Search Results (77)

Background: Nanomedicine approaches for cancer therapy face significant challenges, including a poor tumor accumulation, limited therapeutic efficacy, and systemic toxicity. We hypothesized that controlling the clustering of poly(acrylic acid-co-maleic acid) (PAM)-coated superparamagnetic iron oxide nanoparticles (SPIONs) would enhance their magnetic properties for improved targeting, while enabling a pH-responsive drug release in tumor microenvironments. Methods: PAM-stabilized SPION clusters were synthesized via arrested precipitation, characterized for physicochemical and magnetic properties, and evaluated for doxorubicin loading and pH-dependent release. A dual targeting approach combining antibody conjugation with magnetic guidance was assessed in cellular models, including a novel alternating magnetic field (AMF) pre-treatment protocol. Results: PAM-SPION clusters demonstrated controlled size distributions (60–100 nm), excellent colloidal stability, and enhanced magnetic properties, particularly for larger crystallites (13 nm). The formulations exhibited a pH-responsive drug release (8.5% at pH 7.4 vs. 14.3% at pH 6.5) and a significant enhancement of AMF-triggered release (17.5%). The dual targeting approach achieved an 8-fold increased cellular uptake compared to non-targeted formulations. Most notably, the novel AMF pre-treatment protocol demonstrated an 87% improved therapeutic efficacy compared to conventional post-treatment applications. Conclusions: The integration of targeting antibodies, magnetic guidance, and a pH-responsive PAM coating creates a versatile theranostic platform with significantly enhanced drug delivery capabilities. The unexpected synergistic effect of the AMF pre-treatment represents a promising new approach for improving the therapeutic efficacy of nanoparticle-based cancer treatments. Full article

Despite the development of a wide plethora of different anticancer agents, most of them are not used for patient treatment due to adverse effects caused by untargeted cytotoxicity. To prevent this unwanted toxicity, it is necessary to develop therapies discriminating between healthy and cancerous cells. One possible method is to target proteins overexpressed in cancer but not in normal cells. CD320 is a receptor responsible for the uptake of the transcobalamin-bound fraction of vitamin B12 (cobalamin), which is necessary for DNA synthesis, and thus, cell proliferation. CD320 was shown to be overexpressed in many cancers and its potential role as an early cancer biomarker was confirmed in several studies. Consequently, CD320 may represent a promising anti-cancer therapy target. This review summarizes the current advances and perspectives of anti-cancer CD320 targeting therapy, including therapeutic conjugates of vitamin B12, CD320-specific antibodies and nanobodies, nanoparticles loaded with cytotoxic drugs, porphyrin, and the potential of targeted CD320 therapy in attenuation of tumor tissues. Given the growing interest in CD320 as a novel target for anti-cancer therapy, further in vivo studies are required for the investigation of CD320 targeting effects on systemic cytotoxicity. Full article

The Wnt signalling pathway plays a crucial role in tissue homeostasis and cancer biology due to its regulation of cellular processes, including proliferation, migration, and stem cell activity. Frizzled receptor 7 (FZD7) (a member of the F-class G protein-coupled receptors) has emerged as a key Wnt receptor within this pathway, which is elevated in several human malignancies. FZD7 is notably upregulated in gastrointestinal, breast, pancreatic, and hepatocellular carcinomas and transmits oncogenic Wnt signalling through canonical and non-canonical pathways. FZD7 promotes tumour initiation, and emerging evidence implicates FZD7 in cancer stem cell maintenance and epithelial–mesenchymal transition (EMT), reinforcing its role in metastasis. Therapeutic strategies targeting FZD7 have shown promise, including FZD7-specific monoclonal antibody-drug conjugates (ADCs), human single-chain fragment variable (scFVs) antibodies, and nanoparticles. Notably, our recent development of FZD7-ADC has demonstrated tumour-selective cytotoxicity with reduced off-target effects, positioning FZD7 as an attractive therapeutic target. Additionally, nanoparticle-based drug delivery systems have enhanced the precision of existing chemotherapies by targeting FZD7-expressing tumour cells. Despite significant advances, clinical translation remains a challenge due to potential on-target toxicity and the complexity of tumour microenvironments. Future research should focus on optimising delivery systems, refining antibody specificity, and conducting comprehensive preclinical and clinical trials. This review will focus on novel discoveries regarding FZD7 in cancer and provide an update on our original review on this subject in 2016. Additionally, we present new figures generated by our group using the publicly available Pan-Cancer Atlas RNAseq datasets, highlighting FZD7 expression patterns in patient samples. This integrated approach aims to provide updated insights into the function of FZD7 during cancer and its growing status as an attractive target for therapy. In summary, FZD7 stands out as a promising molecular target in cancer therapy due to its selective overexpression in tumours, functional role in Wnt-driven oncogenesis, and potential for innovative therapeutic applications. This review underscores the critical need for the continued exploration of FZD7-targeted therapies to improve patient outcomes in cancer treatment. Full article

