Nanoparticle-based Drug Delivery Systems: Review and Current Status

In recent years, drug delivery technology has greatly advanced the development of numerous pharmaceutical products, significantly promoting their clinical translation. With the evolution of therapeutic drugs, delivery strategies and technologies must keep pace to meet changing drug delivery needs. Decades ago, small molecule drugs were the primary therapeutic agents, and since their physicochemical properties often affected bioavailability, delivery efforts initially focused on enhancing solubility, controlling release, expanding activity, and adjusting pharmacokinetics (PKs). The development of new therapeutic approaches, such as proteins, peptides, monoclonal antibodies, and nucleic acids, has introduced additional challenges, particularly regarding stability (e.g., proteins and peptides) and intracellular delivery efficiency (e.g., nucleic acids). Thus, drug delivery strategies must continuously improve to address the challenges of different delivery requirements.

What is Nanoparticle?

The goal of drug delivery is to transport and release drugs (passively or actively) at the target site, minimizing off-target effects to maximize therapeutic efficacy. This can be achieved by controlling drug PKs, reducing toxicity, and increasing drug accumulation at target sites. Nanodelivery systems refer to submicron drug carriers at the nanoscale, formed from inorganic or polymer materials. Based on the properties of nanomaterials, they can be classified into organic (liposomes, micelles, dendrimers, polymers, etc.) and inorganic (silica, metals, carbon nanotubes, quantum dots, etc.) categories. Nanomaterial structural units are generally smaller than cell volume, displaying unique functions and characteristics. Nanodrug delivery systems can also increase drug solubility, alter biodistribution, and enhance targeting, thereby improving therapeutic outcomes and reducing adverse effects. Consequently, nanomaterials are widely used in drug delivery systems. Additionally, nanomaterials can accumulate in tumor sites to enhance tumor treatment effectiveness and reduce toxicity. Due to their physicochemical properties, nanomaterials can be functionalized to achieve targeted drug delivery and combined tumor therapy, which is crucial for improving cancer treatment efficiency.

Fig. 1. Types of Nanoparticles (Nat Rev Drug Discov. 2021, 20(2): 101-124).

Characteristics of Nanoparticles

• Solubilization: Significantly improves the solubility and absorption of poorly soluble drugs, enhancing bioavailability.
• Protection and Barrier Function: Reduces degradation of drugs in vivo and in vitro, increasing drug stability.
• Controlled Release: By utilizing the type and properties of carrier materials, combined with different preparation processes, drugs can exhibit various environment-responsive release characteristics.
• Sustained Release: Slowly releases drugs, alters drug half-life in vivo, and extends duration of action.
• Long Circulation: Through modifications with hydrophilic materials (e.g., polyethylene glycol), it extends drug exposure time in systemic circulation, enhancing efficacy.
• Targeting: Through surface functionalization, drugs can be delivered to specific sites in the body, minimizing non-specific distribution in other organs or tissues.
• Specialized Carriers for Macromolecules: Nanodelivery systems can also serve as specialized carriers for macromolecules (peptides and proteins, DNA and RNA, vaccines) for administration through oral, injectable, and pulmonary routes.

Fig. 2. Characteristics of nanoparticles (Nat Rev Drug Discov. 2021, 20(2): 101-124).

Design and Synthesis of Nanoparticles

Surface modification and structural regulation of nanocarriers significantly impact their performance in drug delivery. Designing and synthesizing nanocarriers are critical steps in developing nano drug delivery systems. Efficient drug delivery and targeted therapy can be achieved through the thoughtful design of nanocarrier shape, size, surface properties, and structure, along with appropriate synthesis methods.

Nanocarrier Design

Nanocarrier design aims to achieve efficient drug delivery and stability while reducing adverse effects on healthy tissues. By adjusting the shape, size, and surface properties of nanocarriers, researchers can influence their distribution within the body and control the drug release rate. Surface modification imparts targeting capabilities to nanocarriers, achieved through covalent attachment or non-covalent adsorption. Common modifiers include antibodies, peptides, and glycosyl groups, which can bind to specific receptors or molecular targets, enhancing drug targeting and specificity.

