Porous Silicon and Mesoporous Silica Nanoparticles in Peptide Delivery: A Comprehensive Review
Introduction
Peptide therapeutics have emerged as promising biological agents, offering high specificity, target diversity, and ease of production at a lower cost. However, their clinical application is hampered by poor physiological and storage stability, unfavorable pharmacokinetics, and rapid clearance from the body. To overcome these limitations, nanocarrier-based strategies have been developed, with porous silicon (pSi) and mesoporous silica nanoparticles (MSNs) gaining significant attention as potential carriers for peptide delivery. This review provides a comprehensive overview of pSi and MSNs, focusing on their fabrication, surface modification, and properties that make them suitable carriers for peptide therapeutics. Furthermore, it presents a systematic analysis of studies that have utilized these porous carriers for peptide delivery, highlighting significant in vitro and in vivo results, and offering a critical comparison of their physicochemical properties and biocompatibility.
Peptide Therapeutics: An Overview
Peptide therapeutics are short chains of amino acids, typically consisting of fewer than 50 residues linked by amide bonds. These molecules act as signaling agents, selectively binding to receptors with specific surface structures and triggering intracellular effects. They have been used to treat various diseases, including cancer, cardiovascular diseases, infectious diseases, pain management, neurological disorders, and metabolic disorders. Peptide-based probes are also employed in bioimaging systems to observe processes like metabolism, gene expression, receptor binding, and biochemical pathways in real-time.
Peptides offer several advantages, including high specificity, low toxicity, and the ability to target specific cellular pathways. They are metabolized and excreted relatively quickly, reducing the risk of toxicity or accumulation. Similar to antibody-based biologics, therapeutic peptides bind to target cells with high affinity and specificity, minimizing off-target effects and the need for repeated dosing.
However, peptide therapeutics can be immunogenic, potentially triggering an immune response. This issue has been addressed through surface modifications like PEGylation, glycosylation, and lipidation, which improve their safety and tolerance. Compared to proteins, peptides have shorter amino acid chains and simpler structures, enhancing their ability to penetrate cell membranes. They can also be easily synthesized using solid-phase peptide synthesis techniques, allowing for large-scale production.
Challenges in Peptide Delivery
The route of administration significantly impacts the efficacy and safety of peptides. Oral administration leads to degradation by proteolytic enzymes and poor mucus layer penetration, resulting in low bioavailability. Intravenous administration provides high bioavailability but is limited by a short circulation half-life and rapid clearance. Topical and transdermal delivery face challenges due to limited permeation of macromolecular peptides and enzymatic degradation in the skin. Therefore, appropriate delivery systems are needed to protect peptides from degradation and enable controlled release.
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Nanocarriers for Peptide Delivery
Nanocarriers, including lipid-based and polymer-based systems, have been explored to improve the stability and bioavailability of peptide therapeutics. However, many of these systems suffer from poor peptide encapsulation rates, leaching, and difficulty in incorporating larger peptides. Mesoporous nanocarriers like pSi and MSNs have emerged as promising alternatives due to their tunable porous structures with pore sizes ranging from 2 to 50 nm, which are well-suited for encapsulating macromolecular payloads like peptides. These porous structures can hold peptides with minimal premature release during in vivo transportation and circulation, while also exhibiting high thermal and chemical stability.
Porous Silicon (pSi) as a Drug Carrier
Porous silicon (pSi) is a material with nanosized open pores, making it an effective container for therapeutic payloads. The porous structure significantly increases the surface area, making it suitable for drug loading and controlled elution. pSi materials are typically synthesized using an electrochemical etching-based "top-down" approach, where silicon wafers are etched in the presence of hydrofluoric acid (HF) based electrolytes. The pore size is controlled by varying etching parameters such as current density, electrolyte concentration, crystal orientation, and dopant concentration. Other synthesis methods include photochemical, stain, gas-induced, and spark-induced etching.
The pSi layer can be removed to create free-standing porous films that are milled into micron- or nano-sized particles. These particles can be used for both depot and systemic delivery of therapeutic payloads. The pore structure and surface chemistry of pSi contribute to improved drug adsorption, solubility, and drug release.
