2.1 Targeted drug delivery
10 min read•august 20, 2024
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
Key Terms to Review (26)
Active targeting: Active targeting refers to the strategic approach in drug delivery systems that enhances the specificity of therapeutic agents towards particular cells or tissues, often utilizing ligands that bind to specific receptors. This technique improves the effectiveness of treatments by minimizing side effects and maximizing drug concentration at the desired site, which is crucial for areas like targeted drug delivery, theranostics, growth factor delivery, and pharmacokinetics in nanomedicine.
Antibody-drug conjugates: Antibody-drug conjugates (ADCs) are targeted cancer therapies that combine an antibody, which can specifically bind to cancer cells, with a cytotoxic drug. This unique pairing allows for the direct delivery of the drug to the cancer cells while minimizing damage to surrounding healthy tissue. By leveraging the specificity of antibodies, ADCs enhance the effectiveness of treatment and reduce systemic toxicity, making them a promising option in targeted drug delivery strategies.
Bioavailability: Bioavailability refers to the extent and rate at which an active pharmaceutical ingredient or active moiety is absorbed and becomes available at the site of action. This concept is crucial in determining how effectively a drug can exert its therapeutic effect, especially in the context of various drug delivery systems and formulations that aim to enhance the absorption and effectiveness of medications.
Biocompatibility: Biocompatibility refers to the ability of a material to perform with an appropriate host response when introduced to the body. It’s essential for ensuring that materials, especially in nanotechnology, do not provoke adverse reactions, allowing them to integrate effectively within biological systems and function as intended without causing toxicity or rejection.
Cancer therapy: Cancer therapy encompasses a range of treatments designed to manage and eliminate cancer cells while minimizing damage to healthy tissues. These therapies aim to target the unique characteristics of cancer cells, enhancing the effectiveness of treatment. By utilizing various approaches, such as targeted drug delivery and combination therapies, these methods work towards improving patient outcomes and reducing side effects.
Caveolae-mediated endocytosis: Caveolae-mediated endocytosis is a specific type of cellular uptake mechanism that involves the invagination of the plasma membrane to form small, flask-shaped pockets known as caveolae. These structures are rich in cholesterol and certain proteins called caveolins, which play critical roles in various biological processes, including signaling and nutrient uptake. This pathway allows for the selective internalization of molecules, making it particularly significant for targeted drug delivery applications.
Cell Membrane Permeability: Cell membrane permeability refers to the ability of substances to cross the cell membrane, which is a selective barrier that regulates what enters and exits the cell. This property is crucial in maintaining homeostasis within the cell and is influenced by various factors such as the size, charge, and solubility of the substances as well as the composition of the lipid bilayer. Understanding how permeability works is essential for developing targeted drug delivery systems that can effectively introduce therapeutic agents into specific cells.
Clathrin-mediated endocytosis: Clathrin-mediated endocytosis is a cellular process where cells internalize molecules by engulfing them in a membrane-bound vesicle. This process is initiated when clathrin proteins coat the cytoplasmic side of the cell membrane, forming a pit that eventually invaginates and pinches off to form a vesicle. It plays a crucial role in the selective uptake of nutrients, hormones, and other signaling molecules, making it essential for targeted drug delivery and cellular communication.
Dendrimers: Dendrimers are highly branched, tree-like macromolecules that exhibit a well-defined structure with a central core, branching units, and terminal functional groups. Their unique architecture allows for versatile applications in drug delivery, imaging, and diagnostics, making them important players in nanotechnology and nanomedicine.
Endocytosis: Endocytosis is a cellular process where substances are brought into the cell by engulfing them with the cell membrane, forming a vesicle. This mechanism is crucial for transporting various molecules, including nutrients and signaling proteins, and plays a vital role in both targeted drug delivery and gene delivery methods by ensuring that therapeutic agents can enter target cells effectively.
Enhanced Permeability and Retention Effect: The enhanced permeability and retention (EPR) effect refers to the phenomenon where nanoparticles and macromolecules tend to accumulate in tumor tissues more than in normal tissues due to the unique characteristics of tumor vasculature. This effect is crucial for developing targeted drug delivery systems, as it allows for a higher concentration of therapeutic agents in cancerous tissues, thereby improving the efficacy of treatments while minimizing side effects.
Fluorescence Imaging: Fluorescence imaging is a powerful optical imaging technique that uses fluorescence to visualize and quantify biological samples at the molecular level. This method relies on the emission of light from fluorescent molecules, which are excited by a specific wavelength of light, allowing researchers to track and observe cellular processes in real-time. It's particularly valuable in studying complex biological systems, enhancing our understanding of disease mechanisms and therapeutic interventions.
Gene Therapy: Gene therapy is a medical technique that aims to treat or prevent disease by directly altering the genes inside a person's cells. This innovative approach can address genetic disorders by either correcting faulty genes, replacing missing genes, or introducing new genes that help fight disease, linking it closely with concepts like targeted delivery systems and personalized treatment options.
