Role of Stem Cells in the Ovarian Tissue Cryopreservation and Transplantation for Fertility Preservation

Although the cancer survival rate has increased, cancer treatments, including chemotherapy and radiotherapy, can cause ovarian failure and infertility in women of reproductive age. Preserving fertility throughout cancer treatment is critical for maintaining quality of life. Fertility experts should propose individualized fertility preservation methods based on the patient’s marital status, pubertal status, partner status, and the urgency of treatment. Widely practiced fertility preservation methods, including ovarian transposition and embryo and oocyte cryopreservation, are inappropriate for prepubertal girls or those needing urgent initiation of cancer treatment. Ovarian tissue cryopreservation and transplantation, an emerging new technology, may be a solution for these cancer patients. The use of stem cells in ovarian tissue cryopreservation and transplantation increases oxygenation, angiogenesis, and follicle survival rates. This review discusses the recent advances in ovarian tissue cryopreservation and transplantation with special focus on the use of stem cells to improve fertilization techniques.     

Estrogen Receptors as Molecular Targets of Endocrine Therapy for Glioblastoma

Hormonal factors may participate in the development and progression of glioblastoma, the most aggressive primary tumor of the central nervous system. Many studies have been conducted on the possible involvement of estrogen receptors (ERs) in gliomas. Since there is a tendency for a reduced expression of ERs as the degree of malignancy of such tumors increases, it is important to understand the role of these receptors in the progression and treatment of this disease. ERs belong to the family of nuclear receptors, although they can also be in the plasmatic membrane, cytoplasm and mitochondria. They are classified as estrogen receptors alpha and beta (ER⍺ and ERβ), each with different isoforms that have a distinct function in the organism. ERs regulate multiple physiological and pathological processes through the activation of genomic and nongenomic pathways in the cell. Nevertheless, the role of each isoform in the development and progression of glioblastoma is not completely clear. Diverse in vitro and in vivo studies have shown encouraging results for endocrine therapy as a treatment for gliomas. At the same time, many questions have arisen concerning the nature of ERs as well as the mechanism of action of the proposed drugs. Hence, the aim of the current review is to describe the drugs that could possibly be utilized in endocrine therapy for the treatment of high-grade gliomas, analyze their interaction with ERs, and explore the involvement of these drugs and receptors in resistance to standard chemotherapy.     

Acetylenic Synthetic Betulin Derivatives Inhibit Akt and Erk Kinases Activity,Trigger Apoptosis and Suppress Proliferation of Neuroblastoma and Rhabdomyosarcoma Cell Lines

Neuroblastoma (NB) and rhabdomyosarcoma (RMS), the most common pediatric extracranial solid tumors, still represent an important clinical challenge since no effective treatment is available for metastatic and recurrent disease. Hence, there is an urgent need for the development of new chemotherapeutics to improve the outcome of patients. Betulin (Bet), a triterpenoid from the bark of birches, demonstrated interesting anti-cancer potential. The modification of natural phytochemicals with evidenced anti-tumor activity, including Bet, is one of the methods of receiving new compounds for potential implementation in oncological treatment. Here, we showed that two acetylenic synthetic Bet derivatives (ASBDs), EB5 and EB25/1, reduced the viability and proliferation of SK-N-AS and TE671 cells, as measured by MTT and BrdU tests, respectively. Moreover, ASBDs were also more cytotoxic than temozolomide (TMZ) and cisplatin (cis-diaminedichloroplatinum [II], CDDP) in vitro, and the combination of EB5 with CDDP enhanced anti-cancer effects. We also showed the slowdown of cell cycle progression at S/G₂ phases mediated by EB5 using FACS flow cytometry. The decreased viability and proliferation of pediatric cancers cells after treatment with ASBDs was linked to the reduced activity of kinases Akt, Erk1/2 and p38 and the induction of apoptosis, as investigated using Western blotting and FACS. In addition, in silico analyses of the ADMET profile found EB5 to be a promising anti-cancer drug candidate that would benefit from further investigation.     

