Journal of Cellular and Molecular Pharmacology
Open Access

Cellular drug uptake; Drug delivery; Transport mechanisms; Pharmacology; Membrane transporters; Drug efficacy; Targeted therapies; Drug absorption

Introduction

The process by which drugs enter cells is a fundamental step in determining their therapeutic effects. Cellular drug uptake is a complex process that depends on multiple factors, including the physicochemical properties of the drug, the presence of specific transporters, and the characteristics of the cell membrane. For a drug to exert its desired effect, it must first cross the cell membrane [1], which acts as a selective barrier. The efficiency of this process can significantly impact the drug's bioavailability, therapeutic efficacy, and side-effect profile.

Understanding how drugs are taken up by cells has far-reaching implications for the development of new and more effective therapies [2]. This is especially true for targeted treatments such as cancer therapies, where drugs need to be delivered specifically to tumor cells without affecting surrounding healthy tissues. In this article, we will explore the key mechanisms involved in cellular drug uptake, the factors that influence this process, and the challenges associated with ensuring that drugs reach their intended targets.

Mechanisms of Cellular Drug Uptake

Cellular drug uptake occurs through several mechanisms, each tailored to the properties of the drug and the cell type. These mechanisms can be broadly categorized into passive diffusion, active transport, and endocytosis.

Passive diffusion: Passive diffusion is the most common mechanism for small, lipophilic (fat-soluble) drugs. In this process, drugs move across the cell membrane along a concentration [3] gradient, from areas of higher concentration to areas of lower concentration, without the need for energy or specific transport proteins. Lipid-soluble drugs, such as many steroids and antibiotics, can easily pass through the lipid bilayer of the membrane. The rate of diffusion depends on factors like the drug’s size, lipid solubility, and the concentration gradient.

Active transport: Active transport is a more energy-dependent process that allows drugs to move against a concentration gradient, from lower to higher concentrations. This process requires specific transport proteins, such as pumps and carriers, which actively shuttle drugs into or out of cells. Active transport is essential for the uptake of hydrophilic (water-soluble) drugs or larger molecules that cannot diffuse passively through the lipid membrane. For example, the organic anion transporting polypeptides (OATPs) are involved in the uptake of various drugs, including antivirals and statins [4].

Endocytosis: Endocytosis is a process in which cells engulf extracellular material, including drugs, by forming vesicles around them. This mechanism is particularly important for larger drug molecules or nanoparticles that cannot enter the cell by passive diffusion or active transport. Depending on the size and nature of the drug, endocytosis can occur via clathrin-mediated, caveolin-mediated, or non-clathrin-mediated pathways. Once internalized, the drug is transported to various intracellular compartments, such as the lysosome or endosome, for processing.

Factors Influencing Cellular Drug Uptake

Several factors affect the efficiency of drug uptake at the cellular level:

Physicochemical properties of the drug: The solubility, charge, and size of a drug play a critical role in its ability to cross the cell membrane [5]. Lipophilic drugs, which are soluble in fats, tend to diffuse more easily through the lipid bilayer of the cell membrane, whereas hydrophilic drugs often require the assistance of transporters or endocytosis.

Membrane transporters: The presence of specific transport proteins on the cell membrane can enhance or inhibit drug uptake. Membrane transporters, such as ATP-binding cassette (ABC) transporters and solute carrier (SLC) transporters, can actively move drugs into or out of cells. For example, the P-glycoprotein (P-gp) efflux pump, which is overexpressed in many cancer cells [6], can expel chemotherapy drugs, reducing their efficacy.

Cell type: Different cell types have different membrane structures and transport mechanisms, which can influence drug uptake. Tumor cells, for example, may have altered transporter expression or enhanced endocytosis pathways, which can be leveraged for drug delivery. Additionally, some cells, such as those in the blood-brain barrier, are highly selective in allowing drug entry, making drug delivery to the brain a particular challenge.

Formulation and delivery system: The formulation of the drug, including its physical state (solid, liquid, or nanoparticle-based), can influence its uptake. Nanoparticle-based drug delivery systems have been increasingly used to overcome cellular uptake challenges. These systems can encapsulate drugs, protect them from degradation, and enhance their uptake into target cells, often through endocytosis or receptor-mediated processes.

Challenges in Cellular Drug Uptake

Barriers to drug delivery: One of the primary challenges in drug uptake is the presence of physiological barriers that [7] prevent drugs from reaching their target cells. For example, the blood-brain barrier (BBB) restricts the entry of many therapeutic agents into the brain, making it difficult to treat neurological disorders. Similarly, the expression of efflux transporters, such as P-gp, in cancer cells can pump out drugs, leading to multidrug resistance.

Selective targeting: Achieving selective drug uptake in specific cells is a significant challenge, particularly in diseases like cancer, where tumor cells need to be specifically targeted without affecting healthy tissues. Drugs must be able to distinguish between normal and diseased cells based on unique biomarkers, which requires the development of advanced targeting strategies, such as ligand-based targeting or nanoparticle delivery systems.

Drug resistance: Over time, cells may develop resistance to drugs, either through changes in transporter expression or through mutations that allow them to evade drug uptake [8]. This phenomenon is particularly concerning in cancer treatment, where tumors may evolve to resist chemotherapy or targeted therapy.

Implications for Drug Development and Therapeutic Strategies

Understanding the mechanisms of cellular drug uptake is crucial for the development of more effective therapeutic strategies [9,10]. By identifying and modulating the transport mechanisms involved in drug uptake, researchers can design drugs that are more efficiently delivered to their targets. This is especially important for the development of targeted therapies, where drugs need to be delivered specifically to diseased cells, such as in cancer or neurological disorders.

In addition, novel drug delivery systems, such as nanoparticles, liposomes, and dendrimers, are being explored to improve drug uptake. These systems can be engineered to enhance drug stability, facilitate cellular entry, and reduce off-target effects, offering new possibilities for treating complex diseases.

Conclusion

Cellular drug uptake is a critical process in the development and effectiveness of therapeutic agents. The mechanisms that govern drug entry into cells—such as passive diffusion, active transport, and endocytosis—are influenced by multiple factors, including the drug's chemical properties, the type of cell, and the presence of specific transporters. While challenges remain, such as overcoming drug resistance and achieving selective targeting, advances in drug delivery systems and molecular biology are paving the way for more effective and personalized treatments. Understanding and manipulating cellular drug uptake will continue to play a central role in the future of drug development and therapeutic strategies.

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