Oral Chemotherapeutic Silver Nanoparticles: Input of Drug Combinations

Abstract

Cytotoxic drugs are used during cancer chemotherapy to inhibit tumor growth and metastasis. However, manychemotherapeutic drugs, such as doxorubicine (Dox), have limited cellular uptake and a strong tendency to bind to offtargetmacromolecules. Together these characteristics lead to low therapeutic indices. Increasing the intracellular uptake ofcancer drugs could prevent these complications.Another pitfall of chemotherapy is drug resistance. One strategy for avoiding drug resistance is drug combination. Thisapproach can prevent side effects by allowing for reduced dosages and can improve efficacy if the chosen drugs act synergistically.For example, bisphosphonates act synergistically with many other anti-cancer agents. Alendronate (Ald), one of the most potentbisphosphonates, has been shown to increase cancer cell death in vitro when combined with Dox in breast cancer cells.We present here the synthesis of a silver nanoparticle-based drug delivery system that improves the anticancer therapeuticindices of doxorubicin (Dox) using alendronate (Ald) as an adjuvent. Water, under microwave irradiation, was used as thesole reducing agent for the size-controlled, bisphosphonate-mediated preparation of silver nanoparticles (AgNPs). The AgNPswere coated with and stabilized by the bisphosphonate alendronate (Ald). The bisphosphonate group of Aldtemplated theformation of the AgNPs, and was the site of the drug’s attachment to the nanoparticles. The free primary ammonium group ofAld was subsequently functionalized with either Rhodamine B (RhB) by amide linker formation or Dox through imine bondformation. The RhB-conjugated nanoparticles (RhB-Ald@AgNPs) were studied in HeLa cell cultures. Confocal fluorescencemicroscopy studies determined the main mechanisms of cellular uptake of the nanoparticles. The imine linker of the Doxmodifiednanoparticles had significantly greater anti-cancer activity in vitro than either Ald or Dox alone.Thus, the ability of Ald to promote the assembly of Ald@AgNPs in a one step reaction, and the straightforward postmodificationof Ald@AgNPs, offer an easy and environmentally friendly strategy for the formation of stable nanoparticles thatcouple the antiproliferative properties of the AgNPs, themselves, to those of the drug mixtures they carry. This system featuresa high degree of functionality and potency and is of potential therapeutic benefit.