In Vivo Distribution of Poly Alkyl Cyanoacrylate Nanoparticles

Colloidal drug carriers such as liposomes and nanoparticles are able to modify the distribution of an associated substance. They can therefore be used to improve the therapeutic index of drugs by increasing their efficacy or reducing their toxicity. The polymer nanoparticles, particularly PACA nanoparticles, have attracted considerable attention as potential drug delivery systems, not only for their enhancement of therapeutic efficacy but also because they reduce the toxicity associated with a variety of drugs. Careful design of these delivery systems with respect to the target and route of administration may provide a solution to some of the delivery problems posed by many anti-cancer drugs, including doxorubicin and amphotericin B,71 and new classes of active molecules such as peptides, proteins, genes, and oligonucleotides.

The use of colloidal particulate carrier systems with controlled particle size (25 nm to 1.7 mm in diameter) is significant in such applications where diminished uptake by mononuclear phagocytes and specific targeting of carriers to particular tissues or cells is of great importance. Studies conducted on the tissue distribution of PBCA nanoparticles with a diameter of 127 nm, loaded with 1-(2-chloroethyl)-3-(1-oxyl-2,2,6,6-tetramethyl piperidinyl)-1-nitrosourea (spin-labeled nitrosourea, SLCNU) suspensions injected intraperitoneally (i.p.) into Lewis lung carcinoma-bearing mice showed a relatively low accumulation of nanoparticles in the liver and spleen; the nanoparticles were mainly found in the lungs, kidneys, and heart.72 The highest content of the particles was observed in the lungs of tumor-bearing experimental animals damaged by metastases, suggesting the possible usefulness of SLCNU-PBCA nanoparticles for targeting the lung metastases.

Reddy and Murthy73 compared the pharmacokinetics and tissue distribution of doxorubicin (Dox) solution with Dox-loaded PBCA nanoparticles synthesized by DP and EP techniques after intravenous (i.v.) and intraperitoneal (i.p.) injection in healthy rats. The elimination half-life (T1/2) and mean residence time (MRT) in blood was significantly higher than the free Dox after i.v. injection. After i.p. injection, DP nanoparticles quickly appeared in the blood and underwent rapid distribution to the organs of RES, whereas the EP nanoparticles were absorbed slowly into the blood and remained in the circulatory system for a longer time. The bioavailability (F) of DP (~ 1.9-fold) and EP nanoparticles (~ 2.12-fold) was higher compared to that of the Dox solution after i.p. injection. The distribution to the heart of both types of nanoparticles was low after i.v. and i.p. injection, compared to Dox. This was further proved by experiments using nanoparticles radiolabeled with 99mTc to study their distribution in Dalton's lymphoma implanted in the thigh region of mice, when administered subcutaneously below the tumor region.74 A significantly high tumor uptake of 99mTc-EP nanoparticles (13-fold higher at 48 h post-injection) (P<0.001) was found compared to the 99mTc-Dox solution.

Blank [14C]-poly(hexyl cyanoacrylate) nanoparticles with diameters of 200-300 nm injected intravenously into nude mice bearing a human osteosarcoma showed distribution to the liver, spleen, lung, heart, kidney, GI tract, gonads, brain, and muscle, as well as in serum and transplanted tumor fragments when investigated by liquid scintillation counting.75 The peak levels in all organs with the exception of tumors and the spleen were reached within 24 h; the highest levels of radioactivity were found after 7 days in the tumor and spleen. The tissue distribution of naked and either normal immunoglobulin G or monoclonal antibody (antitumor osteogenic sarcoma)-coated poly(hexyl-2-cyanoacrylate) nanoparticles in mice bearing human tumor xenografts showed similar results: the nanoparticles were deposited mainly in the liver and spleen, and no significant uptake was found in the tumors.76

The PACA nanoparticles exhibited rapid extravascular distribution after intravenous administration. Intravenous injection of isobutyl-2-cyanoacrylate nanoparticles resulted in high concentrations in the organs of the reticuloendothelial system such as the liver, spleen, and bone marrow. Similar observations were made by Kante et al.77 in the case of PBCA nanoparticles injected intravenously in rats. In the case of mice with subcutaneously grafted Lewis lung carcinoma cells, the nanoparticles exhibited higher lung concentrations, indicating the use of nanoparticles in the treatment of lung metastasis.17 However, the results were somewhat different for polybutyl-2-cyanoacrylate nanoparticles injected intravenously into rabbits.78 The lung accumulation of nanoparticles was very low in that case, indicating that the nanoparticles (126 nm) were not mechanically filtered through the capillary bed of the lungs. The difference in lung concentrations compared to the observations of Grislain et al.17 can be explained by the difference in particle size (254 nm). Coating with azidothymidine-loaded poly(hexyl cyanoacrylate) (PHCA) nanoparticles with polysorbate 80 led to higher brain levels of azidothymidine after intravenous injection in rats, indicating the facilitation of drug passage across the blood-brain barrier (BBB).79 Physicochemical studies have shown that the coating of nanoparticles with block copolymers such as poloxamers and poloxamines induces a steric repulsion effect, minimizing the adhesion of particles to the surface of macrophages which in turn results in decreased phagocytic uptake and significantly higher levels in blood and non-RES organs, the brain, intestine, kidneys, etc. Borchard et al.80 showed that coating the nanoparticles with surfactants resulted in uptake by brain endothelial cells, and that polysorbate 80 was the most effective surfactant for this purpose. Further investigations unequivocally demonstrated that polysorbate 80-coated PBCA nanoparticles loaded with enkaphalin analogue dalargin enabled the delivery of this drug across the BBB, achieving a significant pharmacological effect. Gulyaev et al.81 reported significantly higher brain concentrations of intravenously injected polysorbate 80-coated Dox-PBCA nanoparticles in rats. Three probable mechanisms were proposed for the enhanced brain transport of polysorbate 80 coated nanoparticles: (1) endocytosis, (2) the opening of the tight endothelial junctions between the brain endothelial cells,81 and (3) the inhibition of the P-glycoprotein efflux pump responsible for multi-drug resistance, which is a major obstacle to cancer chemotherapy.82,83

