In situ tumor-triggered subcellular precise delivery of multi-drugs for enhanced chemo-photothermal-starvation combination antitumor therapy

Abstract

Rationale: Drug combination therapy for cancer treatment exerts a more potent antitumor effect. The targeted delivery and release of multiple drugs in a patient's body thus presents a more effective treatment approach, warranting further research. Methods: Two antitumor drugs (ICG: indocyanine green and THP: pirarubicin) were successfully screened to sequentially trigger self-assembling peptides (P60) to produce bacteria-sized particles (500-1000 nm, P60-ICG-THP). First, after mixing equal amount of P60 and ICG, trace amount of water (the mass ratio between P60 and water: 100:1) was used to trigger their assembly into P60-ICG. Subsequently, the assembly of P60-ICG and THP was further triggered by ultrasound treatment to produce P60-ICG-THP. Results: P60-ICG-THP constituted a cluster of several nanoparticles (50-100 nm) and possessed a negative charge. Owing to its size and charge characteristics, P60-ICG-THP could remain outside the cell membrane, avoiding the phagocytic clearance of blood and normal tissue cells in vivo . However, after localizing in the tumor, the size and charge switches of P60-ICG-THP, rapidly triggered by the low pH of the tumor microenvironment, caused P60-ICG-THP to segregate into two parts: (i) positively charged nanoparticles with a size of approximately 50 nm, and (ii) negatively charged particles of an uneven size. The former, mainly carrying THP (chemotherapeutic agent), could immediately cross the cell membrane and deliver pirarubicin into the nucleus of tumor cells. The latter, carrying ICG (used for photothermal therapy), could also enter the cell via the endocytosis pathway or accumulate in tumor blood vessels to selectively block the supply of nutrients and oxygen (cancer starvation). Both these particles could avoid the rapid excretion of ICG in the liver and were conducive to accumulation in the tumor tissue for photothermal therapy. Conclusion: Our drug delivery system not only achieves the precise subcellular delivery of two anticancer drugs due to their size and charge switches in the tumor site, but also provides a new strategy to combine chemotherapy, photothermal therapy, and cancer starvation therapy for the development of a highly efficient antitumor therapeutic regimen.

Hyaluronic acid functionalized ZnO nanoparticles co-deliver AS and GOD for synergistic cancer starvation and oxidative damage

“…Compared with before treatment, the ATP concentration in the tumor was significantly decreased after administration (Fig. S3 ), indicating that AS/GOD@HAZnO played a role in starvation therapy 29 .…”

Dynamic responsiveness of self‐assembling peptide‐based nano‐drug systems

“…used two antitumor drugs, photothermal therapeutic agent indocyanine green (ICG) and chemotherapeutic agent THP to sequentially trigger self‐assembling peptides (P60) to form slightly larger negatively charged particles (P60‐ICG‐THP), avoiding phagocytic clearance in the blood and normal tissue cells in vivo. The slightly acidic environment in tumor tissue triggered dissociation, releasing positively charged tiny NPs loaded with THP into the nucleus and simultaneously delivering ICG into the cell for PTT, achieving the precise target of two therapeutic agents for a synergistic effect 174 . Controlled dynamic self‐assembly to obtain specific functional nanostructures for nano‐drug systems shall guide the development of revolutionary nanotherapeutics in the future 175…”

Upconversion-Nanoparticle-Based Smart Drug-Delivery Platforms for Multimodal Imaging-Guided Cancer Therapies

“…Angiogenesis inhibition and nutrient depletion at the tumor site can achieve tumor starvation therapy (ST), which is a promising strategy for cancer treatment, especially for suppressing the metastasis of tumor cells. − The rapid division of tumor cells leads to a lack of O 2 at the tumor site, which leads to the tumor inducing the overexpression of HIF-1α, which, in turn, triggers the upregulation of proangiogenic mediators such as vascular endothelial growth factor (VEGF). − In tumors, overexpressed VEGF provides not only a rich nutrient and growth matrix for tumors but also important channels for tumor metastasis; therefore, the inhibition of HIF-1α is essential for tumor treatment . Moreover, the nonenergy consumption of nutrients (e.g., Glu) at the tumor site causes tumor cells to suffer from energy deficiency, which is not conducive to tumor growth and metastasis. , Therefore, ST is a potential method to improve the survival rate of advanced breast cancer by simultaneously suppressing tumor growth and metastasis.…”