Physical Properties of Nanoparticles That Result in Improved Cancer Targeting

Purpose: Drug penetration into tumors is limited by abnormal vasculature and high interstitial pressure, and chemotherapy causes undesirable adverse effects including bone marrow and gastrointestinal toxicity. Nanotechnology-based drug delivery systems aim to reduce these adverse effects by enhancing penetration and selective drug retention in tumor tissues. A thorough knowledge of the physical properties (size, surface charge, shape, mechanical strength) and chemical attributes of nanoparticles is crucial to facilitate biomedical applications.

Hypothesis: No formal experimental hypothesis. Central thesis: optimizing the physical properties of nanoparticles—size, shape, charge, and surface coating—can improve tumor targeting, biodistribution, and penetration. The authors propose that an ideal nanoparticle should have different properties during circulation (larger size, nonspherical shape, neutral charge) versus after reaching the tumor (smaller size, positively or slightly negatively charged, lower aspect ratio), with surfactants removed once in the extracellular matrix.

Aims: Summarize how the attributes of nanoparticles can be exploited to improve therapeutic efficacy. - Address physicochemical parameters affecting biodistribution and those affecting tumor uptake. - Discuss the protein corona and biological barriers that nanoparticles encounter. - Propose characteristics of an ideal nanoparticle to guide future development for improved drug targeting in vivo.

Delivery system: Nanoparticle types: gold NPs (AuNPs), silver NPs (AgNPs), polymeric NPs, micelles, liposomes, quantum dots, iron oxide NPs, silica NPs, carbon nanotubes, filomicelles, nanorods, discoidal particles, nanohydrogels, spherical particles, cylindrical particles. - Payloads: doxorubicin (Doxil/Caelyx), daunorubicin (DaunoXome), paclitaxel (Abraxane), siRNA, imaging agents, therapeutic drugs. - Surface coatings: PEG (polyethylene glycol), zwitterionic polycarboxybetaine (PCB), CD47 "self" peptides, polysorbate 80, cell membranes (erythrocyte, leukocyte), poly(hydroxyethyl-L-asparagine) (PHEA), polyglycerol (PG), breviscapine (BVP), cell-penetrating peptides (CPP, TAT), F3 peptide, NaLS04. - Targeting strategies: passive targeting (EPR effect), active targeting (ligand-receptor interactions), "personalized protein corona" (PPC), delayed charge reversal, ligand-switchable NPs. - Key design parameters: size (5–200 nm), zeta potential (neutral ±10 mV optimal for circulation), shape (spherical, rod, filamentous, discoidal, ellipsoidal), aspect ratio, mechanical strength, surface hydrophobicity.

Approach: Comprehensive review of preclinical and clinical literature; no primary experiments. In vitro systems include human umbilical vein endothelial cells, breast cancer cells, head and neck cancer cells, melanoma cells, and 3D spheroid models. In vivo models include mice (breast cancer, melanoma, hepatic lesions, head and neck cancer, glioma), rats, and hairless mice (skin penetration). Clinical context includes FDA-approved nanomedicines (Doxil, DaunoXome, Abraxane). The review includes mathematical modeling of NP transport across vessel walls and multiscale simulations of tissue penetration.

Key methods: Review-level synthesis of: - Biodistribution studies: organ accumulation (liver, spleen, tumor, kidney, brain, lung) by NP size and charge. - Tumor penetration and uptake: 3D spheroid models, in vivo tumor models. - Protein corona characterization: hard vs soft corona, composition, disease-specific fingerprints. - Macrophage uptake/phagocytosis assays: contact angle, aspect ratio effects. - Mathematical modeling: electrostatic interactions, hydrodynamic and steric forces, Debye length, pore size effects. - Imaging and tracking: fluorescence, MRI, photoacoustic imaging. - Skin penetration studies: dermatological applications.

Key results: 15 nm AuNPs showed highest accumulation in organs (liver, lung, spleen, kidney); only 15 and 50 nm AuNPs crossed the blood-brain barrier. - Renal clearance is rapid for particles <5–6 nm; clearance by liver and spleen is rapid for particles >200 nm; particles ≥200 nm mostly removed by mononuclear phagocytic system (MPS/RES). - 100 nm NPs have poor diffusion within dense collagen matrix of interstitial space. - 8 nm NPs showed more cytotoxicity compared to larger size NPs. - Neutral NPs (zeta potential within ±10 mV) exhibit least RES interaction and longer circulation time; negatively charged NPs (ξ < −10 mV) exhibit strong RES uptake; positively charged NPs (ξ > 10 mV) induce serum protein aggregation. - PEGylation reduced liver accumulation to one-half to one-third of non-PEGylated NPs; significant reduction in spleen, liver, and pancreas accumulation. - Anti-PEG antibodies after first injection cause accelerated blood clearance (ABC) after second injection. - Best tumor accumulation (EPR effect) requires NP size between 100 and 150 nm; best tumor penetration requires smaller size <12 nm (conflict between these two requirements). - Filamentous NPs (filomicelles) persisted in circulation longer than spherical particles; PEGylation further enhanced this effect. - Rod-shaped and discoidal NPs marginate better than spheres; discoidal particles (AR = 0.5) showed highest drift velocities and oscillatory trajectories. - Positively charged NPs better target tumor vessels; neutral charge allows more rapid diffusion within tumor tissue after extravasation. - Delayed charge reversal strategy (positive → neutral inside tumor) improved intratumoral penetration and tumor growth inhibition. - NaLS04 coating achieved maximum skin penetration, followed by PG and PEG. - Coated BVP-PLA NPs avoided RES and prolonged half-life.

Interpretation: The authors conclude that the major factors improving tissue biodistribution are physicochemical properties, whereas the major factor affecting cellular uptake is the coating. They propose an ideal NP with stage-dependent properties: (1) during circulation—larger size (>100 nm), nonspherical shape, neutral charge for better circulation and tumor accumulation; (2) once in contact with tumor—positively or slightly negatively charged, smaller size (<12 nm), lower aspect ratio for better penetration and internalization. Surfactants should be removed once NPs enter the ECM. They emphasize that coatings and ligands mainly affect intracellular uptake by target cells and do not necessarily improve tumor targeting. Novel hydrophilic polymers other than PEG may be potential alternatives due to PEG immunogenicity.

Limitations: Review article; no primary data. - EPR effect is size-dependent, can be slow and inefficient compared to active targeting; effective only on well-vascularized primary tumors and ineffective in metastatic disease with small deposits. - Protein corona formation is not well understood; no mathematical model exists to predict NP-surface interactions. - PEG immunogenicity: anti-PEG antibodies cause accelerated blood clearance after repeated injections. - No ideal NP exists that meets all requirements; conflicting requirements for tumor accumulation (100–150 nm) vs. penetration (<12 nm). - Most studies are preclinical; clinical translation limited (only 1 in 10 drugs gain FDA approval). - Tumor type and stage affect NP behavior; tumor uptake is dynamic and varies as tumor progresses. - Brain distribution is poor for all NP sizes studied; only traces of large diameters found in tumor. - Cell-particle interactions may moderate particle-size effects, making in vitro results not always predictive of in vivo behavior. - Lack of cell specificity and unclear mode of delivery for CPP-based strategies. - More investigations required to improve tumor delivery and reduce side effects of CPPs.