Prostate cancer is the most common tumor in men in developed countries and it often responds poorly to conventional treatments. Monoclonal antibody (MoAb) therapy, for this pathology, has grown tremendously in the past decades, exploiting naked and conjugated antibodies to cytotoxic payloads to form antibody drug conjugates (ADCs). Several studies have been carried out conjugating biomolecules against prostate-specific membrane antigen (PSMA), highly expressed in this tumor, to cytotoxic drugs. Nano-based formulations show high potential in targeted drug delivery to enhance the bioavailability of drugs. Our research aimed to evaluate the feasibility of setting up a nanoparticle-based multimodal tool for targeted drug delivery, describing the step-by-step approach and to perform a first screening of these fluorescent PEGylated silica nanoparticles employed in selective cancer cell targeting and killing. These nanoparticles featured a core–shell structure to contemporarily conjugate the antibody and the cytotoxic payload monomethyl auristatin E (MMAE) using a step-by-step approach. We compared the cytotoxic effect of this multimodal nanotool near the antibody-MMAE and free MMAE. We found a lower cytotoxicity effect of the nanoparticle-based construct compared to free drugs, likely because of the preservation of the previously observed receptor-mediated endocytosis. Nanomedicine is confirmed as a powerful alternative to organic drug delivery systems, even if some aspects, such as drug loading efficacy, release, scalable manufacturing and long-term stability, need to be deepened. Full article

Advanced biotherapeutic systems such as gene therapy, mRNA lipid nanoparticles, antibody–drug conjugates, fusion proteins, and cell therapy have proven to be promising platforms for delivering targeted biologic therapeutics. Preserving the intrinsic stability of these advanced therapeutics is essential to maintain their innate structure, functionality, and shelf life. Nevertheless, various challenges and obstacles arise during formulation development and throughout the storage period due to their complex nature and sensitivity to various stress factors. Key stability concerns include physical degradation and chemical instability due to various factors such as fluctuations in pH and temperature, which results in conformational and colloidal instabilities of the biologics, adversely affecting their quality and therapeutic efficacy. This review emphasizes key stability issues associated with these advanced biotherapeutic systems and approaches to identify and overcome them. In gene therapy, the brittleness of viral vectors and gene encapsulation limits their stability, requiring the use of stabilizers, excipients, and lyophilization. Keeping cells viable throughout the whole cell therapy process, from culture to final formulation, is still a major difficulty. In mRNA therapeutics, stabilization strategies such as the optimization of mRNA nucleotides and lipid compositions are used to address the instability of both the mRNA and lipid nanoparticles. Monoclonal antibodies are colloidally and conformationally unstable. Hence, buffers and stabilizers are useful to maintain stability. Although fusion proteins and monoclonal antibodies share structural similarities, they show a similar pattern of instability. Antibody–drug conjugates possess issues with conjugation and linker stability. This review outlines the stability issues associated with advanced biotherapeutics and provides insights into the approaches to address these challenges. Full article

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Common treatments following surgical resection include PD-1-targeting checkpoint inhibitors (pembrolizumab), as 20% of tumors are PD-L1 positive with or without systemic chemotherapy. Over the last several years, our laboratory has developed nano-immune conjugates (NIC) in which hydrophobic chemotherapy drugs like paclitaxel (PTX) and SN38, the active metabolite of irinotecan, are made water soluble by formulating them into albumin-based nanoparticles (nab) that are hydrophobically linked to various IgG1 monoclonal antibodies, creating an antigen-targetable nano-immune conjugate. To date, we have successfully tested PTX containing NICs linked to either VEGF- or CD20-targeted antibodies in two phase I clinical trials against multiple relapsed ovarian/uterine cancer or non-Hodgkin’s lymphoma, respectively. Herein, we describe a novel NIC created with either PTX or SN38 that is coated with anti-PD-L1-targeting antibodies for the treatment of a preclinical model of TNBC. In vitro testing suggests that the chemotherapy drug and antibody retain their toxicity and ligand binding capability in the context of the NIC. Furthermore, both the PTX and SN-38 NIC demonstrate superior anti-tumor efficacy relative to antibody and chemotherapy drugs alone in a PD-L1 + MDA-MB-231 human TNBC xenograft model, which could translate clinically to patients with TNBC. Full article