Tumor-Activated Prodrug with Synergistic Anti-Stemness Chemical and Photodynamic Therapies

Photodynamic therapy (PDT) has received extensive attention as a promising cancer treatment approach. Still, challenges to in vivo photodynamic therapy have existed for decades. First, the “always on” nature of conventional photosensitizers will cause damage to normal tissues thereby limiting the treatment efficiency of PDT. Second, the hypoxic TME protects cancer stem cells (CSCs) deeply harbored in the center of tumors from PDT administration, thus contributing to the recrudescence and metastasis of tumors. Herein, a ROS-triggered self-immolative therapeutic prodrug ( Mu-PS ) is reported, comprising of an activatable photosensitizer, an indomethacin (IMC) part, and a ROS-responsive trigger, for the anti-stemness chemical and photodynamic therapy of tumors. Intriguingly, Mu-PS can target the tumor and selectively release the photosensitizer and IMC upon the activation of TME-related ROS, generating massive phototoxic ¹O₂ to kill most non-CSCs tumor cells under the action of PDT and block the growth of CSCs by IMC, hence, it multiplies the therapeutic index. Noteworthy, the anti-stemness mechanism of IMC in tumors is confirmed and elucidated for the first time. Overall, this study introduces a self-immolatative prodrug for combined CSCs-involved chemical therapy and activatable PDT for tumors and provides a design paradigm of prodrug for the precise prognosis and treatment of tumors.     

DNA Nanobarrel-Based Drug Delivery for Paclitaxel and Doxorubicin

Co-delivery of anticancer drugs and target agents by endogenous materials is an inevitable approach towards targeted and synergistic therapy. Employing DNA base pair complementarities, DNA nanotechnology exploits a unique nanostructuring method and has demonstrated its capacity for nanoscale positioning and templated assembly. Moreover, the water solubility, biocompatibility, and modifiability render DNA structure suitable candidate for drug delivery applications. We here report single-stranded DNA tail conjugated antitumor drug paclitaxel (PTX), and the co-delivery of PTX, doxorubicin and targeting agent mucin 1 (MUC-1) aptamer on a DNA nanobarrel carrier. We investigated the effect of tail lengths on drug release efficiencies and dual drug codelivery-enabled cytotoxicity. Owing to the rapidly developing field of structural DNA nanotechnology, functional DNA-based drug delivery is promising to achieve clinical therapeutic applications.     

Ferrocene-Based Polymeric Nanoparticles Carrying Doxorubicin for Oncotherapeutic Combination of Chemotherapy and Ferroptosis

Mono-chemotherapy has significant side effects and unsatisfactory efficacy, limiting its clinical application. Therefore, a combination of multiple treatments is becoming more common in oncotherapy. Chemotherapy combined with the induction of ferroptosis is a potential new oncotherapy. Furthermore, polymeric nanoparticles (NPs) can improve the antitumor efficacy and decrease the toxicity of drugs. Herein, a polymeric NP, mPEG-b-PPLGFc@Dox, is synthesized to decrease the toxicity of doxorubicin (Dox) and enhance the efficacy of chemotherapy by combining it with the induction of ferroptosis. First, mPEG-b-PPLGFc@Dox is oxidized by endogenous H₂O₂ and releases Dox, which leads to an increase of H₂O₂ by breaking the redox balance. The Fe(II) group of ferrocene converts H₂O₂ into ·OH, inducing subsequent ferroptosis. Furthermore, glutathione peroxidase 4, a biomarker of ferroptosis, is suppressed and the lipid peroxidation level is elevated in cells incubated with mPEG-b-PPLGFc@Dox compared to those treated with Dox alone, indicating ferroptosis induction by mPEG-b-PPLGFc@Dox. In vivo, the antitumor efficacy of mPEG-b-PPLGFc@Dox is higher than that of free Dox. Moreover, the loss of body weight in mice treated mPEG-b-PPLGFc@Dox is lower than in those treated with free Dox, indicating that mPEG-b-PPLGFc@Dox is less toxic than free Dox. In conclusion, mPEG-b-PPLGFc@Dox not only has higher antitumor efficacy but it reduces the damage to normal tissue.     

