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Targeted drug delivery aims to maximize therapeutic efficacy while minimizing side effects. This approach uses nanocarriers to encapsulate drugs and deliver them to specific sites in the body, exploiting unique features of diseased tissues and cells.

Nanocarrier systems like liposomes, , and offer advantages in drug protection and delivery. Passive and strategies help accumulate drugs at target sites. Overcoming biological barriers remains a key challenge for successful clinical translation.

Principles of targeted drug delivery

  • Targeted drug delivery aims to selectively deliver therapeutic agents to specific sites in the body, maximizing therapeutic efficacy while minimizing off-target effects and systemic toxicity
  • Key principles include utilizing nanocarriers to encapsulate and protect drugs, exploiting specific ligand-receptor interactions for active targeting, and designing systems that respond to biological cues for controlled release
  • Targeted delivery has the potential to revolutionize treatment for various diseases, particularly in and drug delivery to the brain

Nanocarrier systems for drug delivery

  • Nanocarriers are nanoscale materials designed to encapsulate, protect, and deliver therapeutic agents to target sites in the body
  • Advantages of nanocarriers include improved drug solubility, prolonged circulation time, reduced immunogenicity, and the ability to cross biological barriers
  • Common nanocarrier systems include liposomes, polymeric nanoparticles, dendrimers, and , each with unique properties and applications

Liposomes as nanocarriers

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  • Liposomes are spherical vesicles composed of a phospholipid bilayer enclosing an aqueous core
  • Hydrophilic drugs can be encapsulated in the aqueous core, while hydrophobic drugs can be incorporated into the lipid bilayer
  • Liposomes are biocompatible, biodegradable, and can be surface-modified with targeting ligands for active targeting (antibodies, peptides)
  • Examples of liposomal drug formulations include Doxil (doxorubicin) and AmBisome (amphotericin B)

Polymeric nanoparticles

  • Polymeric nanoparticles are solid colloidal particles composed of biocompatible and biodegradable polymers (PLGA, PLA, chitosan)
  • Drugs can be encapsulated within the polymer matrix or adsorbed onto the surface
  • Polymeric nanoparticles offer controlled drug release kinetics, tunable size and surface properties, and the ability to co-deliver multiple therapeutic agents
  • Examples include Abraxane (paclitaxel-albumin nanoparticles) and Genexol-PM (paclitaxel-loaded polymeric micelles)

Dendrimers in drug delivery

  • Dendrimers are highly branched, monodisperse polymeric macromolecules with a well-defined structure and multiple functional groups on the surface
  • Drugs can be covalently conjugated to the dendrimer surface or physically encapsulated within the dendritic structure
  • Advantages include precise control over size and surface functionality, high drug loading capacity, and the ability to deliver both hydrophobic and hydrophilic drugs
  • Examples of dendrimer-based drug delivery include PAMAM (polyamidoamine) and PPI (polypropylenimine) dendrimers

Inorganic nanoparticles

  • Inorganic nanoparticles include gold nanoparticles, magnetic nanoparticles (iron oxide), and mesoporous silica nanoparticles
  • These nanoparticles offer unique properties such as surface plasmon resonance (gold), magnetic responsiveness (iron oxide), and high surface area and pore volume (silica)
  • Drugs can be adsorbed onto the surface or loaded into the pores of these nanoparticles
  • Inorganic nanoparticles can be functionalized with targeting ligands and can be used for combined imaging and therapy ()

Passive vs active targeting strategies

  • relies on the enhanced permeability and retention (EPR) effect, where nanocarriers accumulate in tumor tissues due to leaky vasculature and impaired lymphatic drainage
  • Active targeting involves the functionalization of nanocarriers with targeting ligands that specifically bind to receptors overexpressed on the surface of target cells
  • Active targeting can improve the selectivity and cellular uptake of nanocarriers, leading to enhanced therapeutic efficacy and reduced off-target effects
  • Combination of passive and active targeting strategies can further improve the targeting efficiency and therapeutic outcomes

