Nanomedicine‐boosting icaritin-based immunotherapy of advanced hepatocellular carcinoma

Traditional treatments for advanced hepatocellular carcinoma (HCC), such as surgical resection, transplantation, radiofrequency ablation, and chemotherapy are unsatisfactory, and therefore the exploration of powerful therapeutic strategies is urgently needed. Immunotherapy has emerged as a promising strategy for advanced HCC treatment due to its minimal side effects and long-lasting therapeutic memory effects. Recent studies have demonstrated that icaritin could serve as an immunomodulator for effective immunotherapy of advanced HCC. Encouragingly, in 2022, icaritin soft capsules were approved by the National Medical Products Administration (NMPA) of China for the immunotherapy of advanced HCC. However, the therapeutic efficacy of icaritin in clinical practice is impaired by its poor bioavailability and unfavorable in vivo delivery efficiency. Recently, functionalized drug delivery systems including stimuli-responsive nanocarriers, cell membrane-coated nanocarriers, and living cell-nanocarrier systems have been designed to overcome the shortcomings of drugs, including the low bioavailability and limited delivery efficiency as well as side effects. Taken together, the development of icaritin-based nanomedicines is expected to further improve the immunotherapy of advanced HCC. Herein, we compared the different preparation methods for icaritin, interpreted the HCC immune microenvironment and the mechanisms underlying icaritin for treatment of advanced HCC, and discussed both the design of icaritin-based nanomedicines with high icaritin loading and the latest progress in icaritin-based nanomedicines for advanced HCC immunotherapy. Finally, the prospects to promote further clinical translation of icaritin-based nanomedicines for the immunotherapy of advanced HCC were proposed

Biomaterial-based platforms for modulating immune components against cancer and cancer stem cells

Immunotherapy involves the therapeutic alteration of the patient's immune system to identify, target, and eliminate cancer cells. Dendritic cells, macrophages, myeloid-derived suppressor cells, and regulatory T cells make up the tumor microenvironment. In cancer, these immune components (in association with some non-immune cell populations like cancer-associated fibroblasts) are directly altered at a cellular level. By dominating immune cells with molecular cross-talk, cancer cells can proliferate unchecked. Current clinical immunotherapy strategies are limited to conventional adoptive cell therapy or immune checkpoint blockade. Targeting and modulating key immune components presents an effective opportunity. Immunostimulatory drugs are a research hotspot, but their poor pharmacokinetics, low tumor accumulation, and non-specific systemic toxicity limit their use. This review describes the cutting-edge research undertaken in the field of nanotechnology and material science to develop biomaterials-based platforms as effective immunotherapeutics. Various biomaterial types (polymer-based, lipid-based, carbon-based, cell-derived, etc.) and functionalization methodologies for modulating tumor-associated immune/non-immune cells are explored. Additionally, emphasis has been laid on discussing how these platforms can be used against cancer stem cells, a fundamental contributor to chemoresistance, tumor relapse/metastasis, and failure of immunotherapy. Overall, this comprehensive review strives to provide up-to-date information to an audience working at the juncture of biomaterials and cancer immunotherapy. Statement of significance: Cancer immunotherapy possesses incredible potential and has successfully transitioned into a clinically lucrative alternative to conventional anti-cancer therapies. With new immunotherapeutics getting rapid clinical approval, fundamental problems associated with the dynamic nature of the immune system (like limited clinical response rates and autoimmunity-related adverse effects) have remained unanswered. In this context, treatment approaches that focus on modulating the compromised immune components within the tumor microenvironment have garnered significant attention amongst the scientific community. This review aims to provide a critical discussion on how various biomaterials (polymer-based, lipid-based, carbon-based, cell-derived, etc.) can be employed along with immunostimulatory agents to design innovative platforms for selective immunotherapy directed against cancer and cancer stem cells

Nanotechnology Synergised Immunoengineering for Cancer

Novel strategies modulating the immune system yielded enhanced anticancer responses and improved cancer survival. Nevertheless, the success rate of immunotherapy in cancer treatment has been below expectation(s) due to unpredictable efficacy and off-target effects from systemic dosing of immunotherapeutic. As a result, there is an unmet clinical need for improving conventional immunotherapy. Nanotechnology offers several new strategies, multimodality, and multiplex biological targeting advantage to overcome many of these challenges. These efforts enable programming the pharmacodynamics, pharmacokinetics, delivery of immunomodulatory agents/co-delivery of compounds to prime at the tumor sites for improved therapeutic benefits. This review provides an overview of the design and clinical principles of biomaterials driven nanotechnology and their potential use in personalized nanomedicines, vaccines, localized tumor modulation, and delivery strategies for cancer immunotherapy. In this review, we also summarize the latest highlights and recent advances in combinatorial therapies avail in the treatment of cold and complicated tumors. It also presents key steps and parameters implemented for clinical success. Finally, we analyse, discuss, and provide clinical perspectives on the integrated opportunities of nanotechnology and immunology to achieve synergistic and durable responses in cancer treatment

