Therapeutic Opportunities in Neuroblastoma Using Nanotechnology.

Neuroblastoma (NB) is the most common extracranial solid tumor preferentially occurring in preschoolers. Its characteristic aggressiveness and heterogeneous clinical behavior are especially visible in relapsed or refractory cases and hamper therapeutic success. Although the introduction of novel antitumor agents, such as dinutuximab, isotretinoin, irinotecan, or I-131- metaiodobenzylguanidine, has increased survival rates, the situation in high-risk NB remains dismal. Moreover, treatment is particularly aggressive in these patients, leading to short- and long-term toxicities. The extensive research performed using nanotechnology in recent decades has prompted its application as a therapeutic alternative to overcome some of the common limitations of conventional chemotherapy. Nevertheless, the therapeutic role of nanomedicine in pediatric tumors like NB is not fully elucidated, and to date, only albumin-bound paclitaxel nanoparticles have reached clinic stages. In this review, we summarize the current therapeutic strategies for NB with special attention to the use of nanomedicine. We also highlight the preclinical studies on passive and active targeting nanodelivery of therapeutics in experimental NB models.

Nanocrystals and nanosuspensions: an exploration from classic formulations to advanced drug delivery systems.

Nanocrystals and nanosuspensions have become realistic approaches to overcome the formulation challenges of poorly water-soluble drugs. They also represent a less-known but versatile platform for multiple therapeutic applications. They can be integrated into a broad spectrum of drug delivery systems including tablets, hydrogels, microneedles, microparticles, or even functionalized liposomes. The recent progresses, challenges, and opportunities in this field are gathered originally together with an informative case study concerning an itraconazole nanosuspension-in-hydrogel formulation. The translational aspects, historical and current clinical perspectives are also critically reviewed here to shed light on the incoming generation of nanocrystal formulations.

Nanocrystal-chitosan particles for intra-articular delivery of disease-modifying osteoarthritis drugs.

Osteoarthritis is the most common chronic joint disease and a major health care concern due to the lack of efficient treatments. This is mainly related to the local and degenerative nature of this disease. Kartogenin was recently reported as a disease-modifying osteoarthritis drug that promotes cartilage repair, but its therapeutic effect is impeded by its very low solubility. Therefore, we designed a unique nanocrystal-chitosan particle intra-articular delivery system for osteoarthritis treatment that merges the following formulation techniques: nanosize reduction of a drug by wet milling and spray drying. The intermediate formulation (kartogenin nanocrystals) increased the solubility and dissolution rates of kartogenin. The final drug delivery system consisted of an easily resuspendable and ready-to-use microsphere powder for intra-articular injection. Positively charged chitosan microspheres with a median size of approximately 10 µm acted as a mothership drug delivery system for kartogenin nanocrystals in a simulated intra-articular injection. The microspheres showed suitable stability and a controlled release profile in synovial fluid and were nontoxic in human synoviocytes. The cartilage retention skills of the microspheres were also explored ex vivo using cartilage. This drug delivery system shows promise for advancement to preclinical stages in osteoarthritis therapy and scale-up production.

Rna-loaded nanoparticles for the treatment of hematological cancers.

Hematological cancers encompass a diverse group of malignancies affecting the blood, bone marrow, lymph nodes, and spleen. These disorders present unique challenges due to their complex etiology and varied clinical manifestations. Despite significant advancements in understanding and treating hematological malignancies, innovative therapeutic approaches are continually sought to enhance patient outcomes. This review highlights the application of RNA nanoparticles (RNA-NPs) in the treatment of hematological cancers. We delve into detailed discussions on in vitro and preclinical studies involving RNA-NPs for adult patients, as well as the application of RNA-NPs in pediatric hematological cancer. The review also addresses ongoing clinical trials involving RNA-NPs and explores the emerging field of CAR-T therapy engineered by RNA-NPs. Finally, we discuss the challenges still faced in translating RNA-NP research to clinics.

Spray-dried nanocrystal-loaded polymer microparticles for long-term release local therapies: an opportunity for poorly soluble drugs.

Nano- and micro-technologies can salvage drugs with very low solubility that were doomed to pre-clinical and clinical failure. A unique design approach to develop drug nanocrystals (NCs) loaded in extended release polymeric microparticles (MPs) for local treatments is presented here through the case of a potential osteoarthritis (OA) drug candidate for intra-articular (IA) administration. Optimizing a low-shear wet milling process allowed the production of NCs that can be subsequently freeze-dried (FD) and redispersed in a hydrophobic polymer-organic solvent solution to form spray-dried MPs. Results demonstrated a successful development of a ready-to-upscale formulation containing PLGA MPs with high drug NC encapsulation rates that showed a continuous and controlled drug release profile over four months. The screenings and procedures described allowed for identifying and overcoming common difficulties and challenges raised along the drug reduction to nano-size and spray-drying process. Above all, the technical knowledge acquired is intended for formulation scientists aiming to improve the therapeutic perspectives of poorly soluble drugs.

