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The successful utilization of nanoparticles in drug delivery due to its ability to penetrate through several anatomical barriers, stability of the particle in nanometer size and sustained release of active moiety.
The scarcity of safe polymers with regulatory approval and high cost has limited the application of polymeric nanoparticles in clinical medicine. These limitations of the polymeric nanoparticles have been replaced with lipid as alternative carrier, particularly for lipophilic pharmaceuticals.
The hydrophobic internal structural, make them suitable for lipophilic drug delivery. The hydrophilic surface of Lipid Nanoparticle (LNP) will help in easy dispersion in aqueous solutions and used in lipophilic drug delivery system in the body.
In recent studies with LNP assisted drug delivery suggest that bioavailability of LNP could be increased through surface modification, like surfactant protein coating, pegylation and use of chitosan.
The lipid nanoparticles have opened doors in pharma industry for exploring its role in drug delivery technology for the transport and delivery of diversity of therapeutic agents from biotechnological products to small drug molecule.
The main advantages of LNPs for use in drug delivery technology include biodegradability, biocompatibility, entrapment efficiency physicochemical behaviors like high bioavailability, large scale production, cross blood brain barrier, delivery of macromolecules like protean, oligonucleotide DNA, and possible administration through different routes.
The drug delivery system using lipid based nano particles include liposomes, nano structured lipid carrier and solid lipid nanoparticles have shown tremendous clinical success in delivering both hydrophobic and hydrophilic therapeutics agents for various ailments.
The lipid nanoparticles are now extensively investigated as carrier for nucleic acids like DNA, MRNA and Si RNA. The total market value of LNP based gene therapy have reached about $3.5 billion in 2021 and expected to grow by 18.5 per cent. The market value of LNP used for cancer treatment is approximately $ 3.72 bn in 2021 and expected to grow by $7 bn by 2027.
The lipid-based nanoparticles can be classified into three different group’s namely solid lipid nanoparticles (SLN), nanostructured ipid carriers and self-emulsification drug delivery system. The SLN offers advantages over liposomes and polymeric nanoparticles due to its omission of organic solvents during the preparations, have good reproducibility, feasible for large scale production and increased stability.
Liposomes are spherical shape artificial vesicles created from natural non-toxic phospholids. The major components in liposomes are phospholipids organized in a bilayer structure having amphipathic properties.
In presence of water, they form vesicles, which improve solubility and stability of therapeutic moiety during loading into the structure. Other components can be added to liposomes, which include addition of phospholipids like cholesterol.
Cholesterol can decrease the fluidity of the nanoparticle and increases the permeability of hydrophobic drugs. There are many research conducted with liposomes with the goal of reducing the drug toxicity and for targeting specific cells/organs.
Liposmoes can be classified into two categories namely multilamellar vesicles and unilamellar vesicles. The unilamellar vesicles are further classified as large and small unilamellar vesicles. The liposomes are used in diagnostic and for therapeutic applications.
The use of liposomal formulations of all-trans-retinoic acid and daunorubicin has received FDA consent as a first line treatment of AIDS advanced Kaposi’s sarcoma. Liposomes are also used in parasitic diseases like leishmaniasis. Numerous liposomes based anticancer formulation has shown low toxicity than the free form of drugs.
Liposomes have shown positive results in drug delivery systems for anti-sense molecules, ribosomes, proteins/peptides and DNA. Liposomes are now achieving clinical acceptance by enhancing drug delivery to disease locations by prolonging circulation residence time.
Solid lipid nanoparticle
The solid lipid nanoparticles (SLNs) are colloidal particles having size range from 10 to 1000 nm. The SLNs are safe carriers and are first generation of lipid nanoparticles with a solid matrix.
They are produced from physiological and biodegradable lipids like triglycerides, partial glycerides, waxes, steroids, fatty acids and other materials generally recognized safe for human use.
The SLNs can be prepared by high pressure homogenization, and widely used for preparing nanoemulsion. There are two approaches used to produce SLNs which are hot and cold homogenization. SLNs can also be prepared by high-speed stirring and ultra sonication methods and is the simplest and most cost-effective way.
In high stirring and ultra sonication lipids are first melted at high temperature and the drugs are either dissolved or dispersed using a high- shear mixer, resulting in the formation of hot oil/water [O/W] emulsion. The product is cooled to obtain SLNs.