Integrating Pillar[5]arene and BODIPY for a Supramolecular Nanoplatform To Achieve Synergistic Photodynamic Therapy and Chemotherapy

BODIPY photosensitizers have been integrated with a hypoxia-activated prodrug to achieve synergistic photodynamic therapy (PDT) and chemotherapy. A novel BODIPY derivative BDP-CN was designed and synthesized. It had two cyano groups to make it complex well with a water-soluble pillar[5]arene. Their association constant was calculated to be (6.8±0.9)×10⁶ M⁻¹. After self-assembly in water, regular spherical nanocarriers can be formed; these were used to encapsulate the hypoxia-activated prodrug tirapazamine (TPZ). BDP-CN displayed excellent photodynamic activity to complete PDT. In this process, O₂ can be continuously consumed to activate TPZ to allow it to be converted to a benzotriazinyl (BTZ) radical with high cytotoxicity to complete chemotherapy. As a result, the formed nanoparticles showed excellent synergistic photodynamic therapy and chemotherapy efficacy. The synergistic therapy mechanism is discussed in detail.     

The Construction of Polyphotocage Platform for Anticancer Photochemotherapy

Photocages enable the precise activation of molecular function with light in many research fields, such as anticancer treatment, where remote spatiotemporal control over the release of an active drug is needed. However, the poor physiological stability and tumor accumulation of conventional small molecular photocages are significant obstacles to developing efficient therapy in vivo. In this study, a new concept of “polyphotocage” is proposed through photocage–polymer hybrid macromolecular engineering. Photoresponsive Ru complex photocage is designed and fused with PEGylated polycarbonates, resulting in the polyphotocage. Various anticancer drugs can be readily conjugated to the polyphotocage via coordination linkage, which can be cut off to release drugs by red light. The polyphotocages can self-assemble into nanoparticles, which enhances the stability of the Ru photocage and demonstrates the efficient accumulation in different-sized tumorswith a high signal-to-background ratio. Furthermore, rapid cellular internalization and mitochondrial anchoring capability allowed the polyphotocages to deliver drugs into the mitochondria, which induces mitochondrial dysfunction and cell death. These properties ensure the effective delivery of anticancer drugs to solid tumors and multiple tiny tumors, ultimately inhibiting tumor proliferation. This strategy of polyphotocages provides a new platform for the future design of drug-delivery systems for cancer photochemotherapy.     

Surface-Engineered Extracellular Vesicles with CDH17 Nanobodies to Efficiently Deliver Imaging Probes and Chemo-Photothermal Drugs for Gastric Cancer Theragnostic

Extracellular vesicles (EVs) are widely used as natural nanoparticles to deliver various cargos for disease diagnosis and therapy. However, unmodified EVs cannot efficiently transport the cargos to desired sites due to non-specific uptake. Here, a delivery system is designed to display nanobodies against cadherin 17 (CDH17) on the surface of EVs isolated from HEK-293 cells and loaded with dye Indocyanine green (ICG) and/or anti-cancer drug dinitroazetidine derivative RRx-001, a blocker for CD47/ signal regulatory protein alpha (SIRPα) axis. CDH17 is a promising target for gastric cancer (GC) therapy. In this study, ICG loaded in the EVs engineered with CDH17 nanobodies can realize rapid tumor imaging in a CDH17-positive GC model and can produce significant anti-tumor photothermal therapeutic (PTT) effect after irradiation. Meanwhile, PTT effect can induce immunogenic cell death and macrophage polarization from M2 to M1 phenotype. The engineered EVs loaded with RRx-001 can significantly repress GC tumor growth. Finally, dual loading of ICG/RRx-001 in engineered EVs show maximal anti-tumor efficacy in both cancer cell and patient-derived GC models after only single injection. Collectively, CDH17 nanobody-functionalized EVs loaded with ICG and/or RRx-001 hold great promise to image and treat GC by combining fluorescent dye-induced PTT with chemotherapy.