Hollow Silica Nanoparticles Penetrate the Peripheral Nerve and Enhance the Nerve Blockade from Tetrodotoxin

Abstract

The efficacy of tetrodotoxin (TTX), a very potent local anesthetic, is limited by its poor penetration through barriers to axonal surfaces. To address this issue, we encapsulated TTX in hollow silica nanoparticles (TTX-HSN) and injected them at the sciatic nerve in rats. TTX-HSN achieved an increased frequency of successful blocks, prolonged the duration of the block, and decreased the toxicity compared to free TTX. In animals injected with fluorescently labeled HSN, the imaging of frozen sections of nerve demonstrated that HSN could penetrate into nerve and that the penetrating ability of silica nanoparticles was highly size-dependent. These results demonstrated that HSN could deliver TTX into the nerve, enhancing efficacy while improving safety.

Matrix Metalloproteinase‐9‐Responsive Surface Charge‐Reversible Nanocarrier to Enhance Endocytosis as Efficient Targeted Delivery System for Cancer Diagnosis and Therapy

“…[ 31 ] Finally, frozen sections were carried out to determine the delivery efficiency of NPs loading agents into intratumor and cellular permeation. [ 32 ] We found that N‐NP‐Cy2 and P‐NP‐Cy2 showed little intratumor cell penetration. In consistent with imaging in vivo, O‐NP‐Cy2 exhibited high accumulation in the LS180 tumor and notably cellular penetration (Figure 5C).…”

Mesoporous Silica Nanoparticles for Co-Delivery of Drugs and Nucleic Acids in Oncology: A Review

“…MSN drug carriers have been developed for a wide variety of therapeutic applications, such as anesthesia [ 48 ], infection [ 49 , 50 ], osteoporosis [ 51 ] and allergy [ 52 ], among others. However, the most studied application by far is cancer therapy [ 53 ], developing MSNs to deliver anticancer drugs such as doxorubicin [ 37 , 54 , 55 , 56 , 57 , 58 ], camptothecin [ 59 ], topotecan [ 60 ], paclitaxel [ 61 ], gemcitabine [ 62 ], and 5-fluorouracil [ 63 ].…”

Addressing the Issue of Tetrodotoxin Targeting

“…The efficacy of NaV channels in blocking toxins, including TTX, is limited due to their relatively weak penetration to the site of action through different tissue barriers [ 70 ]. High concentrations of the toxin are required to overcome these barriers and to achieve sufficient levels and duration of the nerve fibers to induce a blocking effect, which can lead to significant systemic toxicity [ 71 ].…”

“…Adams et al showed that the simultaneous administration of TTX with various local anesthetics (procaine, lidocaine, tetracaine, cinchocaine, cocaine, and bupivacaine) increased the sciatic nerve block rate to 100% and prolonged its average duration by 2.5–5 times in comparison with the test anesthetics alone [ 75 ]. Several studies have also shown the beneficial effect of bupivacaine on the nerve block caused by the administration of TTX, depending on the toxin concentration [ 70 , 71 , 76 ]. Such a synergistic effect on cornea anesthesia in rats, caused by TTX together with proparacaine, was also observed in other studies [ 74 ].…”

“…Thus, the injection of particles into the free connective tissue surrounding the nerve can cause an acute inflammatory response, and their injection into the abdominal cavity can cause the formation of substandard peritoneal adhesions. In another study, hollow silica nanoparticles were used for TTX delivery [ 70 ]. Experiments showed a significant increase in the neural block frequency and duration, as well as a systemic toxicity reduction, with the use of 28 nm silica nanoparticles with TTX, as compared to the pure toxin.…”