Breast Cancer Vaccines: New insights into Immunomodulatory and Nano-therapeutic Approaches

Breast cancer (BC) is known to be a highly heterogeneous disease that is clinically subdivided into four primary molecular subtypes, each having distinct morphology and clinical implications. These subtypes are principally defined by hormone receptors and other proteins involved (or not involved) in BC development. BC therapeutic vaccines [including peptide-based vaccines, protein-based vaccines, nucleic acid-based vaccines (DNA/RNA vaccines), bacterial/viral-based vaccines, and different immune cell-based vaccines] have emerged as an appealing class of cancer immunotherapeutics when used alone or combined with other immunotherapies. Employing the immune system to eliminate BC cells is a novel therapeutic modality. The benefit of active immunotherapies is that they develop protection against neoplastic tissue and readjust the immune system to an anti-tumor monitoring state. Such immunovaccines have not yet shown effectiveness for BC treatment in clinical trials. In recent years, nanomedicines have opened new windows to increase the effectiveness of vaccinations to treat BC. In this context, some nanoplatforms have been designed to efficiently deliver molecular, cellular, or subcellular vaccines to BC cells, increasing the efficacy and persistence of anti-tumor immunity while minimizing undesirable side effects. Immunostimulatory nano-adjuvants, liposomal-based vaccines, polymeric vaccines, virus-like particles, lipid/calcium/phosphate nanoparticles, chitosan-derived nanostructures, porous silicon microparticles, and selenium nanoparticles are among the newly designed nanostructures that have been used to facilitate antigen internalization and presentation by antigen-presenting cells, increase antigen stability, enhance vaccine antigenicity and remedial effectivity, promote antigen escape from the endosome, improve cytotoxic T lymphocyte responses, and produce humoral immune responses in BC cells. Here, we summarized the existing subtypes of BC and shed light on immunomodulatory and nano-therapeutic strategies for BC vaccination. Finally, we reviewed ongoing clinical trials on BC vaccination and highlighted near-term opportunities for moving forward

Lipid-core nanoparticles: Classification, preparation methods, routes of administration and recent advances in cancer treatment

Nanotechnological drug delivery platforms represent a new paradigm for cancer therapeutics as they improve the pharmacokinetic profile and distribution of chemotherapeutic agents over conventional formulations. Among nanoparticles, lipid-based nanoplatforms possessing a lipid core, that is, lipid-core nanoparticles (LCNPs), have gained increasing interest due to lipid properties such as high solubilizing potential, versatility, biocompatibility, and biodegradability. However, due to the wide spectrum of morphologies and types of LCNPs, there is a lack of consensus regarding their terminology and classification. According to the current state-of-the-art in this critical review, LCNPs are defined and classified based on the state of their lipidic components in liquid lipid nanoparticles (LLNs). These include lipid nanoemulsions (LNEs) and lipid nanocapsules (LNCs), solid lipid nanoparticles (SLNs) and nanostructured lipid nanocarriers (NLCs). In addition, we present a comprehensive and comparative description of the methods employed for their preparation, routes of administration and the fundamental role of physicochemical properties of LCNPs for efficient antitumoral drug-delivery application. Market available LCNPs, clinical trials and preclinical in vivo studies of promising LCNPs as potential treatments for different cancer pathologies are summarized.MCIN/AEI FPU18/05336European Social Fund (ESF)Ph.D. program of Biomedicine of the University of GranadaMCIN/AEI/FEDER "Una manera de hacer Europa" RTI2018.101309B-C21 RTI2018.101309B-C2

Nanotechnology approaches in the current therapy of skin cancer

Skin cancer is a high burden disease with a high impact on global health. Conventional therapies have several drawbacks; thus, the development of effective therapies is required. In this context, nanotechnology approaches are an attractive strategy for cancer therapy because they enable the efficient delivery of drugs and other bioactive molecules to target tissues with low toxic effects. In this review, nanotechnological tools for skin cancer will be summarized and discussed. First, pathology and conventional therapies will be presented, followed by the challenges of skin cancer therapy. Then, the main features of developing efficient nanosystems will be discussed, and next, the most commonly used nanoparticles (NPs) described in the literature for skin cancer therapy will be presented. Subsequently, the use of NPs to deliver chemotherapeutics, immune and vaccine molecules and nucleic acids will be reviewed and discussed as will the combination of physical methods and NPs. Finally, multifunctional delivery systems to codeliver anticancer therapeutic agents containing or not surface functionalization will be summarized