Ligand-receptor interactions in targeting

  • Ligand-receptor interactions form the basis of active targeting, where targeting ligands on the nanocarrier surface specifically bind to receptors overexpressed on target cells
  • Common targeting ligands include antibodies, peptides, aptamers, and small molecules (folate, transferrin)
  • Ligand-receptor binding can trigger receptor-mediated , leading to the internalization of nanocarriers and intracellular drug release
  • Selection of appropriate targeting ligands depends on the target receptor expression, specificity, and affinity

Antibodies for active targeting

  • Monoclonal antibodies (mAbs) and antibody fragments (Fab, scFv) can be conjugated to nanocarriers for active targeting
  • Antibodies offer high specificity and affinity for target antigens, enabling selective delivery to target cells
  • Examples of antibody-targeted nanocarriers include Herceptin (trastuzumab) for HER2-positive breast cancer and Rituxan (rituximab) for CD20-positive lymphoma
  • Challenges include immunogenicity, large size, and high production costs

Peptides and aptamers

  • Peptides are short amino acid sequences that can bind to specific receptors with high affinity and specificity
  • Aptamers are single-stranded oligonucleotides (DNA or RNA) that fold into specific three-dimensional structures and bind to target molecules
  • Peptides and aptamers offer advantages such as smaller size, lower immunogenicity, and easier synthesis compared to antibodies
  • Examples include RGD peptides targeting integrin receptors and AS1411 aptamer targeting nucleolin in cancer cells

Folate and transferrin receptors

  • Folate receptor (FR) and transferrin receptor (TfR) are commonly overexpressed on the surface of cancer cells and can be exploited for targeted drug delivery
  • Folic acid (vitamin B9) and transferrin (iron-binding protein) can be conjugated to nanocarriers for active targeting via FR and TfR, respectively
  • Folate and transferrin ligands offer high affinity, specificity, and non-immunogenicity
  • Examples include folate-conjugated liposomes and transferrin-conjugated polymeric nanoparticles for cancer therapy

Challenges of targeted delivery

  • Despite the promise of targeted drug delivery, several challenges need to be addressed for successful clinical translation
  • These challenges include nanoparticle size and shape, surface properties, biological barriers, and potential toxicity and immunogenicity
  • Understanding and overcoming these challenges is crucial for the development of safe and effective targeted drug delivery systems

Nanoparticle size and shape

  • Nanoparticle size and shape play a critical role in their biodistribution, circulation time, and cellular uptake
  • Optimal size range for nanocarriers is typically 10-200 nm to ensure long circulation time and effective extravasation into tumor tissues
  • Smaller nanoparticles (<10 nm) are rapidly cleared by renal excretion, while larger particles (>200 nm) are prone to hepatic and splenic clearance
  • Shape also influences nanoparticle interactions with cells and tissues, with spherical and rod-shaped particles showing different uptake and biodistribution patterns

Surface properties of nanocarriers

  • Surface properties of nanocarriers, such as charge, hydrophobicity, and surface chemistry, impact their stability, , and interactions with biological systems
  • Positively charged nanoparticles can enhance cellular uptake but may cause non-specific interactions and toxicity
  • Hydrophobic surfaces can lead to protein adsorption and opsonization, resulting in rapid clearance by the mononuclear phagocyte system (MPS)
  • Surface modification with hydrophilic polymers (PEG, poloxamers) can improve nanoparticle stability and stealth properties, reducing MPS recognition and prolonging circulation time

Biological barriers to delivery

  • Biological barriers, such as the mononuclear phagocyte system (MPS), blood-brain barrier (BBB), and extracellular matrix (ECM), pose significant challenges to targeted drug delivery
  • MPS, consisting of macrophages and monocytes, can recognize and clear nanoparticles from the circulation, reducing their
  • BBB, composed of tight junctions between endothelial cells, restricts the entry of most nanocarriers into the brain, limiting drug delivery to the central nervous system
  • ECM, a complex network of proteins and glycosaminoglycans, can hinder the penetration and distribution of nanocarriers within solid tumors