The microemulsion method is also commonly used for preparing SLNs in which dilution of microemulsion is initiated to precipitate the lipid. In brief optically transparent mixture containing a low melting point fatty acid, emulsifier, co emulsifiers and water is stirred at 65-70oC.
The hot microemulsion is dispersed in cold water under stirring, the volume ratio of hot micro emulsion to cold water is kept in range 1:25 to 1:50. The addition of hot microemulsion to cold water under mild mechanical mixing leads to precipitation of lipid phase into SLNs.
The solvent emulsification evaporation method is also used for preparing SLNs, which involves three steps like addition of lipid materials to known volume of organic solvent and mixed to form homogenous clear solution of lipid, formation of coarse emulsion which is later converted to nano emulsion by using high pressure homogenizer.
The double emulsion is also a method adopted for preparing SLNs for hydrophilic drugs and biomolecules. The phase inversion temperature is adapted for preparing SLNs and is based on temperature-induced inversions of W/O to O/W emulsions and vice versa. This method requires the use of non-ionic polyoxyethylated surfactants with temperature-dependent properties.
The others methods used for preparing SLNs include Membrane contactor, supercritical fluid-based method, solvent injection and coacervation methods. In membrane contractor a specific membrane is used for producing SLNs, in which the lipid phase is pressed through the pores of membrane while temperature is maintained above solid lipids melting point resulting in formation of small droplets.
Nanostructured Lipid Carriers (NLCs)
The NLCs are considered the second generation of lipid –based nanocarriers, which is formed from a mixture of solid and liquid lipids. The NLCs have unstructured-matrix, which may be due to different moieties of the constituents of NLCs.
The NLCs have several advantages over SLNs which include increased drug loading, prevent pH and enzyme degradation, easy to modulate drug release profile, production of final dosage form preparation is easy and drug leakage during storage is less.
The increase in drug solubility in lipid matrix with NLCs can be used for controlled release formulation. The NLCs can be prepared by different methods which include micro emulsion, probe sonication, solvent emulsification evaporation, high pressure homogenization, solvent diffusion, solvent injection/solvent displacement and phase inversion techniques.
The lipid-based nanoparticles (LBNPs) are used in cancer treatment and various research are on the way in clinical trials and others in in-vitro in-vivo studies in relation to most frequent cancer treatment.
The LBNPs based therapy represents a potential mechanism in improving the current treatment for metastatic colon cancer. The drugs like 5-FU alone or in combination with other drugs/ monoclonal antibodies have low efficiency for treating colon cancer.
The researchers tried for getting a solution to treat colorectal cancer, were thermosensitive gel-mediated 5-FU microemulsion showed increase permeability and cell uptake of Caco-2. The pancreatic cancer is often diagnosed in advanced stages when surgery could not be applied. LNPs offer some therapeutic strategies for improving the prognosis of these patients.
The formulation containing stearoyl chitosan-coated LNPs using ME cold dilution techniques loaded with CUR could increase the inhibition of cell growth 3-fold for CUR in PANC-1 cells. The use of LNPs associated with molecules like Arg-Gly-Asp peptide, SATB1 siRNA/CD44 antibodies or by forming DNA complex could increase drug accumulation in tumor cells in animal model.
The LNPs also demonstrated improved targeting precision and able to silence gene expression. The treatment associated with liver cancer are often limited due to poor physicochemical properties of therapeutic moiety. The chemotherapy/ and drug targeting have minimal impact in treatment outcome, radiotherapy are ineffective.
The LNPs 5-FU-loaded cubosomes and PTX-loaded NLCs have shown promising result in liver cancer. The LNPs have demonstrated the ability of drug to cross blood-brain barrier and help to remain in glioblastoma multiforme (GBM) tissues facilitating active targeting of drugs towards GBM tissues.
The patients treated with chemotherapy and radiotherapy for lung cancer develops a recurrence of disease that is more resistant to subsequent therapy. Significant advancement is made with LNPs for diagnosis and for therapy in lung cancer.
The nanoparticles like bromo-noscapine NE, lipophilic diferuloylmethane NE, CXUR-water-free-NE and docetaxel-NE have shown increased antitumor activity in A-549 cells. The use of nanoparticles like NEs loaded with DOX and bromotetratrandrine (W198, P-glycoprotein [P-gp] inhibitors) have sown better result in breast cancer in cell line studies.
(The author is Professor & Principal, National College of Pharmacy, Manassery PO, Kozhikode, Kerala)
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