Nanocarrier Synthesis

A variety of methods exist for synthesizing nanocarriers, including physical, chemical, biological, or hybrid approaches. Common techniques include nanoprecipitation, ion gelation, ultrasonic methods, microfluidics, and co-precipitation. Several factors must be considered in synthesizing nanocarriers, such as material selection, drug compatibility, and optimization of synthesis conditions. Suitable nanocarriers should offer excellent biocompatibility and biodegradability to avoid unnecessary side effects. Stability and controllability are also important factors to consider during synthesis.

Lipids from BOC Sciences

BOC Sciences is a leading lipid product provider, offering a comprehensive product offering for the synthesis and preparation of nanocarriers. We offer specialized lipids such as phospholipids, cholesterol derivatives, and PEGylated lipids, all of which are necessary to create stable, targeted nanocarriers with high encapsulation efficiency.

Nanoparticle Delivery Systems

Several nanocarriers have been developed for drug delivery, including lipid-based nanocarriers, inorganic nanoparticles, and polymeric nanoparticles. Biocompatible and biodegradable nanocarriers can stably deliver drugs, improving solubility and stability. Many pharmaceutical companies are now investing in and collaborating on nano drug delivery systems as scientific research progresses. In cancer treatment, strategies such as targeted delivery to tumors and combination therapies are actively researched and developed.

Lipid-Based Nanocarriers

Liposomes

Liposomes are spherical vesicles with a phospholipid bilayer and an aqueous core, making them suitable for encapsulating both hydrophilic and hydrophobic drugs. Their structural similarity to cell membrane phospholipids and favorable pharmacokinetic properties make liposomes an attractive tool for therapeutic drug delivery. In addition to enhancing compound stability, liposomes meet biodegradability, biocompatibility, and biodistribution requirements. Their unique structure, including the bilayer and aqueous phase, allows for the transport of hydrophilic and hydrophobic drugs. When applied for topical ocular delivery, bioadhesive polymers in liposome formulations enhance corneal adhesion, penetration, and targeted distribution at the site of action. Factors such as liposome size, charge, and bilayer fluidity are considered in drug delivery design, with positively charged liposomes showing greater corneal penetration than their neutral or negatively charged counterparts. Liposome-based formulations loaded with drugs like triamcinolone acetonide, ibuprofen, and voriconazole have been investigated for therapeutic purposes.

Lipid Nanoparticles

Lipid Nanoparticles (LNPs) are widely used for nucleic acid delivery, differing from traditional liposomes by the micellar structure formed within the core, which can be modified by formulation and synthesis parameters. LNPs typically consist of four main components: cationic lipids or ionizable lipids (which complex with negatively charged genetic material and aid in its release), phospholipids (which provide structural stability), cholesterol (which enhances stability and mediates membrane fusion), and PEGylated lipids (which improve stability and circulation). LNPs are highly effective, easy to synthesize, and have controllable sizes, making them essential in research and therapy. PEGylated lipid-based drug loading in LNPs can exceed 90%, and some encapsulated drugs, such as CPX-1, have shown to improve disease control rates in colorectal cancer patients by up to 73%. Surface modification of LNPs with small molecules, vitamins, sugars, peptides, proteins, or antibodies further enhances solubility, stability, circulation time, and even targeting characteristics.

Solid Lipid Nanoparticles

Solid Lipid Nanoparticles (SLNs) are a novel nanoscale drug delivery system composed of solid lipids, phospholipids, and surfactants. SLNs offer several advantages, including good biocompatibility, high drug-loading capacity, sustained release, and enhanced drug stability compared to other nano delivery systems. Their solid core effectively encapsulates and protects unstable drugs, preventing degradation. The SLN surface can be modified to achieve targeted delivery, increasing therapeutic efficacy while reducing side effects. SLNs provide a stable and efficient drug delivery system, enabling sustained, targeted drug release that improves treatment outcomes and reduces adverse effects.

Nanoemulsions

Nanoemulsions are nanoscale dispersion systems composed of oil, water, and surfactants, forming stable oil droplets. These droplets can effectively encapsulate and protect drugs, enabling sustained drug release and enhancing bioavailability. Nanoemulsions improve drug solubility and bioavailability, leading to better therapeutic outcomes. Their surfaces can also be modified for targeted delivery, enhancing therapeutic efficacy and minimizing side effects.