Combination of mesenchymal stem cells and bioactive molecules in hydrogels for osteoarthritis treatment.

Osteoarthritis (OA) is a chronic and inflammatory disease with no effective regenerative treatments to date. The therapeutic potential of mesenchymal stem cells (MSCs) remains to be fully explored. Intra-articular injection of these cells promotes cartilage protection and regeneration by paracrine signaling and differentiation into chondrocytes. However, joints display a harsh avascular environment for these cells upon injection. This phenomenon prompted researchers to develop suitable injectable materials or systems for MSCs to enhance their function and survival. Among them, hydrogels can absorb a large amount of water and maintain their 3D structure but also allow incorporation of bioactive agents or small molecules in their matrix that maximize the action of MSCs. These materials possess advantageous cartilage-like features such as collagen or hyaluronic acid moieties that interact with MSC receptors, thereby promoting cell adhesion. This review provides an up-to-date overview of the progress and opportunities of MSCs entrapped into hydrogels, combined with bioactive/small molecules to improve the therapeutic effects in OA treatment.

Nanomedicines and cell-based therapies for embryonal tumors of the nervous system.

Embryonal tumors of the nervous system are neoplasms predominantly affecting the pediatric population. Among the most common and aggressive ones are neuroblastoma (NB) and medulloblastoma (MB). NB is a sympathetic nervous system tumor, which is the most frequent extracranial solid pediatric cancer, usually detected in children under two. MB originates in the cerebellum and is one of the most lethal brain tumors in early childhood. Their tumorigenesis presents some similarities and both tumors often have treatment resistances and poor prognosis. High-risk (HR) patients require high dose chemotherapy cocktails associated with acute and long-term toxicities. Nanomedicine and cell therapy arise as potential solutions to improve the prognosis and quality of life of children suffering from these tumors. Indeed, nanomedicines have been demonstrated to efficiently reduce drug toxicity and improve drug efficacy. Moreover, these systems have been extensively studied in cancer research over the last few decades and an increasing number of anticancer nanocarriers for adult cancer treatment has reached the clinic. Among cell-based strategies, the clinically most advanced approach is chimeric-antigen receptor (CAR) T therapy for both pathologies, which is currently under investigation in phase I/II clinical trials. However, pediatric drug research is especially hampered due not only to ethical issues but also to the lack of efficient pre-clinical models and the inadequate design of clinical trials. This review provides an update on progress in the treatment of the main embryonal tumors of the nervous system using nanotechnology and cell-based therapies and discusses key issues behind the gap between preclinical studies and clinical trials in this specific area. Some directions to improve their translation into clinical practice and foster their development are also provided.

Oral lipid nanomedicines: Current status and future perspectives in cancer treatment.

Oral anticancer drugs have earned a seat at the table, as the need for homecare treatment in oncology has increased. Interest in this field is growing as a result of their proven efficacy, lower costs and positive patient uptake. However, the gastrointestinal barrier is still the main obstacle to surmount in chemotherapeutic oral delivery. Anticancer nanomedicines have been proposed to solve this quandary. Among these, lipid nanoparticles are described to be efficiently absorbed while protecting drugs from early degradation in hostile environments. Their intestinal lymphatic tropism or mucoadhesive/penetrative properties give them unique characteristics for oral administration. Considering that chronic cancer cases are increasing over time, it is important to be able to provide treatments with low toxicity and low prices. The challenges, opportunities and therapeutic perspectives of lipid nanoparticles in this area will be discussed in this review, taking into consideration the pre-clinical and clinical progress made in the last decade.

Decoration of Squalenoyl-Gemcitabine Nanoparticles with Squalenyl-Hydroxybisphosphonate for the Treatment of Bone Tumors.

Therapeutic perspectives of bone tumors such as osteosarcoma remain restricted due to the inefficacy of current treatments. We propose here the construction of a novel anticancer squalene-based nanomedicine with bone affinity and retention capacity. A squalenyl-hydroxybisphosphonate molecule was synthetized by chemical conjugation of a 1-hydroxyl-1,1-bisphosphonate moiety to the squalene chain. This amphiphilic compound was inserted onto squalenoyl-gemcitabine nanoparticles using the nanoprecipitation method. The co-assembly led to nanoconstructs of 75 nm, with different morphology and colloidal properties. The presence of squalenyl-hydroxybisphosphonate enhanced the nanoparticles binding affinity for hydroxyapatite, a mineral present in the bone. Moreover, the in vitro anticancer activity was preserved when tested in commercial and patient-treated derived pediatric osteosarcoma cells. Further in vivo studies will shed light on the potential of these nanomedicines for the treatment of bone sarcomas.

