Clinical Pharmacology & Biopharmaceutics
Open Access

Biological barriers; Drug delivery; Biopharmaceutics; Nanoparticle-based delivery; Prodrugs; Efflux transporters; Enzymatic degradation; Blood-brain barrier; Mucosal barriers; Peptide modification; Transdermal delivery; Immune response

Introduction

The field of biopharmaceutics is dedicated to understanding the relationship between the physical and chemical properties of drugs, their formulations, and their biological effects. One of the most significant challenges in this field is overcoming biological barriers to ensure effective drug delivery. These barriers include physiological, cellular, and molecular obstacles that hinder the absorption, distribution, metabolism, and excretion of therapeutic agents. This article delves into the primary biological barriers to drug delivery and explores innovative strategies to overcome these challenges [1].

Physiological barriers

• Gastrointestinal Tract: The gastrointestinal (GI) tract presents a formidable barrier due to its acidic environment, digestive enzymes, and variable pH levels. Drugs must be stable in this environment to be effectively absorbed.
• Blood-Brain Barrier (BBB): The BBB protects the brain from harmful substances but also restricts the entry of potentially beneficial drugs. It consists of tightly joined endothelial cells, astrocyte end-feet, and pericytes, making it highly selective.
• Mucosal Barriers: Mucosal surfaces, such as those in the respiratory and reproductive tracts, have a mucus layer that traps and clears foreign particles, including drugs. This barrier limits drug absorption and necessitates strategies to enhance permeability.
• Skin Barrier: The stratum corneum, the outermost layer of the skin, acts as a robust barrier to drug penetration. Transdermal drug delivery systems must overcome this barrier to achieve therapeutic effects [2].

Cellular barriers

• Cell Membranes: Drug molecules must cross cell membranes to reach their target sites. This process is often hindered by the lipophilic nature of cell membranes, which restricts the passage of hydrophilic drugs.
• Efflux Transporters: These proteins, such as P-glycoprotein, actively pump drugs out of cells, reducing intracellular drug concentrations and limiting therapeutic efficacy.
• Endosomal and Lysosomal Trapping: After cellular uptake, drugs can be trapped in endosomes or lysosomes, where they may be degraded before reaching their target.

Molecular barriers

• Enzymatic Degradation: Enzymes in the body can degrade drugs before they reach their target sites. Proteases, nucleases, and other enzymes present significant challenges for peptide, protein, and nucleic acid-based drugs.
• Immune Response: The immune system can recognize and neutralize therapeutic agents, particularly biologics such as monoclonal antibodies and gene therapies. This immune response can reduce efficacy and cause adverse effects [3].

Strategies to overcome biological barriers

Nanoparticle-Based Drug Delivery: Nanoparticles can protect drugs from degradation, enhance absorption, and provide targeted delivery. Liposomes, polymeric nanoparticles, and dendrimers are among the platforms used to improve drug stability and bioavailability.

Prodrug Approaches: Prodrugs are inactive derivatives of drugs that are metabolized in the body to release the active drug. This strategy can enhance stability, solubility, and permeability.

Transporter Inhibition: Inhibiting efflux transporters can increase intracellular drug concentrations. Co-administering drugs with transporter inhibitors or designing drugs that evade transporter recognition are potential strategies.

Peptide and Protein Modification: Modifying peptides and proteins to resist enzymatic degradation can extend their half-life. PEGylation, glycosylation, and fusion with other proteins are common modification techniques.

Chemical Penetration Enhancers: For transdermal delivery, chemical penetration enhancers can disrupt the stratum corneum to increase drug permeation. Examples include alcohols, fatty acids, and surfactants.

Use of Carriers for BBB Penetration: Carrier systems, such as receptor-mediated transport and cell-penetrating peptides, can facilitate the delivery of drugs across the BBB. Conjugating drugs with ligands that target BBB transporters is a promising approach.

Mucus-Penetrating Particles: Designing particles that can penetrate the mucus barrier without being trapped can enhance drug delivery to mucosal surfaces. These particles are typically small and have hydrophilic surfaces to avoid mucus adhesion [4].

Materials and Methods

Materials

Drugs and prodrugs

• Selection of therapeutic agents, including small molecules, peptides, proteins, and nucleic acids.
• Synthesis of prodrugs with designed linkers for controlled activation.

Nanoparticle formulations

• Liposomes, polymeric nanoparticles, dendrimers, and solid lipid nanoparticles.
• Materials for nanoparticle synthesis: lipids, polymers (e.g., PLGA, PEG), surfactants, and stabilizers [5].

Chemical penetration enhancers

• Alcohols, fatty acids, surfactants, and other compounds known to enhance skin and mucosal permeability.
• Transporter Inhibitors
• Specific inhibitors for efflux transporters such as P-glycoprotein (e.g., verapamil, cyclosporine).
• Cell-Penetrating Peptides
• Peptides such as TAT, penetratin, and others known to facilitate drug transport across cellular membranes.
• pH-Responsive and Endosomolytic Agents
• Polymers and compounds that respond to pH changes and disrupt endosomal membranes to release encapsulated drugs [6].

Methods

Nanoparticle synthesis and characterization

• Preparation: Utilize solvent evaporation, nanoprecipitation, or microfluidic methods to synthesize nanoparticles.
• Characterization: Assess particle size, zeta potential, encapsulation efficiency, and drug loading using dynamic light scattering (DLS), scanning electron microscopy (SEM), and high-performance liquid chromatography (HPLC) [7].

