Cancer resistance to treatment and antiresistance tools offered by multimodal multifunctional nanoparticles.

Chemotherapeutic agents have limited efficacy and resistance to them limits today and will limit tomorrow our capabilities of cure. Resistance to treatment with anticancer drugs results from a variety of factors including individual variations in patients and somatic cell genetic differences in tumours. In front of this, multimodality has appeared as a promising strategy to overcome resistance. In this context, the use of nanoparticle-based platforms enables many possibilities to address cancer resistance mechanisms. Nanoparticles can act as carriers and substrates for different ligands and biologically active molecules, antennas for imaging, thermal and radiotherapy and, at the same time, they can be effectors by themselves. This enables their use in multimodal therapies to overcome the wall of resistance where conventional medicine crash as ageing of the population advance. In this work, we review the cancer resistance mechanisms and the advantages of inorganic nanomaterials to enable multimodality against them. In addition, we comment on the need of a profound understanding of what happens to the nanoparticle-based platforms in the biological environment for those possibilities to become a reality.

An Iron Oxide Nanocarrier Loaded with a Pt(IV) Prodrug and Immunostimulatory dsRNA for Combining Complementary Cancer Killing Effects.

There is major current interest in harnessing the immune system against cancer and in developing drugs that provide complementary cancer killing mechanisms. Although the recent advent of nanoparticle-based drug delivery systems has improved the efficacy of platinum drugs for chemotherapy, one of the fundamental paradigms in their design and use is evading surveillance by the immune system to enhance anticancer efficacy. However, new studies are showing that chemotherapy can profit from actively targeting stimulation of the immune system and that suitably functionalized nanomaterials might be ideal for overcoming some key challenges in immunotherapy. Pt(IV) prodrug-modified PEGylated phospholipid micelles that encapsulate biocompatible iron oxide nanoparticles (IONPs) as a new delivery system for cisplatin are reported. The Pt(IV)-IONPs are functionalized with polyinosinic-polycytidylic acid (poly (I:C))--a double stranded RNA (dsRNA) analog widely used as an adjuvant in clinical trials of cancer immunotherapy. The Pt(IV)-IONPs and poly (I:C)--Pt(IV)-IONPs enhance by more than an order of magnitude the prodrug cytotoxicity in different tumor cells, while greatly increasing the ability of cisplatin and poly (I:C) to activate dendritic cells--the key cellular players in immunotherapy. The results suggest that these constructs hold promise for targeted chemoimmunotherapy.

An iron oxide nanocarrier for dsRNA to target lymph nodes and strongly activate cells of the immune system.

The success of nanoparticle-based therapies will depend in part on accurate delivery to target receptors and organs. There is, therefore, considerable potential in nanoparticles which achieve delivery of the right drug(s) using the right route of administration to the right location at the right time, monitoring the process by non-invasive molecular imaging. A challenge is harnessing immunotherapy via activation of Toll-like receptors (TLRs) for the development of vaccines against major infectious diseases and cancer. In immunotherapy, delivery of the vaccine components to lymph nodes (LNs) is essential for effective stimulation of the immune response. Although some promising advances have been made, delivering therapeutics to LNs remains challenging. It is here shown that iron-oxide nanoparticles can be engineered to combine in a single and small (<50 nm) nanocarrier complementary multimodal imaging features with the immunostimulatory activity of polyinosinic-polycytidylic acid (poly (I:C)). Whilst the fluorescence properties of the nanocarrier show effective delivery to endosomes and TLR3 in antigen presenting cells, MRI/SPECT imaging reveals effective delivery to LNs. Importantly, in vitro and in vivo studies show that, using this nanocarrier, the immunostimulatory activity of poly (I:C) is greatly enhanced. These nanocarriers have considerable potential for cancer diagnosis and the development of new targeted and programmable immunotherapies.

Iron oxide-filled micelles as ligands for fac-[M(CO)3]+ (M = (99m)Tc, Re).

Magnetite-filled micelles capture fac-[M(OH(2))(3)(CO)(3)](+) complexes (M = (99m)Tc, Re), creating versatile self-assembled constructs for multimodal SPECT/MR/optical imaging and radiopharmaceutical guided delivery.