Hurtado Niubò, Pau
Systemic delivery of therapeutics is the mainstay of metastatic cancer therapy, as cancer cells are not only confined in the primary tumor and they can spread throughout the organism. A large number of factors can influence the distribution of small drugs as well as larger nanoparticles systems and extensive efforts have been made to overcome the penetration obstacles inherent in nanoparticle systems. The use of nanoparticles (NP) to deliver anticancer therapeutics aided in mitigating some of the toxicities associated with systemic drug delivery, and a wide number of materials and strategies have emerged to improve this technique and enhance the cancer treatment. However, low penetration of anticancer drugs and nanoparticles into many tumors remains as a major challenge for antitumor nanomedicine limiting their therapeutic effect. This is a result of distinct biological barriers that the NPs must overcome to reach the target cells, leading to low accumulation and retention.
The particle size is a vital factor in determining the arrival and penetration ability of nanoparticles into the tumor site as diffusion is inversely proportional to the particle size. It has been reported that large particles tend to accumulate at the tumor site, while small particles show superior tumor penetration, albeit their retention is still compromised. Moreover, the tumor microenvironment is characterized for the anomalous properties present, which have been widely studied to trigger responses in the nanocarriers.
In this study we have designed a tunable and versatile dual-nanoparticle system to improve accumulation, retention and penetration into primary tumor and metastatic lesions. The system is based in dextran-oxidized nanoparticles, with sizes around 200 nm, surrounded by smaller dendrimer nanoparticles with a therapeutic agent conjugated. Moreover, big size nanoparticles, carrying small size drug-conjugated nanoparticles, were developed to physiochemically interact with the tumor microenvironment (TME) through matrix metalloproteinase and pH sensitive linkers, allowing higher retention and prolonged drug release due to a hydrogel formation produced thanks to the direct interaction of the functional groups of both nanoparticles after the linkers cleavage.
Therefore, our newly designed dual-nanoparticle system, will allow to systemically deliver therapeutic drugs (facilitating the targeting of metastatic lesions), and, moreover, it will benefit of local delivery advantages of sustained release thanks to the hydrogel formation in situ.