Polymeric Nanoparticles

Polymeric nanoparticles are amphiphilic solid colloidal particles with diameters between 10 and 100 nm. They consist of block copolymers with a hydrophobic core for loading hydrophobic drugs and a hydrophilic shell. Synthesis methods include emulsion (via solvent displacement or diffusion), nanoprecipitation, ion gelation, and microfluidic techniques, each yielding different polymer particles. Polymeric nanoparticles support various drug-loading strategies, such as polymer-drug conjugates, polymeric micelles, and polymeric vesicles. These particles offer excellent biocompatibility, low toxicity, and low immunogenicity, enhancing drug targeting and therapeutic efficacy while reducing side effects. Currently, the main types of polymer nanoparticles used for delivery include polymer micelles and dendrimers.

Polymer Micelles

Polymer micelles are typical stimuli-responsive block copolymers, primarily self-assembled into nanoscale spheres with a hydrophobic core and a hydrophilic outer layer. This structure protects hydrophilic drug delivery agents and improves their stability. Hydrophobic drugs can be encapsulated within the hydrophobic core of the micelles. Due to their small particle size, they can easily penetrate lymphatic vessels and reach lymph nodes, facilitating the delivery of tumor antigens and immune adjuvants. Polymer micelles can carry a variety of therapeutic agents, including small molecules and proteins, and are already being investigated in clinical trials for the delivery of cancer therapeutics.

Dendrimers

Another representative polymer nanoparticle is the dendrimer, a hyperbranched polymer with a complex three-dimensional structure, whose mass, size, shape, and surface properties can be controlled during synthesis. The active functional groups on the surface of dendrimers allow for the attachment of biomolecules or fluorescent tags, while organic small molecules, such as drugs, can be encapsulated within. Dendrimers can carry various types of cargo but are most commonly used for the delivery of nucleic acids and small molecules. One dendrimer-based nanomedicine, Viva-Gel®, has been approved for use as a preventive treatment for HIV and herpes simplex virus (HSV) infections.

Inorganic Nanoparticles

Inorganic nanomaterials are synthesized via physical or chemical methods and exhibit diverse morphologies with sizes ranging from 1 to 500 nm. These materials are easily surface-modifiable and can bind with drug molecules through interactions such as electrostatic, hydrophobic, and covalent bonding to enable responsive release. Silicon dioxide nanoparticles (SNPs), gold, and iron are widely studied for in vivo delivery. SNPs, in particular, have a tunable porous structure and high surface area, making them a prominent choice in drug delivery. Currently, SNPs are used to deliver drugs like camptothecin, doxorubicin, cisplatin, peptide drugs, protein drugs, and gene drugs in cancer therapy. Optimizing SNP size, shape, and porosity to deliver the most effective treatment for specific diseases is a key challenge.

Clinical Trials of Nanodelivery Systems

With continuous innovation in nanomaterials and nanotechnology, new types of nanodrugs, such as Goserelin sustained-release implants and Albumin-bound paclitaxel, have emerged. The goserelin sustained-release implant utilizes polylactic-co-glycolic acid (PLGA) as a carrier for the gonadotropin-releasing hormone goserelin, achieving a sustained-release effect. With just one injection, the therapeutic effects can last for up to a month, greatly enhancing patient compliance. This treatment is widely used in hormone therapy for breast and prostate cancers. Albumin-bound paclitaxel uses albumin as a nanocarrier to deliver paclitaxel, effectively reducing allergic reactions while enabling rapid delivery of paclitaxel to tumor tissues, where it remains for an extended duration. In breast cancer treatment, standard paclitaxel has a response rate of only 19%, whereas albumin-bound paclitaxel can increase this to 33%.

Table 1. FDA-approved nanomedicines.

Over the past few decades, the U.S. FDA has approved nearly 100 nanodrugs for clinical trials. With the increasing market penetration of existing nanoproducts, the number of approved products is expected to continue growing. According to market data, the global nanodrug market size was approximately $53 billion in 2009, rising to $134.4 billion in 2017, and is projected to reach $293.1 billion by 2022.

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Reference

1. Mitchell, M.J. et al. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov. 2021, 20(2): 101-124.