Bioinspired low-density lipoprotein co-delivery system for targeting and synergistic cancer therapy.

Epithelial-mesenchymal transition (EMT) is the culprit of tumor invasion and metastasis. As a critical transcription factor that induces EMT, snail is of great importance in tumor progression, and knocking down its expression by small interfering RNA (siRNA) may inhibit tumor metastasis. Herein, we developed a core-shelled bioinspired low-density lipoprotein (bio-LDL) in which snail siRNA-loaded calcium phosphate nanoparticles were wrapped as the core and doxorubicin was embedded in the outer phospholipids modified with a synthetic peptide of apoB100 targeting LDL receptor-abundant tumor cells. Bio-LDL exhibited pH-responsive release, lysosomal escape ability, enhanced cytotoxicity and apoptotic induction. Bio-LDL could significantly inhibit the expression of snail and regulate EMT-related proteins to reduce tumor migration and invasion in vitro. Bio-LDL also displayed favorable tumor targeting and synergistic inhibition of tumor growth and metastasis in vivo. Therefore, the multifunctional bio-LDL will be a promising co-delivery vector and holds potential value for clinical translation.

Strategies to enhance drug delivery to solid tumors by harnessing the EPR effects and alternative targeting mechanisms.

The Enhanced Permeability and Retention (EPR) effect has been recognized as the central paradigm in tumor-targeted delivery in the last decades. In the wake of this concept, nanotechnologies have reached phenomenal levels in research. However, clinical tumors display a poor manifestation of EPR effect. Factors including tumor heterogeneity, complicating tumor microenvironment, and discrepancies between laboratory models and human tumors largely contribute to poor efficiency in tumor-targeted delivery and therapeutic failure in clinical translation. In this article, approaches for evaluation of EPR effect in human tumor were overviewed as guidance to employ EPR effect for cancer treatment. Strategies to augment EPR-mediated tumoral delivery are discussed in different dimensions including enhancement of vascular permeability, depletion of tumor extracellular matrix and optimization of nanoparticle design. Besides, the recent development in alternative tumor-targeted delivery mechanisms are highlighted including transendothelial pathway, endogenous cell carriers and non-immunogenic bacteria-mediated delivery. In addition, the emerging preclinical models better reflect human tumors are introduced. Finally, more rational applications of EPR effect in other disease and field are proposed. This article elaborates on fundamental reasons for the gaps between theoretical expectation and clinical outcomes, attempting to provide some perspective directions for future development of cancer nanomedicines in this still evolving landscape.

Size-adaptable and ligand (biotin)-sheddable nanocarriers equipped with avidin scavenging technology for deep tumor penetration and reduced toxicity.

The conventional active-targeting nano-chemotherapy suffers from poor tumor tissue penetration and non-negligible toxicity due to the size/ligand dilemmas and insufficient target selectivity. In this report, a stimuli-responsive size-adaptable and ligand (biotin)-sheddable drug delivery system (DDS) combined with two-step strategy of biotin-avidin system was designed to seek a balance between tumor targeting and penetration as well as to self-scavenge the nonresponsive nanocarriers in normal tissues. This DDS was composed of 'multi-seed' polymeric liposomes (ASL-BIO-MPL) with asulacrine-loaded micelles as seeds in their aqueous cavities. The shell of such liposomes was modified with MMP-9 cleavable polymer-polypeptide functionalized with the tumor targeting ligand biotin. ASL-BIO-MPL could disintegrate into mixture of irregularly-shaped liposomes (~200 nm) and scattered tiny micelles (~40 nm) after incubation with MMP-9. The fluorescence-labeled BIO-MPL could travel to the center of the 4T1 breast tumor spheroids under the action of MMP-9, possibly benefited from the relay of released tiny micelles. Conversely, neither the biotin-modified micelles nor non-MMP-9-responsive multi-seed liposomes could penetrate into the spheroids possibly due to the potent binding-site barrier of biotin and large size, respectively. In tumor-bearing mice, ASL-BIO-MPL exhibited the strongest drug penetrability and thus the optimal inhibition of tumor growth compared to other formulations. Following administration of avidin with a rational dosage regimen, the number of apoptotic cells in normal tissues induced by ASL-BIO-MPL reduced without affecting their targeting effect, suggesting the followed administration of adivin could scavenge the DDS in non-target site. Overall, the size/ligand adapting MPL system combined with two-step strategy of biotin-avidin may provide potential avenues for nanocarriers to enhance deep tumor tissue targeting and protect normal tissues.