Cellular uptake mechanisms

  • Understanding the cellular uptake mechanisms of nanocarriers is crucial for designing effective targeted drug delivery systems
  • Cellular uptake can occur through various endocytosis pathways, including , , and
  • Nanocarrier properties, such as size, shape, and surface chemistry, can influence the specific endocytosis pathway and intracellular trafficking

Endocytosis pathways

  • Clathrin-mediated endocytosis involves the formation of clathrin-coated pits that invaginate and pinch off to form endocytic vesicles
  • Caveolae-mediated endocytosis occurs through flask-shaped invaginations called caveolae, which are rich in cholesterol and caveolin proteins
  • Macropinocytosis is a non-specific uptake mechanism involving the formation of large, actin-driven membrane ruffles that engulf extracellular fluid and particles
  • Nanocarrier uptake through specific endocytosis pathways can influence their intracellular fate, such as lysosomal degradation or cytosolic release

Enhancing cellular internalization

  • Strategies to enhance the cellular internalization of nanocarriers include surface modification with cell-penetrating peptides (CPPs) and targeting ligands
  • CPPs, such as TAT and penetratin, are short cationic or amphipathic peptides that can facilitate the translocation of nanocarriers across the cell membrane
  • Targeting ligands, such as antibodies and peptides, can promote receptor-mediated endocytosis by binding to specific cell surface receptors
  • Combination of CPPs and targeting ligands can synergistically improve the cellular uptake and specificity of nanocarriers

Drug release from nanocarriers

  • Controlled and targeted drug release from nanocarriers is essential for achieving optimal therapeutic efficacy and minimizing off-target effects
  • Drug release can be classified as controlled release, which follows a predetermined rate, or triggered release, which responds to specific stimuli
  • Stimuli-responsive nanocarriers can release drugs in response to changes in pH, temperature, enzymes, or external stimuli such as light or magnetic fields

Controlled vs triggered release

  • Controlled release systems aim to maintain drug concentrations within the therapeutic window for a prolonged period
  • Examples of controlled release mechanisms include diffusion-controlled, swelling-controlled, and erosion-controlled release
  • Triggered release systems respond to specific stimuli, enabling on-demand drug release at the target site
  • pH-sensitive nanocarriers can exploit the acidic tumor microenvironment or endosomal compartments for triggered drug release
  • Temperature-sensitive nanocarriers, such as thermosensitive liposomes, can release drugs in response to hyperthermia or external heating

Stimuli-responsive systems

  • Stimuli-responsive nanocarriers can be designed to respond to a variety of internal or external stimuli for triggered drug release
  • pH-responsive nanocarriers include acid-labile linkers (hydrazones, acetals) and pH-sensitive polymers (PMAA, PEAA) that degrade or swell in acidic environments
  • Enzyme-responsive nanocarriers can be triggered by tumor-specific enzymes, such as matrix metalloproteinases (MMPs) or cathepsins
  • Light-responsive nanocarriers incorporate photosensitive moieties (o-nitrobenzyl, spiropyran) that undergo structural changes upon light irradiation, leading to drug release
  • Magnetic-responsive nanocarriers, such as iron oxide nanoparticles, can be triggered by external magnetic fields for localized drug release

Targeted delivery in cancer therapy

  • Cancer is a major focus of targeted drug delivery due to the limitations of conventional chemotherapy, such as systemic toxicity and drug resistance
  • Targeted delivery in cancer therapy aims to exploit the unique features of the tumor microenvironment and specific tumor cell receptors for selective drug accumulation and release
  • Key strategies include passive targeting via the enhanced permeability and retention (EPR) effect and active targeting using tumor-specific ligands

Enhanced permeability and retention effect

  • The EPR effect is a passive targeting mechanism based on the abnormal vasculature and impaired lymphatic drainage in solid tumors
  • Tumor blood vessels are leaky, with gaps between endothelial cells, allowing nanocarriers (<200 nm) to extravasate and accumulate in the tumor interstitium
  • Impaired lymphatic drainage in tumors leads to the retention of nanocarriers, further enhancing their accumulation
  • The EPR effect has been exploited for the delivery of various nanomedicines, such as Doxil (liposomal doxorubicin) and Abraxane (albumin-bound paclitaxel)