Due to their biocompatibility, nontoxicity, and surface conjugation properties, nanomaterials are effective nanocarriers capable of encapsulating chemotherapeutic drugs and facilitating targeted delivery across the blood–brain barrier (BBB). Although research on nanoparticles for brain cancer treatment is still in its early stages, these systems hold great potential to revolutionize drug delivery. Glioblastoma multiforme (GBM) is one of the most common and lethal brain tumors, and its heterogeneous and aggressive nature complicates current treatments, which primarily rely on surgery. One of the significant obstacles to effective treatment is the poor penetration of drugs across the BBB. Moreover, GBM is often referred to as a “cold” tumor, characterized by an immunosuppressive tumor microenvironment (TME) and minimal immune cell infiltration, which limits the effectiveness of immunotherapies. Therefore, developing novel, more effective treatments is critical to improving the survival rate of GBM patients. Current strategies for enhancing treatment outcomes focus on the controlled, targeted delivery of chemotherapeutic agents to GBM cells across the BBB using nanoparticles. These therapies must be designed to engage specialized transport systems, allowing for efficient BBB penetration, improved therapeutic efficacy, and reduced systemic toxicity and drug degradation. Lipid and inorganic nanoparticles can enhance brain delivery while minimizing side effects. These formulations may include epitopes—small antigen fragments that bind directly to free antibodies, B cell receptors, or T cell receptors—that interact with transport systems and enable BBB crossing, thereby boosting therapeutic efficacy. Lipid-based nanoparticles (LNPs), such as liposomes, niosomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), are among the most promising delivery systems due to their unique properties, including their size, surface modification capabilities, and proven biosafety. Additionally, inorganic nanoparticles such as gold nanoparticles, mesoporous silica, superparamagnetic iron oxide nanoparticles, and dendrimers offer promising alternatives. Inorganic nanoparticles (INPs) can be easily engineered, and their surfaces can be modified with various elements or biological ligands to enhance BBB penetration, targeted delivery, and biocompatibility. Strategies such as surface engineering and functionalization have been employed to ensure biocompatibility and reduce cytotoxicity, making these nanoparticles safer for clinical applications. The use of INPs in GBM treatment has shown promise in improving the efficacy of traditional therapies like chemotherapy, radiotherapy, and gene therapy, as well as advancing newer treatment strategies, including immunotherapy, photothermal and photodynamic therapies, and magnetic hyperthermia. This article reviews the latest research on lipid and inorganic nanoparticles in treating GBM, focusing on active and passive targeting approaches. Full article

Apart from HER2-positive, triple-negative breast cancer (TNBC) is the second most highly invasive type of breast cancer. Although TNBC does not overexpress HER2 receptors, it has been observed that EGFR protein expression is present in this specific type of tumor, making it an attractive target for immune and radiopharmaceutical treatments. In our current study, we used ¹⁰⁹Pd (T_1/2 = 13.7 h) in the form of a ¹⁰⁹Pd/^109mAg in vivo generator as a source of β⁻ particles and Auger electrons in targeted radionuclide therapy for TNBC. ¹⁰⁹Pd, obtained through neutron irradiation of the ¹⁰⁸Pd target, was deposited onto 15 nm gold nanoparticles to form Au@¹⁰⁹Pd core–shell nanoparticles, which were then conjugated to the panitumumab antibody. Au@¹⁰⁹Pd-PEG-panitumumab nanoparticles were bound, internalized, and partially routed to the nucleus in MDA-MB-231 human breast cancer cells overexpressing EGFR receptors. The Au@¹⁰⁹Pd-panitumumab radioconjugate significantly reduced the metabolic activity of MDA-MB-231 cells in a dose-dependent manner. In conclusion, we have found that Au@¹⁰⁹Pd-PEG-panitumumab nanoparticles show potential as a therapeutic agent for combined β⁻–Auger electron targeted radionuclide therapy of TNBC. The simultaneous emission of β⁻, conversion, and Auger electrons from the ¹⁰⁹Pd/^109mAg generator, similar to ¹⁶¹Tb conjugates, significantly enhances the therapeutic effect. The partial localization of these nanoparticles into the cell nucleus, provided by the panitumumab vector, ensures effective therapy with Auger electrons. This is particularly important for the treatment of drug-resistant TNBC cells. Full article

