Understanding What are the two targeted drug delivery systems?

October 10, 2025 •

5 min read

The concept of targeted drug delivery traces back to Paul Ehrlich's 'magic bullet' idea, a century-old vision of selectively targeting a pathogen without harming the host. Today, the realization of this vision is manifested in two primary targeted drug delivery systems: passive and active targeting. These systems utilize nanoscale carriers to concentrate therapeutic agents at a specific site in the body, optimizing drug effectiveness while drastically reducing side effects on healthy tissue.

Quick Summary

Targeted drug delivery utilizes either passive or active methods to concentrate medication at a specific site. Passive targeting relies on natural physiological processes, such as leaky tumor vasculature, while active targeting uses specific ligands to bind to cellular receptors for precise delivery.

Key Points

Passive Targeting: This system exploits natural physiological conditions, such as the leaky vasculature and poor lymphatic drainage in tumors (Enhanced Permeability and Retention or EPR effect), to accumulate drug-loaded nanoparticles at a disease site.
Active Targeting: This system utilizes specific targeting ligands, like antibodies or peptides, attached to drug carriers to bind to and enter target cells that express complementary receptors, offering greater specificity than passive methods.
Nanocarrier Technology: Both systems often use nanocarriers such as liposomes, polymeric nanoparticles, and micelles to encapsulate drugs, protecting them from degradation and modulating their distribution in the body.
Evasion of the Immune System: To prolong circulation time and increase delivery efficiency in passive targeting, nanoparticles are often coated with polymers like PEG to evade the mononuclear phagocyte system.
Enhanced Specificity: Active targeting provides a higher degree of specificity, allowing for more precise delivery to target cells, which helps in minimizing damage to healthy tissues.
Combined Strategies: Some advanced approaches use a combination of passive and active targeting, where the nanocarrier first accumulates via the EPR effect before using ligands to specifically bind to and internalize into target cells.
Systemic Challenges: Both delivery systems face challenges, including high costs, ensuring stability, evading immune reactions, and overcoming the natural variability of disease physiology.

Passive Targeting: The Role of the EPR Effect

Passive targeting is one of the two primary targeted drug delivery systems, relying on the natural physiological conditions of diseased tissue to accumulate therapeutic agents. The most prominent example of this is the Enhanced Permeability and Retention (EPR) effect, which is particularly relevant in cancer therapy. Solid tumors exhibit two key characteristics that facilitate this mechanism:

Leaky Vasculature: Unlike healthy blood vessels with tightly connected endothelial cells, the rapidly growing blood vessels in solid tumors are often structurally flawed, with large gaps or pores. This allows macromolecules, such as drug-loaded nanoparticles typically ranging from 10 to 200 nanometers ($<200 ext{ nm}$), to easily extravasate and enter the tumor interstitial space.
Impaired Lymphatic Drainage: Tumor tissue also lacks a functional lymphatic system to drain fluid and macromolecules. This impaired clearance traps the passively accumulated nanoparticles within the tumor microenvironment for a prolonged period, increasing the local drug concentration.

Nanocarriers used for passive targeting

Various types of nanocarriers are engineered to exploit the EPR effect, including:

Liposomes: These spherical vesicles are composed of a lipid bilayer and can encapsulate both hydrophilic (aqueous core) and hydrophobic (lipid bilayer) drugs. By modifying the surface with a polymer like polyethylene glycol (PEG), a process known as PEGylation, liposomes can evade the body's immune system (specifically the mononuclear phagocyte system, or RES) and circulate longer, increasing the likelihood of accumulation in tumors.
Polymeric Nanoparticles and Micelles: Made from biodegradable polymers, these carriers can be designed to encapsulate poorly soluble drugs. Like liposomes, PEGylated versions benefit from longer circulation times.

Challenges of passive targeting

Despite its elegant simplicity, passive targeting has limitations. The EPR effect can be highly variable between different patients and even different regions of the same tumor due to variations in vasculature and interstitial fluid pressure. This heterogeneity makes it less reliable for achieving high therapeutic outcomes in all cases.

Active Targeting: Precision via Molecular Recognition

Active targeting is a more sophisticated targeted drug delivery system that enhances the effects of passive targeting with higher specificity. This method involves attaching specific targeting ligands to the surface of a drug carrier. These ligands are designed to recognize and bind to receptors or antigens that are overexpressed on the surface of target cells, such as cancer cells.

The process typically follows these steps:

Passive Accumulation: The drug-loaded carrier, often a nanoparticle, first accumulates at the general disease site via passive mechanisms like the EPR effect.
Specific Binding: Once in the vicinity, the surface ligands on the carrier bind specifically to the target cells through a lock-and-key mechanism.
Internalization: This binding often triggers receptor-mediated endocytosis, in which the cell actively takes up the carrier, delivering the drug payload intracellularly.