Tumor microenvironment considerations

  • The tumor microenvironment presents unique challenges and opportunities for targeted drug delivery
  • Acidic pH in the tumor extracellular space, due to increased glycolysis and lactate production, can be exploited for pH-triggered drug release
  • Hypoxia in poorly perfused tumor regions can activate hypoxia-inducible factors (HIFs) and promote angiogenesis, which can be targeted by anti-angiogenic agents
  • Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor stroma can be targeted for drug delivery or modulation of the immune response
  • Combination of passive and active targeting strategies, along with consideration of the tumor microenvironment, can enhance the efficacy of targeted cancer therapy

Targeted delivery to the brain

  • The brain is a challenging target for drug delivery due to the presence of the blood-brain barrier (BBB), which restricts the entry of most drugs and nanocarriers
  • Targeted delivery to the brain aims to overcome the BBB and deliver therapeutic agents for the treatment of neurological disorders, such as Alzheimer's disease, Parkinson's disease, and brain tumors
  • Strategies for brain targeting include , cell-mediated delivery, and temporary disruption of the BBB

Blood-brain barrier challenges

  • The BBB is a highly selective barrier formed by tight junctions between endothelial cells, limiting paracellular transport
  • BBB endothelial cells express efflux transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which actively pump out drugs and nanocarriers
  • Limited transcellular transport across the BBB occurs through specific receptors and transporters, such as transferrin receptor (TfR) and glucose transporter (GLUT1)
  • Nanocarriers for brain delivery must be designed to overcome these challenges, either by exploiting receptor-mediated transcytosis or by temporary disruption of the BBB

Receptor-mediated transcytosis

  • Receptor-mediated transcytosis (RMT) is a promising strategy for targeted delivery across the BBB
  • RMT involves the binding of nanocarriers to specific receptors on the luminal side of BBB endothelial cells, followed by endocytosis, transcytosis, and release on the abluminal side
  • Transferrin receptor (TfR) and insulin receptor (IR) are commonly targeted for RMT-based brain delivery
  • Nanocarriers can be functionalized with targeting ligands, such as antibodies (OX26 for TfR) or peptides (angiopep-2 for low-density lipoprotein receptor-related protein 1), to facilitate RMT
  • Examples of RMT-based brain delivery include transferrin-conjugated liposomes and polymeric nanoparticles for the delivery of chemotherapeutics and gene therapies

Clinical applications and examples

  • Targeted drug delivery has shown promise in various clinical applications, including cancer therapy, cardiovascular diseases, infectious diseases, and neurological disorders
  • Examples of clinically approved targeted nanomedicines include:
    • Doxil (PEGylated liposomal doxorubicin) for ovarian cancer and Kaposi's sarcoma
    • Abraxane (albumin-bound paclitaxel) for breast cancer, non-small cell lung cancer, and pancreatic cancer
    • Onivyde (liposomal irinotecan) for metastatic pancreatic cancer
    • Vyxeos (liposomal daunorubicin and cytarabine) for acute myeloid leukemia
  • Clinical trials are ongoing for various targeted delivery systems, such as BIND-014 (docetaxel-loaded polymeric nanoparticles) for solid tumors and SGT-53 (transferrin-targeted liposomes encapsulating p53 gene) for advanced solid tumors
  • Targeted delivery has the potential to improve patient outcomes by enhancing therapeutic efficacy, reducing side effects, and enabling personalized medicine approaches

Safety and biocompatibility of nanocarriers

  • Ensuring the safety
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© 2024 Fiveable Inc. All rights reserved.
AP® and SAT® are trademarks registered by the College Board, which is not affiliated with, and does not endorse this website.

© 2024 Fiveable Inc. All rights reserved.
AP® and SAT® are trademarks registered by the College Board, which is not affiliated with, and does not endorse this website.
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