Prodrug synthesis and evaluation

• Synthesis: Chemical synthesis of prodrugs with linkers cleavable by specific enzymes or environmental conditions (e.g., pH, redox).
• Evaluation: In vitro assays to test stability, activation, and release profiles using enzyme kinetics and mass spectrometry.

In vitro permeability and transport studies

• Cell Culture Models: Use Caco-2 and MDCK cell monolayers to simulate intestinal and blood-brain barrier permeability.
• Transport Assays: Measure drug transport across cell monolayers with and without efflux transporter inhibitors using Transwell systems and quantify using HPLC or mass spectrometry.

Enzymatic stability and degradation studies

• Incubation with Enzymes: Expose drugs to relevant enzymes (e.g., proteases, nucleases) and assess degradation over time.
• Analytical Techniques: Use HPLC, mass spectrometry, and gel electrophoresis to analyze degradation products and remaining intact drug [8].

In vivo pharmacokinetic and biodistribution studies

• Animal Models: Use rodent models (e.g., mice, rats) for pharmacokinetic and biodistribution studies.
• Administration Routes: Administer drugs via oral, intravenous, transdermal, and mucosal routes.
• Sampling and Analysis: Collect blood, tissue, and organ samples at various time points; analyze drug concentrations using HPLC or mass spectrometry [9].

Transdermal and mucosal delivery studies

• Skin Permeation Tests: Use Franz diffusion cells with human or animal skin samples to test transdermal formulations.
• Mucosal Delivery Models: Utilize ex vivo mucosal tissues or in vivo animal models to evaluate drug penetration and absorption.

Statistical analysis

• Data Analysis: Use statistical software (e.g., GraphPad Prism, SPSS) to analyze experimental data.
• Statistical Tests: Apply appropriate statistical tests (e.g., t-tests, ANOVA) to determine significance of results [10].

Discussion

The intricate landscape of biological barriers presents a formidable challenge in the realm of drug delivery, profoundly impacting the pharmacokinetics and pharmacodynamics of therapeutic agents. Overcoming these barriers is pivotal for enhancing drug efficacy and safety, necessitating a multi-faceted approach that integrates advanced technologies and innovative strategies.

Conclusion

Overcoming biological barriers to drug delivery is a critical challenge in biopharmaceutics. By leveraging advanced technologies and innovative strategies, researchers can enhance the efficacy and safety of therapeutic agents. The ongoing development in nanoparticle-based delivery systems, prodrug approaches, transporter inhibition, and other techniques holds promise for overcoming these barriers and improving patient outcomes. As our understanding of these barriers deepens, the potential for more effective and targeted drug delivery continues to grow, heralding a new era in the treatment of various diseases.

References

1. Andersen ME, Mallick P, Clewell HJ 3rd, Yoon M, Olsen GW, et al. (2021) Using quantitative modeling tools to assess pharmacokinetic bias in epidemiological studies showing associations between biomarkers and health outcomes at low exposures. Environ. Res 197:111183.

Indexed at, Google Scholar, Crossref

2. Antontsev V, Jagarapu A, Bundey Y, Hou H, Khotimchenko M, et al. (2021) A hybrid modeling approach for assessing mechanistic models of small molecule partitioning in vivo using a machine learning-integrated modeling platform. Sci Rep 11: 11143.

Indexed at, Google Scholar, Crossref

3. Baranwal M, Magner A, Elvati P, Saldinger J, Violi A, et al. (2020) A deep learning architecture for metabolic pathway prediction. Bioinformatics 36: 2547-2553.

Indexed at, Google Scholar, Crossref

4. Basak SC, Vracko M G (2020)  Parsimony principle and its proper use/application in computer-assisted drug design and QSAR. Curr  Comput Aided Drug Des 16: 1-5.

Indexed at, Google Scholar, Crossref

5. Boyraz B, Sendur MAN, Aksoy S, Babacan T, Roach EC, et al. (2013) Trastuzumab emtansine (T-DM1) for HER2-positive breast cancer. Curr Med Res Opin  29: 405-414.

Indexed at, Google Scholar, Crossref

6. Xaviar S, KumarS , RamasamyK , ChakradharaRao US (2021)  Indo-Swiss Symposium on Advances in Pharmacogenomic Strategies for Pimplementation of personalized Medicine. Pharmacogenomics 22: 67-71.

Indexed at, Google Scholar, Crossref

7. Devanathan R, AlladiCG , RavichandranM , RamasamyK , UppugunduriCRS (2023)  Impact of pharmacogenomics in achieving personalized/precision medicine in the clinical setting: a symposium report. Pharmacogenomics  24: 123-129

Indexed at, Google Scholar, Crossref

8. Zhang X , JiangS , XueJ  (2022) Personalized antiplatelet therapy guided by clopidogrel pharmacogenomics in acute ischemic stroke and transient ischemic attack: a prospective, randomized controlled trial. Front Pharmacol 13: 931405

Indexed at, Google Scholar, Crossref

9. Morris SA, Alsaidi AT, Verbyla A  (2022)  Cost effectiveness of pharmacogenetic testing for drugs with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines: a systematic review. Clin Pharmacol Ther 112: 1318–1328

Indexed at, Google Scholar, Crossref

10. Epstein RS, Moyer TP, Aubert RE (2010) Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin Effectiveness study)  J Am Coll Cardiol 55: 2804-2812

Indexed at, Google Scholar, Crossref