Table 2.
Nanomaterials developed with active and passive targeting modalities improve joint pharmacokinetics and whole-joint retention.
| Nanomaterial type | Tissue targeting modality | Physical properties | Animal model | Major findings | Ref. |
|---|---|---|---|---|---|
| Dextran, fluorescently labeled | None | 10kDa (~1.4nm)[a]
500kDa (~5.2nm)[a] |
Rat (healthy and MMT OA model) | Smaller 10kDa molecules escaped joint more rapidly than larger 500kDa molecules. Larger molecules cleared more slowly in OA knees than healthy knees, while smaller molecules performed similarly in OA and healthy knees. | [78] |
| Carbon nanotube (PEGylated) | None | 20 × 100nm (tube) | Mouse (healthy and DMM OA model) | Significantly improved retention rate relative to free fluorophore for 14 days in both models. | [74] |
| Poly(D, L)-lactide nanoparticle, dye loaded | None | 300nm (spherical) | Mice (healthy and inflamed) | Nanoparticles leaked out of healthy and inflamed knees. Injection with hyaluronic acid slowed release from the joints. | [84] |
| Triblock self-assembly nanoparticle for protein tethering | None | 270nm ± 5nm (spherical) | Rat (healthy) | Significantly improved retention rate relative to free IL-1 receptor antagonist for 14 days. | [75] |
| Polymeric self-assembly nanoparticle for protein encapsulation | None | 500nm & 900nm (spherical) | Rat (healthy) | Significantly improved joint retention for 14 days, with free protein cleared the fastest and the 900nm particles clearing the slowest. | [76] |
| Kartogenin-conjugated chitosan nanoparticles | None | 150nm ± 39nm (spherical) −11.84mV ± 1.2mV |
Rat (ACLT OA model) | Nanoparticles detectable in the joint at 24 days post injection, with the same retention and disease modifying effect as micro-scale particles of the same makeup. | [85] |
| Thermoresponsive pluronic-chitosan-kartogenin nanoparticle | None | 650nm at 4°C 395nm at 37°C |
Rat (ACLT and DMM OA model) | Joint elimination half-life was 115.2 ± 2.2 hr with cold treatment and 109.3 ± 3.6 hr without cold treatment. | [86] |
| Globular protein (Avidin) | Passive (positive charge for cartilage) | ~7nm +20mV |
Rat (healthy) | At 24 hours, significantly more Avidin (cationic) than Neutravidin (neutral) in remained various joint tissues. At 7 days, Avidin is mostly cleared from joint tissues. | [81] |
| PAMAM dendrimer, PEGylated to control surface charge, with IGF-1 conjugated | Passive (positive charge for cartilage) | “Gen 4” 14kDa (~4.5nm), 64 NH2 groups per molecule (less cationic) | Rat (healthy) | Whole joint retention was the greatest for more-charged “Gen 6” dendrimer, with joint half lives of 0.41 days for free IGF-1, 1.08 days for “Gen 4” dendrimers, and 4.21 days for “Gen 6” dendrimers. | [82] |
| “Gen 6” 58kDa (~6.7nm), 256 NH2 groups per molecule (more cationic) | |||||
| Cationic nanoparticle comprised of dextran proprionate and Eudragit RL100, fluorescently tagged | Passive (positive zeta potential for synovial fluid) | 100nm – 150nm (PDI 0.1 – 0.4) Positive zeta potential previously confirmed (data not shown) |
Rat (healthy) | With and without intra-articular injection of exogenous hyaluronate, cationic nanoparticles had significantly improved whole joint retention (74% of signal after 7 days) relative to free tetrapeptide (23% of signal after 2 days). | [80] |
| Cationic nanoparticle comprised of PLGA, PVA, and Eudragit RL, loaded with DiR dye | Passive (positive zeta potential for synovial fluid) | 170.1nm ± 6.0nm (PDI 0.111 ± 0.0006) +21.3mV ± 2.4mV |
Mouse (healthy) | Significantly longer joint retention was observed for the nanoparticles (50% remaining after 28 days) relative to free dye (30% remaining after 3 days) | [79] |
| DOTAM derivative with collagen type II targeting peptide | Active (targeting peptide, cartilage) | N/A | Mouse (healthy) | Knee retention up to 200 hr enhanced by targeting peptide, where increasing the sites of peptide conjugation increases joint retention. | [77] |
[a] Diameter in nm approximated using the equation reported by Erickson [87] as Minimum radius = 0.066 *[mass in Daltons]⅓
AIA = antigen-induced arthritis; ACLT = anterior cruciate ligament transection; DIR = 1,1′-dioctadecyl-3,3,3′,3′ tetramethylindotricarbocyanine iodide; DOTAM = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid amide; DMM = destabilization of the medial meniscus; DAP = dorsal air pouch; IGF-1 = insulin-like growth factor 1; IL-1 = interleukin-1; PAMAM = polyamidoamine; PDI = polydispersity index; PEG = polyethylene glycol; PLGA = poly (lactic co-glycolic acid); PVA = polyvinyl alcohol; MMT = medial meniscus transection