Factors determining the stability, size distribution, and cellular accumulation of small, monodisperse chitosan nanoparticles as candidate vectors for anticancer drug delivery: application to the passive encapsulation of [14C]-doxorubicin

Abstract

Development of parameters for the fabrication of nanosized vectors is pivotal for its successful administration in therapeutic applications. In this study, homogeneously distributed chitosan nanoparticles (CNPs) with diameters as small as 62 nm and a polydispersity index (PDI) of 0.15 were synthesized and purified using a simple, robust method that was highly reproducible. Nanoparticles were synthesized using modified ionic gelation of the chitosan polymer with sodium tripolyphosphate. Using this method, larger aggregates were mechanically isolated from single particles in the nanoparticle population by selective efficient centrifugation. The presence of disaggregated monodisperse nanoparticles was confirmed using atomic force microscopy. Factors such as anions, pH, and concentration were found to affect the size and stability of nanoparticles directly. The smallest nanoparticle population was ∼62 nm in hydrodynamic size, with a low PDI of 0.15, indicating high particle homogeneity. CNPs were highly stable and retained their monodisperse morphology in serum-supplemented media in cell culture conditions for up to 72 hours, before slowly degrading over 6 days. Cell viability assays demonstrated that cells remained viable following a 72-hour exposure to 1 mg/mL CNPs, suggesting that the nanoparticles are well tolerated and highly suited for biomedical applications. Cellular uptake studies using fluorescein isothiocyanate-labeled CNPs showed that cancer cells readily accumulate the nanoparticles 30 minutes posttreatment and that nanoparticles persisted within cells for up to 24 hours posttreatment. As a proof of principle for use in anticancer therapeutic applications, a [14C]-radiolabeled form of the anticancer agent doxorubicin was efficiently encapsulated within the CNP, confirming the feasibility of using this system as a drug delivery vector.

Acute and subacute oral toxicity of copper oxide nanoparticles in female albino Wistar rats

“…From the present study, we inferred that the CuO‐NP suspension was strongly anionic. The PDI was used as an indicator of NP stability and uniformity of formulation (Masarudin, Cutts, Evison, Phillips, & Pigram, ). The PDI value of CuO‐NPs suspended in Milli‐Q water in the present study was 0.385, indicating it as a stable suspension (Table ).…”

Ionotropic gelation method in the synthesis of nanoparticles/microparticles for biomedical purposes

“…The interactions between these complex polymers give more stability to the particles than when small anionic species are used with CS. Apparently, large anionic molecules buffer the solution and prevent the hydrolysis of CS protective chains, although an adequate selection of the storage conditions, and the characteristics of the encapsulated molecule, may also be of influence in the long term.…”

“…Other encapsulation techniques, such as electrospraying, are known to obtain a narrow particle size distribution; this is not always the case with IG. Polydispersion indices (PDI) are usually higher than 0.1, reaching values up to 0.5 . This indicates a heterogeneity in particle size that not only could affect the quantity of the drug loaded but could also limit the interaction of the formulation with biological structures.…”

Factorial Design as the Method in the Optimization of Timolol Maleate-Loaded Nanoparticle Prepared by Ionic Gelation Technique

“…Nevertheless, the interaction between the concentration of PC and CS (X1X3) yielded a positive effect. This interaction lead to an increase of polydispersity index values due to the aggregations in the nanoparticle sample that occurs as the result of the increase of ionic interaction between the PC's carboxylate groups and CS's amino groups [24]. The selection of the optimum condition of nanoparticle preparation can be done by considering the desirability value of the solutions provided by the Design-Expert software.…”