Development of Lignin-based Nanoparticles for Cancer Therapy

Lignin is part of the lignocellulosic biomass and represents the second most abundant biopolymer after cellulose. However, only about 2% of the annually isolated lignin is used for low-value applications, mainly due to its complex structure. The fabrication of lignin nanoparticles offers a structural and morphological control of the lignin polymer, which enables lignin to be used for high-value products in biomedical applications like drug delivery and tissue engineering. Therefore, the main aim of this thesis was to exploit the potential of the under-investigated lignin-based nanoparticles as vehicles to deliver different therapeutic compounds for improved cancer therapy. Although multiple treatment options are available to treat cancer diseases, they still represent illnesses with very high incidence and mortality worldwide. Nanotechnology has opened doors to improve the limitations of current therapeutic modalities, such as chemotherapy or administration of immunomodulatory agents, by improving the solubility, stability and circulating half-life of the therapeutics, and by minimizing the systemic side effects. Firstly, different lignin-based nanoparticles were prepared and characterized, and their cytocompatibility investigated towards several cell lines. The ability of lignin nanoparticles to load different chemotherapeutic compounds was assessed, and drug release profiles were evaluated in two different buffers (pH 5.5 and 7.4). Secondly, after a carboxylation reaction of the original lignin polymer, the carboxylated lignin nanoparticles were surface modified with a polymer/peptide, as a proof-of-concept of the nanoparticles’ functionalization. The release profile of a poorly-water soluble cytotoxic compound (benzazulene) from the lignin nanoparticles was evaluated, and the in vitro antiproliferative effect investigated against several cell lines. Next, lignin polymers with different degrees of carboxylation were prepared in order to investigate the long-term stability of the resulting lignin nanoparticles at physiological conditions. After finding the optimal conditions in terms of stability, the lignin nanoparticles were further functionalized with a cell-penetrating peptide, and the cellular interactions of the resulting nanosystem were evaluated and compared with internalizing arginine-glycine-aspartic acid peptide-functionalized lignin nanoparticles, using two- and three-dimensional cell culture models. Finally, the lignin nanoparticles were loaded with resiquimod, an agonist of the toll-like receptors 7 and 8 that can induce the re-education of M2 to M1-like macrophages, and further functionalized with a peptide that targets the mannose receptor expressed by the M2 macrophages. Afterwards, the homing ability of these nanoparticles was investigated in vivo, using an orthotopic 4T1 triple-negative breast cancer model. The therapeutic effect of these nanosystems was studied in combination with a chemotherapeutic compound (vinblastine), and the immunological profile of the cells isolated from the tumors was compared. Overall, this thesis provides new insights on the use of lignin polymer as a novel starting material to develop lignin-based nanocarriers, in particular for cancer therapeutics.Ligniini on osa lignoselluloosapitoista biomassaa ja se on myös maailman toiseksi yleisin biopolymeeriä selluloosan jälkeen. Kuitenkin vain noin 2% vuosittain eristetystä ligniinistä käytetään vähäarvoisiin sovelluksiin, pääasiassa sen monimutkaisen rakenteen vuoksi. Ligniinin käyttö nanohiukkasten raaka-aineena mahdollistaa ligniinipolymeerin rakenteellisen- ja morfologisen hallinnan, mikä edelleen mahdollistaa ligniinin käytön arvokkaammissa biolääketieteellisissä sovelluksissa, kuten esimerkiksi lääkkeiden annostelussa ja kudosteknologiassa. Tämän opinnäytetyön tavoitteena oli tarkastella vähän tutkittujen ligniinipohjaisten nanohiukkasten potentiaalia toimia kuljetushiukkasina erilaisille terapeuttisille yhdisteille syövän hoidon parantamiseksi. Vaikka syöpäsairauksien hoitamiseksi on saatavana useita hoitomuotoja, ne kuuluvat silti sairauksiin, joiden esiintyvyys ja aiheuttama kuolleisuus ovat maailmanlaajuisesti erittäin korkeat. Nanoteknologian avulla on onnistuttu parantamaan nykyisiä terapeuttisia menetelmiä, joihin kuuluu kemoterapeuttisten tai immunomoduloivien aineiden annostelu, parannukset lääkkeiden liukoisuuteen-, stabiilisuuteen- ja puoliintumisaikaan verenkierrossa, sekä vähentämällä systeemisiä sivuvaikutuksia. Ensinnäkin, työssä valmistettiin ja karakterisoitiin erilaisia ligniinipohjaisia nanohiukkasia ja tutkittiin niiden yhteensopivuutta useiden solulinjojen kanssa. Työssä myös arvioitiin ligniini-nanohiukkasten kykyä kuljettaa erilaisia kemoterapeuttisia lääkeaineita sekä mitattiin näiden aineiden vapautumisprofiileja kahdessa eri puskuriliuoksessa (pH 5,5 ja 7,4). Seuraavaksi osoitettiin onnistuneesti ligniini-nanohiukkasten funktionalisaation toteuttamiskelpoisuus: ligniinipolymeerin karboksylaatioreaktion jälkeen ligniini-nanohiukkasten pintaan kiinnitettiin polymeerejä ja peptidejä. Huonosti vesiliukoisen sytotoksisen yhdisteen (bentsatsuleeni) vapautumisprofiili ligniini- nanohiukkasista mitattiin ja proliferatiivista vaikutusta tutkittiin in vitro useita solulinjoja vastaan. Edelleen tutkittiin miten erilaiset ligniinipolymeerin karboksylaatioasteet vaikuttavat ligniini-nanohiukkasten pitkäaikaiseen stabiilisuuteen fysiologisissa olosuhteissa. Kun stabiilisuuden kannalta optimaaliset olosuhteet oli selvitetty, ligniini-nanohiukkaset funktionalisoitiin solukalvon läpäisyn mahdollistavalla peptidillä. Näiden nanohiukkasten soluvuorovaikutuksia arvioitiin ja verrattiin arginiini-glysiini-asparagiinihappo-peptidillä funktionalisoitujen ligniini-nanohiukkasten solunläpäisyyn käyttämällä kaksi- ja kolmiulotteisia soluviljelmämalleja. Lopuksi ligniini-nanohiukkaset funktionalisoitiin peptidillä, joka mahdollistaa M2-makrofageihin kiinnittymisen, ja kuormattiin resikimodilla, joka on Toll-like-reseptorien 7 ja 8 agonisti ja kykenee käynnistämään M2-tyyppisten makrofagien uudelleenkoulutuksen M1-tyyppisiksi makrofageiksi. Näiden nanohiukkasten kohteeseenhakeutumiskykyä tutkittiin in vivo käyttämällä ortotooppista 4T1-kolmoisnegatiivista rintasyöpämallia. Näiden nanosysteemien terapeuttista vaikutusta tutkittiin yhdessä kemoterapeuttisen yhdisteen (vinblastiini) kanssa ja kasvaimista eristettyjen solujen immunologista profiilia verrattiin. Kaiken kaikkiaan tämä opinnäytetyö tarjoaa uutta tietoa ligniinipolymeerin käytöstä raaka-aineena ligniinipohjaisten nanokantajien kehittämisessä erityisesti syöpähoitoon

