Rational Design of Nanotherapeutics Based on the Five Features Principle for Potent Elimination of Cancer Stem Cells

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Cancer stem cells (CSCs), also known as tumor initiating cells or tumor repopulating cells, which comprise only a small fraction of tumor, have received tremendous attention during the past two decades, as they are considered as the ringleader for initiation and progression of tumors, therapy resistance, metastasis, and recurrence in the clinic. Hence, eradicating CSCs is critical for successful cancer treatment. To that end, various CSC-targeting therapeutic agents have been pursued. However, these CSC-specific drugs are ineffective toward bulk cancer cells. Furthermore, these anti-CSC drugs not only eradicate CSCs but also affect conventional stem cells in normal organs or tissues. By virtue of the enhanced permeability and retention (EPR) effect, nanomaterial drug delivery systems (NDDSs) passively accumulate in tumor tissues, thereby alleviating severe side effects toward normal viscera. NDDSs can be further functionalized with CSC-specific binding molecules to promote targeted drug delivery toward CSCs. Moreover, NDDSs have unique advantages in encapsulating CSC-specific drugs and cytotoxic agents, realizing synchronized killing of CSCs and bulk cancer cells both temporally and spatially. For these reasons, leveraging nanotherapeutic strategies to target CSCs has gained tremendous attention recently. Some ten years ago, we summarized five basic features of efficient nanotherapeutics (the five features principle), which consist of long circulation, tumor accumulation, deep penetration, cellular internalization, and drug release. Based on this design rationale, we constructed several NDDSs, including nanogels with adaptive hydrophobicity, CSC-derived microparticles with tailored softness, and tumor exosome sheathed porous silicon biomimetic nanoparticles, for targeted drug delivery to tumor. To our astonishment, these NDDSs that possess the five basic features achieve decent drug delivery efficiency toward not only bulk tumor cells but more importantly CSCs. Consequently, such nanotherapeutics as-designed based on the five features principle are potent in eradicating CSCs, even with only cytotoxic drugs, for instance, doxorubicin. Furthermore, commercialized nanomedicines, such as Doxil and Abraxane, can be endowed with these five basic features by hyperbaric oxygen therapy and therefore achieve outstanding drug delivery efficiency, potent CSC elimination, and efficient cancer therapy. These studies suggest that intractable CSCs can be tackled with a material-based approach, highlight the critical role of the five features principle in designing effective nanotherapeutics, and pinpoint the significance of drug delivery efficiency in eliminating CSCs and bulk cancer cells.

A two-pronged strategy to alleviate tumor hypoxia and potentiate photodynamic therapy by mild hyperthermia

“…This may be the result of the enhanced permeability and retention effect (EPR effect) and the relatively long circulation of Ce6@HMPB NPs than free Ce6 in blood. 67–70 The above results demonstrated that Ce6@HMPB NPs efficiently accumulated and lingered in tumor tissues, which would benefit the following in vivo phototherapy.…”

ING4 Promotes Stemness Enrichment of Human Renal Cell Carcinoma Cells Through Inhibiting DUSP4 Expression to Activate the p38 MAPK/type I IFN-Stimulated Gene Signaling Pathway

“…Therefore, it is pivotal to understand the initiation of metastasis. CSCs have been reported to initiate tumor metastasis ( Zhang et al, 2022 ). The stem cell biomarker CD44 and pluripotent transcription factors NANOG, MYC, and OCT4 have now been validated to contribute to the maintenance of CSCs and are widely used to identify CSCs.…”

“…Cancer stem cells (CSCs) are characterized in many cancers and contribute to tumorigenesis, recurrence, and metastatic spread ( Zhang et al, 2022 ). In RCC, cell populations with stem-like properties have been isolated, and CSCs are highly enriched in tumors with high pathological stage, venous and lymphatic invasion, and distant metastases ( Varna et al, 2015 ; Fendler et al, 2020 ).…”

Natural Products-Based Nanoformulations: A New Approach Targeting CSCs to Cancer Therapy

“…46 Therefore, nanoMedicine plays an important role in tumor therapy. 47 The particle size, shape, arrangement, surface charge distribution, and surface chemistry of nanomedicine carriers are the key factors that determine their physicochemical properties and interactions with the biological environment (molecules, cells, tissues, etc.). 48,49 The first generation of nanoMedicines was based on the enhanced permeability and retention (EPR) effect of the tumor vasculature to load traditional small-molecule antitumor drugs with liposomes as carriers to achieve drug enrichment in tumors.…”

“…However, polymeric nanoparticles have the potential risk of increased toxicity and particle aggregation, so polymers with high biocompatibility and degradability, such as poly (lactic acid) (PLA), poly (lactic acid-hydroxyacetic acid) (PLGA), and polycaprolactone (PCL), are being developed. [45][46][47]…”