Nanoparticle-Based Small Molecule Drug Delivery
Small-molecule drugs are variable-specificity drugs targeted within cells, typically well-defined organic substances with a molecular weight of fewer than 900 Daltons, that help regulate biological processes. Due to differences in size, manufacturing, pharmacokinetics, pharmacodynamics, and suitability, small molecule drugs have certain advantages over larger molecule drugs or biologics:
● The development of classic drugs generally starts with the production of chemically manufactured small molecules of the active substance;
● Small molecules can be processed into easy-to-ingest tablets or capsules;
● The small structure and chemical composition also contribute to the easier penetration of small molecules into cell membranes or target organs, showing intracellular advantages compared to extracellularly directed, highly specific biological proteins;
● Biologics are characterized by high selectivity for their target molecules, while small molecules have a broader target spectrum;
● Small molecules are easier to synthesize, and their synthesis can be accomplished simply by chemical interactions between different organic and/or inorganic compounds.
Nanoparticles (NPs) are a colloidal drug delivery system comprising particles ranging in diameter from 10 to 1000 nm. Nanoparticles may or may not exhibit size-dependent properties that differ substantially from those observed in fine-grained or bulk materials. The key advantages of nanoparticles are that they can increase bioavailability by enhancing water solubility, and they can increase resistance time in vivo (by increasing clearance half-life or increasing the specificity of their cognate receptors, as well as targeting drugs to A specific location in the body (site of action). This results in a corresponding reduction in the dose and toxicity of the required drug, allowing the safe delivery of the therapeutic drug and protecting non-target tissues and cells from serious side effects. They are increasingly used Used in different drug delivery systems for passage through organ barriers such as the blood-brain barrier, cell membranes, etc. They are based on biocompatible lipids and provide sustained effects by diffusion or dissolution.
For example, chemotherapy, as an efficient technique, has been widely used in the clinical treatment of cancer. However, there are several limitations in the direct administration of anticancer drugs with small molecule structures: 1) adverse side effects; 2) rapid drug elimination; 3) nonspecific cytotoxicity; 4) severe drug resistance reactions; 5) bioavailability Low. Some nanoscale drug carriers such as metal nanoparticles, liposomes, ceramic materials, polymer micelles, etc. have been used to overcome the above limitations. These therapeutic NPs (TNPs) have shown advantages in the delivery of small-molecule anticancer drugs :
● TNPs enhanced the solubility of anticancer drugs (Fig. 1a);
● TNPs increased the circulation time of anticancer drugs in blood vessels (Fig. 1b);
● TNPs promoted the accumulation of anticancer drugs in targeted tumor tissues (Fig. 1c);
● The targeting properties of TNPs allow tumor cells to take up drugs through endocytosis, resulting in elevated intracellular drug concentrations (Fig. 1d);
● TNPs can help achieve a controlled and stable release of drugs (Fig. 1e);
● TNPs are not substrates of ATP- binding cassette proteins, thereby minimizing efflux pump-mediated drug resistance (Fig. 1f).
Figure 1: Schematic diagram of the advantages of NPs for small molecule anticancer drug delivery
Several nanocarriers for the delivery of small-molecule drugs are summarized below (Table 1).
Table 1: Nanocarriers for Small Molecule Drug Delivery
PGA:poly-(L-glutamic acid);HPMA:N-(2-hydroxypropyl)-methacrylamide copolymer; PEG:polyethylene glycol;PAA: poly-(L-aspartic acid);PLA:poly-( L-lactide); PAMAM: poly-(amide amine); HSP:heat shock protein;CPMV:cowpea mosaic virus;DOX: doxorubicin;MTX:methotrexate.
Silicon nanoparticles
Folate (FA) receptors are known to be overexpressed in solid tumor cells and macrophages, making them attractive targets for many NPs through receptor-mediated endocytosis. Lv et al. used FA-modified mesoporous silica NPs ( MSNs ) for active targeting and modified the NPs using large gas-filled microbubble (MB) technology. Gas-filled MBs were disrupted by local ultrasound irradiation, resulting in the release of FA -modified MSNs across the endothelial layer into target tissues.
Gold Nanoparticles
PTX is a product isolated from the bark of Pacific yew, and it is one of the most effective chemotherapy drugs at present. Gao et al. prepared sialoprotein receptor (ASGP-R)-targeted and PTX -coupled Au-NPs (galactose / PTX-Au-NPs) for precision therapy of liver cancer (HepG2) cells.
Iron Oxide Nanoparticles
sensitive drug delivery system based on PEGylated Fe3O4 superparamagnetic NPs was investigated by Ji et al. Firstly, citric acid-coated Fe3O4(CIO) NPs were synthesized and then further functionalized into biocompatible PEG bis(carboxymethyl ether) (COOH-PEG-COOH) to obtain PEGylated CIO (GCIO) NPs.
Liposomes
As a class of therapeutic nanoparticles, liposome-formulated drug delivery systems have been developed for decades. Liposomes are self-assembled closed colloidal structures composed of lipid bilayers. They are spherical in shape and maintain a water space in the center. Several small-molecule anticancer drugs have been encapsulated in lipid-based systems.
Polymer
Both natural and synthetic polymers can be used in therapeutic nanoparticle formulations. Depending on the method of preparation, the drug is physically encapsulated or covalently bound to the polymer matrix. Natural polymers including albumin, chitosan, and heparin have been used for the delivery of small-molecule drugs, such as the albumin-based formulation of paclitaxel (Abraxane).
Virus
Many viruses, such as cowpea mosaic virus, cowpea green spot virus, canine parvovirus, heat shock protein (HSP) cages, and bacteriophages, have been used in biomedical and nanotechnology applications, including tissue targeting and drug delivery. Targeting molecules or polypeptides can be displayed on the capsid surface in a biologically functional form by chemical or genetic means. Therefore, several ligands or antibodies such as transferrin, folic acid, and single-chain antibodies can be conjugated to viruses for specific tumor targeting in vivo.
References
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5.Ji, F. , Zhang, K. , Li, J. , Gu, Y. , Zhao, J. , & Zhang, J. . (2018). A dual ph/magnetic responsive nanocarrier based on pegylated Fe3O4 nanoparticles for doxorubicin delivery. Journal of Nanoscience and Nanotechnology. https://doi.org/10.1166/jnn.2018.15275
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