Anti-cancer targeted therapy is a promising approach. However, the identification of target molecules over-expressed in a wide range of tumors remains a significant challenge. The aim of this study was to analyze the expression of cell membrane-exposed heat shock protein 70 kDa (mHSP70) on different tumor cells and to develop a nanoscale delivery system based on a monoclonal antibody (mAb) that recognizes mHSP70 and uses chitosan core–shell nanoparticles (NPs). Several types of tumor cells (breast, pancreas, colon, prostate cancers, and some lymphomas) expressed mHSP70 as was determined by flow cytometry and confocal microscopy both in 2D and 3D cultures. Core NPs were formed by chitosan (C) conjugated to allocolchicinoid, which was used as a model drug (D). mAbs (A) targeting mHSP70 were complexed with succinylchitosan and used as NP shells forming final CAD-NPs. These NPs were characterized by size, charge, and functional activity. CAD-NPs were shown to have additional toxicity in comparison with CD-NPs in mHSP7-positive cells. Taken collectively, this study shows that mAb to mHSP70 can be used as a targeting vector in antitumor therapy. Full article

RNA is a promising nucleic acid-based biomolecule for various treatments because of its high efficacy, low toxicity, and the tremendous availability of targeting sequences. Nevertheless, RNA shows instability and has a short half-life in physiological environments such as the bloodstream in the presence of RNAase. Therefore, developing reliable delivery strategies is important for targeting disease sites and maximizing the therapeutic effect of RNA drugs, particularly in the field of immunotherapy. In this mini-review, we highlight two major approaches: (1) delivery vehicles and (2) chemical modifications. Recent advances in delivery vehicles employ nanotechnologies such as lipid-based nanoparticles, viral vectors, and inorganic nanocarriers to precisely target specific cell types to facilitate RNA cellular entry. On the other hand, chemical modification utilizes the alteration of RNA structures via the addition of covalent bonds such as N-acetylgalactosamine or antibodies (antibody–oligonucleotide conjugates) to target specific receptors of cells. The pros and cons of these technologies are enlisted in this review. We aim to review nucleic acid drugs, their delivery systems, targeting strategies, and related chemical modifications. Finally, we express our perspective on the potential combination of RNA-based click chemistry with adoptive cell therapy (e.g., B cells or T cells) to address the issues of short duration and short half-life associated with antibody–oligonucleotide conjugate drugs. Full article

Glioblastoma multiforme (GBM) is the most severe form of brain cancer and presents unique challenges to developing novel treatments due to its immunosuppressive milieu where receptors like programmed death ligand 1 (PD-L1) are frequently elevated to prevent an effective anti-tumor immune response. To potentially shift the GBM environment from being immunosuppressive to immune-enhancing, we engineered a novel nanovehicle from reduced graphene oxide quantum dot (rGOQD), which are loaded with the immunomodulatory drug resiquimod (R848) and conjugated with an anti-PD-L1 antibody (aPD-L1). The immunomodulatory rGOQD/R8/aPDL1 nanoparticles can actively target the PD-L1 on the surface of ALTS1C1 murine glioblastoma cells and release R848 to enhance the T-cell-driven anti-tumor response. From in vitro experiments, the PD-L1-mediated intracellular uptake and the rGOQD-induced photothermal response after irradiation with near-infrared laser light led to the death of cancer cells and the release of damage-associated molecular patterns (DAMPs). The combinational effect of R848 and released DAMPs synergistically produces antigens to activate dendritic cells, which can prime T lymphocytes to infiltrate the tumor in vivo. As a result, T cells effectively target and attack the PD-L1-suppressed glioma cells and foster a robust photothermal therapy elicited anti-tumor immune response from a syngeneic mouse model of GBM with subcutaneously implanted ALTS1C1 cells. Full article