Unraveling the extracellular matrix-tumor cell interactions to aid better targeted therapies for neuroblastoma.

Treatment in children with high-risk neuroblastoma remains largely unsuccessful due to the development of metastases and drug resistance. The biological complexity of these tumors and their microenvironment represent one of the many challenges to face. Matrix glycoproteins such as vitronectin act as bridge elements between extracellular matrix and tumor cells and can promote tumor cell spreading. In this study, we established through a clinical cohort and preclinical models that the interaction of vitronectin and its ligands, such as αv integrins, are related to the stiffness of the extracellular matrix in high-risk neuroblastoma. These marked alterations found in the matrix led us to specifically target tumor cells within these altered matrices by employing nanomedicine and combination therapy. Loading the conventional cytotoxic drug etoposide into nanoparticles significantly increased its efficacy in neuroblastoma cells. We noted high synergy between etoposide and cilengitide, a high-affinity cyclic pentapeptide αv integrin antagonist. The results of this study highlight the need to characterize cell-extracellular matrix interactions, to improve patient care in high-risk neuroblastoma.

Nanomedicine and drug delivery systems in cancer and regenerative medicine.

Nanomedicine and drug delivery technologies play a prominent role in modern medicine, facilitating better treatments than conventional drugs. Nanomedicine is being increasingly used to develop new methods of cancer diagnosis and treatment, since this technology can modulate the biodistribution and the target site accumulation of chemotherapeutic drugs, thereby reducing their toxicity. Regenerative medicine provides another area where innovative drug delivery technology is being studied for improved tissue regeneration. Drug delivery systems can protect therapeutic proteins and peptides against degradation in biological environments and deliver them in a controlled manner. Similarly, the combination of drug delivery systems and stem cells can improve their survival, differentiation, and engraftment. The present review summarizes the most important steps carried-out by the group of Prof Blanco-Prieto in nanomedicine and drug delivery technologies. Throughout her scientific career, she has contributed to the area of nanomedicine to improve anticancer therapy. In particular, nanoparticles loaded with edelfosine, doxorubicin, or methotrexate have demonstrated great anticancer activity in preclinical settings of lymphoma, glioma, and pediatric osteosarcoma. In regenerative medicine, a major focus has been the development of drug delivery systems for brain and cardiac repair. In this context, several microparticle-based technologies loaded with biologics have demonstrated efficacy in clinically relevant animal models such as monkeys and pigs. The latest research by this group has shown that drug delivery systems combined with cell therapy can achieve a more complete and potent regenerative response. Cutting-edge areas such as noninvasive intravenous delivery of cardioprotective nanomedicines or extracellular vesicle-based therapies are also being explored. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Combinatorial Nanomedicine Made of Squalenoyl-Gemcitabine and Edelfosine for the Treatment of Osteosarcoma.

Due to chemoresistance and a high propensity to form lung metastasis, survival rates in pediatric osteosarcoma (OS) are poor. With the aim to improve anticancer activity in pediatric OS, a multidrug nanomedicine was designed using the alkyl-lysophospholipid edelfosine (EF) co-assembled with squalenoyl-gemcitabine (SQ-Gem) to form nanoassemblies (NAs) of 50 nm. SQ-Gem/EF NAs modified the total Gem pool exposure in the blood stream in comparison with SQ-Gem NAs, which correlated with a better tolerability and a lower toxicity profile after multiple intravenous administrations in mice. For in vivo preclinical assessment in an orthotopic OS tumor model, P1.15 OS cells were intratibially injected in athymic nude mice. SQ-Gem/EF NAs considerably decreased the primary tumor growth kinetics and reduced the number of lung metastases. Our findings support the candidature of this anticancer nanomedicine as a potential pediatric OS therapy.

Nanomedicines for Pediatric Cancers.

Chemotherapy protocols for childhood cancers are still problematic due to the high toxicity associated with chemotherapeutic agents and incorrect dosing regimens extrapolated from adults. Nanotechnology has demonstrated significant ability to reduce toxicity of anticancer compounds. Improvement in the therapeutic index of cytostatic drugs makes this strategy an alternative to common chemotherapy in adults. However, the lack of nanomedicines specifically for pediatric cancer care raises a medical conundrum. This review highlights the current state and progress of nanomedicine in pediatric cancer and discusses the real clinical challenges and opportunities.