Examples of active targeting ligands and carriers

Antibody-Drug Conjugates (ADCs): An ADC is an example of an actively targeted system composed of a monoclonal antibody (the targeting ligand) linked to a potent cytotoxic drug. The antibody guides the drug specifically to cancer cells expressing the corresponding antigen, reducing systemic toxicity. For instance, trastuzumab emtansine targets HER2-positive breast cancer.
Peptide-Based Targeting: Peptides can also act as ligands, binding to specific cell-surface receptors. The RGD motif, for example, can target integrin receptors that are upregulated in angiogenic endothelial cells and certain tumor cells.
Small Molecules: Molecules like folic acid, which is essential for rapidly dividing cells, can be used to target cancer cells that overexpress folate receptors.
Stimuli-Responsive Systems: Some active targeting systems are designed to release their payload only when triggered by a specific condition at the target site, such as a different pH level in tumors or changes in redox potential.

Challenges of active targeting

Developing effective active targeting systems presents several challenges:

Target Identification: Finding truly specific and accessible receptors is difficult. Many potential targets are also expressed on healthy cells, leading to off-target effects.
Receptor Accessibility: The ligand must successfully navigate the complex biological environment and reach the receptors, which can be challenging due to factors like blood flow and tissue density.
Immune System Interactions: The body's immune system can recognize and clear drug carriers, or endogenous ligands may compete with the engineered ligands for receptors.

Comparison of Targeted Drug Delivery Systems


Feature	Passive Targeting	Active Targeting
Mechanism	Relies on natural physiological conditions like the Enhanced Permeability and Retention (EPR) effect.	Involves specific ligand-receptor interactions.
Specificity	Lower specificity, relies on accumulation in leaky vasculature.	Higher specificity, binds directly to specific cellular receptors.
Targeting Moiety	No specific ligand required, depends on carrier size, shape, and surface properties.	Specific ligands (antibodies, peptides, small molecules) attached to the carrier.
Drug Release	Less controlled, depends on passive diffusion or carrier degradation.	More controlled, can be triggered by receptor binding or specific stimuli (e.g., pH, enzymes).
Carriers	Liposomes, micelles, polymeric nanoparticles.	Antibody-Drug Conjugates (ADCs), ligand-decorated nanoparticles.
Clinical Reliability	Variable, dependent on tumor characteristics and stability of the EPR effect.	Can be highly effective, but faces challenges with target accessibility and specificity.

Synergistic Strategies and Future Outlook

Given the limitations of relying solely on one mechanism, advanced strategies often combine both passive and active approaches. For example, a PEGylated liposome (passive targeting) can be modified with an antibody fragment (active targeting) to gain the benefits of prolonged circulation time and highly specific cellular uptake. This dual-targeting strategy offers a potential pathway to overcome the inconsistencies of the EPR effect while maximizing the dose delivered directly to the target cells.

Looking forward, the field continues to evolve with the development of sophisticated nanocarriers and targeted strategies, such as immunotargeting and stimuli-responsive systems. Addressing manufacturing costs, ensuring carrier stability, and mitigating immune responses remain significant hurdles to widespread clinical adoption. The ultimate goal, based on the principle of the 'magic bullet' from which the field originated, is to design and implement targeted therapies that are both highly effective and safe for patients. For further reading on this transformative field, an article published by the National Institutes of Health on Targeted Drug Delivery provides a comprehensive overview.

Conclusion

The two main targeted drug delivery systems, passive and active targeting, represent significant advancements over conventional drug administration. Passive targeting leverages the physiological abnormalities of diseased tissue, like the EPR effect in tumors, to enhance drug concentration at the target site. In contrast, active targeting uses specific ligands to bind to cellular receptors, providing a higher degree of precision and control. While both systems have limitations—such as the variability of the EPR effect and challenges with ligand specificity and accessibility—combinatorial strategies that utilize both mechanisms show great promise. Continued research is vital for overcoming existing challenges and fully realizing the potential of targeted drug delivery to revolutionize medicine and significantly improve therapeutic outcomes for a wide range of diseases.

Frequently Asked Questions

The primary mechanism of passive targeted drug delivery is the Enhanced Permeability and Retention (EPR) effect, which capitalizes on the leaky blood vessels and poor lymphatic drainage found in solid tumors to passively accumulate drug-loaded nanocarriers.

Active targeted drug delivery achieves higher specificity by equipping drug carriers with specific targeting ligands, such as antibodies or peptides. These ligands bind selectively to receptors overexpressed on the surface of target cells, leading to more precise drug delivery.

In passive targeting, drug release is typically less controlled, relying on natural diffusion or carrier degradation. In contrast, active targeting offers more control, with release often triggered by specific stimuli like pH changes or enzymatic activity at the target site.

Various nanocarriers are used, including liposomes, polymeric nanoparticles, and micelles. In active targeting, these carriers are further modified with ligands, while in passive targeting, properties like size and surface coatings are used to enhance accumulation.

Key challenges include high manufacturing costs, the stability of the delivery system, potential immune reactions, and overcoming the natural heterogeneity of target tissues and receptors.

An Antibody-Drug Conjugate (ADC) is a prime example of an active targeting system. It links a cytotoxic drug to a monoclonal antibody that specifically recognizes and binds to an antigen on the surface of cancer cells, delivering the therapeutic agent directly to the target.

Targeted delivery systems improve cancer therapy by concentrating drugs in tumor tissues while minimizing exposure to healthy cells. This increases the drug's effectiveness and reduces severe side effects associated with conventional chemotherapy.