-responsive hydrogels degrade in diseased tissues, and light-responsive carriers use gold nanoparticles. Electric and magnetic fields control drug release via electroactive or magnetic nanoparticles. Ultrasound and redox triggers enable site-specific therapy. Challenges include toxicity, biodegradability, and external stimulus limitations.

Hydrogels for Drug Delivery

Hydrogels are 3D polymer networks that absorb water and control drug release. Types include natural (chitosan, hyaluronic acid) and synthetic (PEG, polyacrylic acid (PAA)). Crosslinking is physical (ionic/hydrogen bonding) or chemical (covalent). Drug release occurs through swelling, covalent tethering, affinity interactions, or hybrid approaches. Stimuli-responsive hydrogels react to pH, temperature, enzymes, or light. Applications include ocular, transdermal, injectable, oral, cancer therapy, tissue engineering, and wound healing. Challenges include burst release, mechanical strength, and scalability.

Implantable Drug Delivery

Implants provide long-term controlled release, enhancing patient compliance. Types include non-degradable (Norplant®, Gliadel®) and biodegradable (Zoladex®, antibiotic sponges). Drug release is controlled by diffusion (Silastic®), polymer degradation (PLGA, polyanhydrides), osmosis (Duros®), or stimuli (magnetic, pH-sensitive implants). Devices include rods (Implanon®), microparticles, in situ gels, and drug-eluting stents. Applications include contraception, cancer, pain management, ophthalmology, and cardiovascular disease. Challenges include surgical risks, biodegradation control, and immune responses.

Mucoadhesive Drug Delivery

Mucoadhesive systems improve absorption by adhering to mucosal surfaces. Sites include oral, nasal, ocular, vaginal, and rectal. Mucoadhesion involves electrostatic, hydrogen bonding, and hydrophobic interactions. Polymers include natural (chitosan, alginate) and synthetic (Carbopol, hydroxypropyl methylcellulose (HPMC)). Delivery forms include films, gels, microspheres, and vaginal rings. Applications include systemic drug delivery, local therapy, vaccines, and cancer treatment. Challenges include mucin turnover, enzymatic degradation, and adhesion variability. Future trends focus on pH-sensitive and nanoparticle-based bioadhesive carriers.