Advances in the design of solid lipid nanoparticles and nanostructured lipid carriers for targeting brain diseases

Purpose: Delivery of therapeutics to the CNS is severely limited by the blood–brain barrier (BBB). Polymeric and inorganic nanoparticles have shown utility but face toxicity, scalability, and organic-solvent concerns. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are biocompatible lipid-based systems with inherent BBB-penetration potential, making them attractive for brain cancer and neurodegenerative diseases.

Hypothesis: If SLNs/NLCs are properly designed with selected solid/liquid lipids, surfactants, and targeting moieties, then they can cross or bypass the BBB, deliver drugs, genes, or other cargo to the brain, improve brain accumulation and therapeutic efficacy, and reduce systemic toxicity compared with conventional nanocarriers.

Aims: Review major brain diseases: brain cancer/glioblastoma multiforme, ischemic stroke, Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis. - Describe SLN and NLC fabrication techniques, characterization, and comparison with other delivery systems. - Summarize the last seven years of active and passive targeting SLN/NLC studies for CNS diseases. - Discuss advantages, disadvantages, and future perspectives for clinical translation.

Delivery system: SLNs: solid lipid core at room and body temperature; lipids include monostearin, stearyl alcohol, stearic acid, glycerol monostearate, Precirol ATO5, Compritol 888 ATO, cetyl palmitate; surfactants include poloxamer 188, Tween 80, and DDAB. - NLCs: solid lipid matrix containing a liquid lipid phase; liquid lipids include almond oil, oleic acid, olive oil, peanut oil, sesame oil, soybean oil, and Capmul MCM C8. Solid:liquid lipid ratio ranges from 4:1 to 1:4; surfactant 0.25–6% w/v; total lipid 1–30% w/v. - Payloads: chemotherapeutics (carmustine, doxorubicin, etoposide, temozolomide, paclitaxel, curcumin, resveratrol), siRNA, DNA, peptides, proteins, antioxidants, and imaging agents. - Targeting/functionalization: passive targeting via size/lipid nature; active targeting with anti-EGFR, transferrin, hyaluronic acid/CD44, anti-Cntn2, anti-Nfasc, OX26 antibody, Fas ligand antibody, lactoferrin, RGD peptide, L1 peptide, and others. - Fabrication methods: high-pressure homogenization (hot/cold), high-speed/shear homogenization, emulsification-ultrasonication, solvent emulsification/evaporation, solvent displacement, supercritical fluid technology, fatty acid coacervation, and microemulsion.

Approach: Review and synthesis of preclinical in vitro and in vivo studies. Cell lines include U87, U87MG, U251, U373, A172, C6, GL-4, hCMEC/D3, HBMEC, BCEC, RAW264.7, THP1, and K562. Animal models include murine/rattus glioma models, orthotopic xenografts, patient-derived brain tumor-initiating cell xenografts, ischemic stroke models, Parkinson’s disease models, Alzheimer’s disease models (e.g., ICV-STZ rats, Aβ25–35), and multiple sclerosis models. As a review, it reports no primary experimental groups, n values, doses, or controls.

Key methods: No primary methods. The review discusses data generated by cited studies using: - Dynamic light scattering for size, polydispersity, and zeta potential. - Differential scanning calorimetry and X-ray diffraction for lipid structure. - Encapsulation efficiency and loading capacity measurements. - In vitro release profiles. - MTT/cytotoxicity assays and flow cytometry for cellular uptake. - BBB monolayer permeation models (e.g., hCMEC/D3). - In vivo biodistribution, pharmacokinetics, tumor inhibition, and survival. - Behavioral and biochemical assays for neurodegenerative disease models.

Key results: Formulation ranges: NLC solid:liquid lipid ratio 4:1–1:4; surfactant 0.25–6% w/v; total lipid 1–30% w/v; high-pressure homogenization can produce particles down to 40 nm. NLCs improve loading and reduce drug expulsion compared with SLNs. - Brain cancer: Cationic SLNs functionalized with anti-EGFR showed size 80–280 nm, zeta potential +14 to +40 mV or −13 to −38 mV, and EE 17–95%. Cytarabine NLCs were ~90 nm with EE ~50%, releasing ~16% in 1 h and ~90% over 72 h. Hyaluronic acid-coated LNPs carrying PLK1 siRNA were 100 nm, −8 mV, EE 80%, reduced PLK1 mRNA by >80%, and prolonged survival. TMZ + vincristine NLCs achieved tumor inhibition of 83.17% vs 26.34% for free TMZ. Curcumin NLCs showed 82.3% tumor growth inhibition in A172 xenografts. - Other CNS diseases: Vinpocetine NLCs had EE ~95% and increased bioavailability by 322%; a cyclodextrin–tartaric acid NLC formulation increased oral bioavailability by 522% vs free drug. Curcumin SLNs improved cognition by 90% and inhibited acetylcholinesterase by 52% in an ischemic stroke model. Riluzole SLNs were <90 nm, −46 mV, and increased brain drug concentration vs free drug. - Targeting: Transferrin-targeted etoposide NLCs were 125–250 nm with zeta +25 to +45 mV and enhanced uptake. Transferrin-conjugated paclitaxel NLCs were ~200 nm, +25.7 mV, EE 92%, and loading capacity 5.38%. LDL-mimicking curcumin SLNs showed ~3× higher brain accumulation than plain SLNs. However, in some MS studies, plain SLNs penetrated the BBB better than PEGylated or antibody-functionalized SLNs.

Interpretation: The authors conclude that SLNs and NLCs are next-generation lipid-based drug delivery systems that combine many advantages of polymeric nanoparticles—small size, functionalizability, controlled release—without their toxicity, organic-solvent, and burst-release limitations. Their inherent BBB penetration, biocompatibility, and scalability make them promising for brain cancer and neurodegenerative diseases. However, clinical translation remains limited by low loading capacity, drug expulsion, off-target organ accumulation, and the need for more specific brain targets and multi-payload formulations.

Limitations: Review article; no primary experimental data, effect sizes, n values, doses, or controls. - SLNs often have low encapsulation efficiency and drug expulsion during storage; NLCs improve but do not fully solve this. - Most studies are preclinical, using murine models; few clinical trials or commercial products exist. - Many brain-targeted SLNs/NLCs also accumulate in liver, heart, lungs, and other organs, raising safety concerns. - Most studies load only one or two therapeutic agents, usually drugs rather than genes, enzymes, or inorganic nanoparticles. - Long-term safety, large-animal validation, and scale-up under GMP conditions remain unresolved. - More specific targets and better understanding of BBB transport are needed to improve brain accumulation and therapeutic efficacy.