In vitro cell activation through specific IgE bound to high-affinity receptors on the basophil surface is a widely used strategy for the evaluation of IgE-mediated immediate hypersensitivity reactions to betalactams. Cellular activation requires drug conjugation to a protein to form a large enough structure displaying a certain distance between haptens to allow the cross-linking of two IgE antibodies bound to the basophil’s surface, triggering their degranulation. However, no information about the size and composition of these conjugates is available. Routine in vitro diagnosis using the basophil activation test uses free amoxicillin, which is assumed to conjugate to a carrier present in blood. To standardize the methodology, we propose the use of well-controlled and defined nanomaterials functionalized with amoxicilloyl. Silica nanoparticles decorated with PAMAM–dendrimer–amoxicilloyl conjugates (NpDeAXO) of different sizes and amoxicilloyl densities (50–300 µmol amoxicilloyl/gram nanoparticle) have been prepared and chemically characterized. Two methods of synthesis were performed to ensure reproducibility and stability. Their functional effect on basophils was measured using an in-house basophil activation test (BAT) that determines CD63⁺ or CD203c^high activation markers. It was observed that NpDeAXO nanocomposites are not only able to specifically activate basophils but also do so in a more effective way than free amoxicillin, pointing to a translational potential diagnosis. Full article

Vaults are eukaryotic ribonucleoproteins consisting of 78 copies of the major vault protein (MVP), which assemble into a nanoparticle with an about 60 nm volume-based size, enclosing other proteins and RNAs. Regardless of their physiological role(s), vaults represent ideal, natural hollow nanoparticles, which are produced by the assembly of the sole MVP. Here, we have expressed in Komagataella phaffi and purified an MVP variant carrying a C-terminal Z peptide (vault-Z), which can tightly bind an antibody’s Fc portion, in view of targeted delivery. Via surface plasmon resonance analysis, we could determine a 2.5 nM affinity to the monoclonal antibody Trastuzumab (Tz)/vault-Z 1:1 interaction. Then, we characterized the in-solution interaction via co-incubation, ultracentrifugation, and analysis of the pelleted proteins. This showed virtually irreversible binding up to an at least 10:1 Tz/vault-Z ratio. As a proof of concept, we labeled the Fc portion of Tz with a fluorophore and conjugated it with the nanoparticle, along with either Tz or Cetuximab, another monoclonal antibody. Thus, we could demonstrate antibody-dependent, selective uptake by the SKBR3 and MDA-MB 231 breast cancer cell lines. These investigations provide a novel, flexible technological platform that significantly extends vault-Z’s applications, in that it can be stably conjugated with finely adjusted amounts of antibodies as well as of other molecules, such as fluorophores, cell-targeting peptides, or drugs, using the Fc portion as a scaffold. Full article

Magnetite nanoparticles (MNPs) are highly favored materials for a wide range of applications, from smart composite materials and biosensors to targeted drug delivery. These multifunctional applications typically require the biofunctional coating of MNPs that involves various conjugation techniques to form stable MNP–biomolecule complexes. In this study, a cost-effective method is developed for the chlorostannate modification of MNP surfaces that provides efficient one-step conjugation with biomolecules. The proposed method was validated using MNPs obtained via an optimized co-precipitation technique that included the use of degassed water, argon atmosphere, and the pre-filtering of FeCl₂ and FeCl₃ solutions followed by MNP surface modification using stannous chloride. The resulting chlorostannated nanoparticles were comprehensively characterized, and their efficiency was compared with both carboxylate-modified and unmodified MNPs. The biorecognition performance of MNPs was verified via magnetic immunochromatography. Mouse monoclonal antibodies to folic acid served as model biomolecules conjugated with the MNP to produce nanobioconjugates, while folic acid–gelatin conjugates were immobilized on the test lines of immunochromatography lateral flow test strips. The specific trapping of the obtained nanobioconjugates via antibody–antigen interactions was registered via the highly sensitive magnetic particle quantification technique. The developed chlorostannate modification of MNPs is a versatile, rapid, and convenient tool for creating multifunctional nanobioconjugates with applications that span in vitro diagnostics, magnetic separation, and potential in vivo uses. Full article

Despite high response rates to initial therapy, most patients with ovarian cancer will ultimately recur and go on to develop resistance to standard treatments. Novel therapies have been developed to overcome drug resistance and alter the tumor immune microenvironment by targeting oncogenic pathways, activating the innate immune response, and enhancing drug delivery. In this review, we discuss the current and future roles of chemotherapy, targeted agents such as poly (ADP-ribose) polymerase (PARP) inhibitors, bevacizumab, and mirvetuximab in the treatment of ovarian cancer. We explore the emerging role of therapeutic targets, including DNA repair pathway inhibitors and novel antibody–drug conjugates. Furthermore, we delve into the role of immunotherapeutic agents such as interleukins as well as immune-promoting agents such as oncolytic viruses and cancer vaccines. Innovative combination therapies using these agents have led to a rapidly evolving treatment landscape and promising results for patients with recurrent ovarian cancer. Full article