Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system

Abstract

In the continuing search for effective treatments for cancer, the emerging model is the combination of traditional chemotherapy with anti-angiogenesis agents that inhibit blood vessel growth. However, the implementation of this strategy has faced two major obstacles. First, the long-term shutdown of tumour blood vessels by the anti-angiogenesis agent can prevent the tumour from receiving a therapeutic concentration of the chemotherapy agent. Second, inhibiting blood supply drives the intra-tumoural accumulation of hypoxia-inducible factor-1alpha (HIF1-alpha); overexpression of HIF1-alpha is correlated with increased tumour invasiveness and resistance to chemotherapy. Here we report the disease-driven engineering of a drug delivery system, a 'nanocell', which overcomes these barriers unique to solid tumours. The nanocell comprises a nuclear nanoparticle within an extranuclear pegylated-lipid envelope, and is preferentially taken up by the tumour. The nanocell enables a temporal release of two drugs: the outer envelope first releases an anti-angiogenesis agent, causing a vascular shutdown; the inner nanoparticle, which is trapped inside the tumour, then releases a chemotherapy agent. This focal release within a tumour results in improved therapeutic index with reduced toxicity. The technology can be extended to additional agents, so as to target multiple signalling pathways or distinct tumour compartments, enabling the model of an 'integrative' approach in cancer therapy.

Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy

“…Over the years, a variety of different drug targeting systems have been developed, ranging in nature from simple polymers (Duncan, 2006) and liposomes (Torchilin, 2005), to stimuli-sensitive polymeric micelles (Rapoport et al, 2007), bacterially derived Minicells (MacDiarmid et al, 2007), and temporally targeted Nanocells (Sengupta et al, 2005). Thus far, however, not very many have managed to reach the final stages of clinical evaluation, and only about a handful have been approved by the responsible regulatory authorities.…”

Exploiting nanotechnology to target cancer

“…Nanotechnology platforms can provide the unique niche within this space by enabling multimodal delivery with a single application. For example, in a recent study, we demonstrated that the spatiotemporal release of an antiangiogenesis agent and a chemotherapeutic agent from a hybrid nanoparticle, a 'nanocell' (Figure 2) could exert a better therapeutic outcome as compared with existing delivery approaches (Sengupta et al, 2005). A nanocell comprises of a pegylated phospholipid outer layer entrapping a nanocore.…”

“…As the tumour becomes hypoxic, the nanocore degrades, focally releasing the chemotherapy agent. (Sengupta et al, 2005).…”

“…Approaches based on the conjugation of chemotherapeutic agents with nanoparticle-forming biodegradable polymers have long been developed (Sengupta et al, 2005), avoiding the 'burst release' associated with nanoparticles. However, the limitation of using polymers such as PLGA remains in the limited number of valent sites to which a chemotherapeutic agent could be coupled.…”

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

“…[166] Alternatively, an active vascular targeting approach has been developed using PLGA-lipid nanoparticles, in which doxorubicin was linked to the PLGA core, and combretastatin, an anti-angiogenic agent, was entrapped in the outer lipid envelope. [167] After the release of combretastatin from the lipid layer, it induced the vasculature disruption and further the trapped PLGA core nanoparticle released the doxorubicin to tumor cells, demonstrating the enhanced therapeutic index of the drug with reduced toxicity.…”