Stabilization and Surface Chemistry of pSi
Native pSi particles can be unstable in physiologically relevant solvents. To address this, novel stabilization chemistries have been developed to improve the biological stability of pSi while retaining biodegradability. Partial oxidation of pSi particles (TOPSi) introduces hydrophilic properties with moderate stability. Thermal hydrocarbonization (THCPSi) creates more stable pSi with a hydrophobic surface covered with hydrocarbons. Thermal functionalization of THCPSi with undecylenic acid (UnTHCPSi) results in moderately hydrophilic surfaces with hydroxyl groups that can be further modified.
These surface chemistries are crucial for the handling stability of pSi and for achieving optimal and precisely controlled drug loading. A study on the pharmacokinetic properties of pSi and peptide YY3-36 (PYY3-36) demonstrated the ability of pSi particles to load and potentially control the release of the peptide in vitro and in vivo. TOPSi showed the maximum release ability and rapid degradation rate, followed by THCPSi and UnTHCPSi. Another study reported better efficacy of cationic pSi compared to anionic TOPSi for in vivo delivery of glucagon-like peptide-1 (GLP-1). Loading of PYY3-36 onto pSi prevented peptide degradation and increased its bioavailability.
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Photoluminescence of pSi
pSi exhibits inherent photoluminescence (PL) in the red and near-infrared region, which can be used for imaging and tracking particles. Luminescent pSi nanoparticles (LPSiNPs) have been used to track biodistribution and accumulation in vivo, with the PL diminishing within one week and clearing completely within four weeks.
Mesoporous Silica Nanoparticles (MSNs) as a Drug Carrier
MSNs are ideal drug carriers due to their unique properties and versatile applications in drug delivery. They possess a mesoporous structure with well-defined and uniform pores, enabling efficient encapsulation and delivery of therapeutic agents. MSNs have a honeycomb-like structure and an active surface area that allows for functionalization, facilitating the incorporation of desirable surface properties and linking with specific molecules.
The synthesis of MSNs typically occurs at low surfactant concentrations, involving the interaction between anionic oligomers of orthosilicic acid and cationic surfactants. One of the key advantages of MSNs is their high surface area, providing ample space for drug loading. The mesoporous nature of MSNs ensures controlled and sustained release of encapsulated drugs, allowing for precise modulation of drug release kinetics. The tunable pore size of MSNs is another crucial attribute, allowing the accommodation of various therapeutic agents. By adjusting synthesis parameters like surfactant concentration or template size, the pore size can be tailored to specific needs.
Applications of pSi and MSNs in Peptide Delivery
Porous silicon and mesoporous silica nanoparticles have been extensively explored for peptide delivery through various routes of administration, including systemic, oral, and topical.
Systemic Delivery
Systemic delivery of peptide therapeutics using pSi and MSNs aims to achieve targeted and controlled release of the drug to specific tissues or organs. Surface modification of these nanocarriers with targeting ligands or stimuli-responsive materials can enhance their accumulation at the desired site and trigger drug release upon encountering specific stimuli, such as pH, enzymes, or redox potential.
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Oral Delivery
Oral delivery of peptide therapeutics is a challenging but highly desirable route of administration. pSi and MSNs can protect peptides from enzymatic degradation in the gastrointestinal tract and enhance their absorption across the intestinal epithelium. Surface modification with mucoadhesive polymers or cell-penetrating peptides can further improve their oral bioavailability.
Topical Delivery
Topical delivery of peptide therapeutics using pSi and MSNs offers the potential for localized treatment of skin disorders and wounds. These nanocarriers can enhance the penetration of peptides through the stratum corneum, the outermost layer of the skin, and provide sustained release of the drug at the target site.
Critical Comparison of pSi and MSNs
Both pSi and MSNs offer unique advantages as carriers for peptide therapeutics. pSi exhibits inherent biodegradability and photoluminescence, while MSNs possess high surface area and tunable pore size. However, pSi can be unstable in physiological conditions, requiring surface modification for stabilization. MSNs, on the other hand, are generally more stable but may require surface functionalization for targeted delivery.
Physicochemical Properties
pSi and MSNs differ in their physicochemical properties, including particle size, pore size, surface area, and surface charge. These properties can influence their drug loading capacity, release kinetics, and interaction with biological systems. pSi typically has a smaller particle size and a more uniform pore size distribution compared to MSNs.
Biocompatibility
The biocompatibility of pSi and MSNs is a critical factor for their clinical translation. Both materials have shown good biocompatibility in vitro and in vivo, but their long-term effects need further investigation. Surface modification and careful selection of synthesis parameters can minimize potential toxicity.
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