Hydrogels: Hydrogels are three-dimensional polymer networks that can absorb and retain significant amounts of water while maintaining their structure. Their unique properties allow them to be used in various applications, including drug delivery systems, tissue engineering, and biosensors, where they can interact with biological environments.
Inorganic nanoparticles: Inorganic nanoparticles are small particles composed of inorganic materials, typically ranging from 1 to 100 nanometers in size. These particles have unique physical and chemical properties that make them highly suitable for various applications, including drug delivery, vaccine development, and diagnostic techniques. Their stability and functionalizability allow them to be tailored for specific uses in medicine and biotechnology, making them versatile tools in the advancement of nanobiotechnology.
Ligand-receptor interaction: Ligand-receptor interaction refers to the specific binding event that occurs when a ligand, typically a molecule such as a hormone or drug, binds to a receptor, which is usually a protein on the surface of a cell. This binding triggers a response within the cell, leading to various biological effects. Understanding this interaction is crucial for designing targeted drug delivery systems that can selectively direct therapeutic agents to specific cells, enhancing their efficacy while minimizing side effects.
Liposomal delivery: Liposomal delivery refers to a drug delivery system that utilizes liposomes, which are tiny spherical vesicles made of lipid bilayers, to encapsulate and transport therapeutic agents to targeted cells or tissues. This approach enhances the bioavailability of drugs while reducing toxicity and improving efficacy by ensuring that the medication reaches its intended site of action more effectively. Liposomal delivery systems can be tailored for specific applications, including the targeted delivery of drugs and growth factors, allowing for more precise and effective treatment options.
Macropinocytosis: Macropinocytosis is a form of endocytosis where cells engulf large volumes of extracellular fluid, along with any dissolved substances, through the formation of membrane protrusions called ruffles. This process allows cells to sample their environment and is particularly important for immune cells in capturing antigens and for cancer cells in taking up nutrients. By facilitating the uptake of larger particles and fluids, macropinocytosis plays a critical role in various biological processes, including targeted drug delivery.
Magnetic Resonance Imaging: Magnetic resonance imaging (MRI) is a non-invasive imaging technique that uses powerful magnets and radio waves to create detailed images of organs and tissues inside the body. It plays a critical role in medical diagnostics, providing high-resolution images that help in the assessment of diseases and conditions. MRI can also be employed in targeted drug delivery strategies by visualizing the precise location and effects of therapeutics at the site of interest.
Passive Targeting: Passive targeting refers to the process by which drug delivery systems exploit the natural physiological characteristics of the body to direct therapeutic agents to specific tissues or cells without needing external guidance. This approach often relies on factors such as blood flow and the permeability of blood vessels, particularly in tumor tissues, to facilitate the accumulation of drugs at desired sites. Understanding passive targeting is essential for enhancing the efficacy of treatments while minimizing side effects.
Polymeric Nanoparticles: Polymeric nanoparticles are small particles made of polymeric materials that typically range from 1 to 1000 nanometers in size. These nanoparticles are highly versatile and are used in various applications, particularly in drug delivery systems, where they can encapsulate therapeutic agents and improve their bioavailability and targeted delivery to specific cells or tissues.
Receptor-mediated transcytosis: Receptor-mediated transcytosis is a cellular process that allows the selective transport of molecules across a cell layer, using specific receptors on the cell membrane to bind to target substances. This process is crucial for transporting larger molecules, such as proteins and antibodies, across endothelial cells that line blood vessels, thereby facilitating targeted drug delivery and enhancing the efficacy of therapeutics in treating various diseases.
RNA interference: RNA interference (RNAi) is a biological process where RNA molecules inhibit gene expression or translation, effectively silencing specific genes. This mechanism plays a crucial role in regulating various cellular processes and has significant implications for targeted drug delivery, as it allows for precise modulation of gene activity, enabling therapeutic interventions at the molecular level.
Stimuli-responsive systems: Stimuli-responsive systems are materials or devices that can undergo a significant change in their properties or behavior in response to specific external stimuli, such as temperature, pH, light, or chemical signals. These systems are crucial for developing targeted drug delivery mechanisms, as they allow for the controlled release of therapeutic agents at desired locations and times within the body, enhancing the efficacy and minimizing side effects of treatments.
Theranostics: Theranostics is a term that combines therapy and diagnostics, focusing on the development of personalized medicine approaches that integrate targeted treatment and real-time monitoring of treatment responses. It allows for the identification of specific biomarkers that can guide therapy, tailoring treatments to individual patients while simultaneously assessing their effectiveness through imaging or biomarker analysis. This dual capability enhances the precision of treatments and improves patient outcomes in various medical fields.
Toxicity assessment: Toxicity assessment is the process of evaluating the harmful effects of substances on living organisms, which is crucial in understanding their safety and risk for human health and the environment. This assessment helps in determining safe exposure levels and potential adverse effects, guiding regulatory decisions, and informing the development of safer nanomaterials and drug delivery systems. In nanobiotechnology, evaluating toxicity is vital for applications involving materials like graphene, ensuring that innovative therapies do not pose additional health risks.