Isobutyl and isohexylcyanoacrylate nanoparticles were used by Ghanem et al.84 as drug carriers, particularly for some anti-cancer drugs. Body distribution as well as pharmacokinetics in animals and partially in humans using a radiolabeled (111In and 99mTc) free drug and its nanoparticles showed 60-75% accumulation in the reticuloendothelial system.

Skidan et al.85 studied the antitumor efficacy of Dox loaded into polysorbate 80-coated nano-particles to the brain. Pharmacokinetics were studied in rats after the intravenous injection of four Dox preparations: (1) solution in saline, (2) solution in polysorbate 80, intravenous (3) bound to nanoparticles, and (4) bound to nanoparticles coated with polysorbate 80. The results showed no significant difference in the body distribution between the two solution formulations, whereas the two nanoparticle formulations showed significantly decreased drug concentrations in the heart. High brain concentrations of Dox (> 6 mg/g) were achieved with the nanoparticles overcoated with polysorbate 80 between 2 and 4 h, whereas the concentrations observed with the other three formulations were always negligible. Antitumor efficacy of Dox associated with polysorbate 80-coated nanoparticles as assessed in rats with intracranially implanted 101/8 glioblastoma resulted in a significant 3.6-fold increase in survival, whereas administration of free Dox or blank nanoparticles did not modify the mortality when compared to the control group.

Following the subcutaneous injections of metoclopramide solution (5 mg/kg) and three different metoclopramide nanosphere suspensions (10 mg/kg) on two phases in wistar rats, there was a rapid absorption, distribution, and elimination of the drug solution. The maximum drug concentration was observed after 30 min of subcutaneous injection of all the tested nanosphere formulations.15 Polyethylcyanoacrylate-hydroxypropyl cyclodextrin showed the highest concentration, followed by polyisobutylcyanoacrylate-dextran and polyethylcyanoacrylate-dextran. The area under the curves of all nanoparticle formulations was 4.8- to 1.88-times higher than that obtained for the solution form.

Earlier studies showed that polystyrene and other biodegradable microspheres delivered to the intestine are preferentially absorbed by the M-cells of the Peyer's patches.86,87 Intragastric administration of azidothymidine-loaded PIHCA nanoparticles resulted in high concentration in the intestinal mucosa as well as in the Peyer's patches.88 Once localized in the mucous or intestinal tissue, the azidothymidine could be slowly released by the enzymatic action of esterases. Very low levels of azidothymidine bound to nanoparticles were detected in the lymph, suggesting an efficient capture of particles through the Peyer's patches resulting in an intracellular localization of the drug. As a result, some immune cells would carry azidothymidine to the mesenteric lymph nodes, the location of an important viral burden and a major replication site of HIV.

PACA nanoparticles are proved to be suitable delivery systems in comparison to other colloidal systems, including liposomes. Reszka et al.89 observed that the mitanxantrone-loaded PBCA nanoparticles showed the highest tumor concentrations in B-16 melanoma-bearing mice after intravenous injection. Four different formulations—mitaxantrone solution, mitaxantrone-loaded negatively charged liposomes (small unilamellar vesicles), 14C-PBCA nanoparticles, and poloxamine 1508-coated 14C-PBCA nanoparticles—were studied for the biodistribution and tumor accumulation in the tumor-bearing mice. The liposomal formulation showed prolonged circulation in the blood and higher accumulation in the liver and spleen after 24 h of injection, compared to the nanoparticle formulations. Despite the longer circulation in the blood, however, the liposomal formulation could not result in high concentrations in the tumors, compared to the nanoparticle formulations, which showed relatively lower circulation time in the blood, indicating the efficacy of PBCA nanoparticles in delivering mitoxantrone to tumors. Similar results involving the higher efficacy of mitoxantrone-loaded PBCA nanoparticles in B-16 melanoma was reported by Beck et al.28

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