Cancer Nanomedicine

This special issue brings together cutting edge research and insightful commentary on the currentl state of the Cancer Nanomedicine field

Smart and Multi-Functional Magnetic Nanoparticles for Cancer Treatment Applications: Clinical Challenges and Future Prospects

Iron oxide nanoparticle (IONPs) have become a subject of interest in various biomedical fields due to their magnetism and biocompatibility. They can be utilized as heat mediators in magnetic hyperthermia (MHT) or as contrast media in magnetic resonance imaging (MRI), and ultrasound (US). In addition, their high drug-loading capacity enabled them to be therapeutic agent transporters for malignancy treatment. Hence, smartening them allows for an intelligent controlled drug release (CDR) and targeted drug delivery (TDD). Smart magnetic nanoparticles (SMNPs) can overcome the impediments faced by classical chemo-treatment strategies, since they can be navigated and release drug via external or internal stimuli. Recently, they have been synchronized with other modalities, e.g., MRI, MHT, US, and for dual/multimodal theranostic applications in a single platform. Herein, we provide an overview of the attributes of MNPs for cancer theranostic application, fabrication procedures, surface coatings, targeting approaches, and recent advancement of SMNPs. Even though MNPs feature numerous privileges over chemotherapy agents, obstacles remain in clinical usage. This review in particular covers the clinical predicaments faced by SMNPs and future research scopes in the field of SMNPs for cancer theranostics