Multimodal, PSMA-Targeted, PAMAM Dendrimer-Drug Conjugates for Treatment of Prostate Cancer: Preclinical Evaluation.

Introduction: Prostate cancer (PC) is the second most common cancer and the fifth most frequent cause of cancer death among men. Prostate-specific membrane antigen (PSMA) expression is associated with aggressive PC, with expression in over 90% of patients with metastatic disease. Those characteristics have led to its use for PC diagnosis and therapies with radiopharmaceuticals, antibody-drug conjugates, and nanoparticles. Despite these advancements, none of the current therapeutics are curative and show some degree of toxicity. Here we present the synthesis and preclinical evaluation of a multimodal, PSMA-targeted dendrimer-drug conjugate (PT-DDC), synthesized using poly(amidoamine) (PAMAM) dendrimers. PT-DDC was designed to enable imaging of drug delivery, providing valuable insights to understand and enhance therapeutic response. Methods: The PT-DDC was synthesized through consecutive conjugation of generation-4 PAMAM dendrimers with maytansinoid-1 (DM1) a highly potent antimitotic agent, Cy5 infrared dye for optical imaging, 2,2',2"-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA) chelator for radiolabeling with copper-64 and positron emission tomography tomography/computed tomography (PET/CT), lysine-urea-glutamate (KEU) PSMA-targeting moiety and the remaining terminal primary amines were capped with butane-1,2-diol. Non-targeted control dendrimer-drug conjugate (Ctrl-DDC) was formulated without conjugation of KEU. PT-DDC and Ctrl-DDC were characterized using high-performance liquid chromatography, matrix assisted laser desorption ionization mass spectrometry and dynamic light scattering. In vitro and in vivo evaluation of PT-DDC and Ctrl-DDC were carried out in isogenic human prostate cancer PSMA+ PC3 PIP and PSMA- PC3 flu cell lines, and in mice bearing the corresponding xenografts. Results: PT-DDC was stable in 1×PBS and human blood plasma and required glutathione for DM1 release. Optical, PET/CT and biodistribution studies confirmed the in vivo PSMA-specificity of PT-DDC. PT-DDC demonstrated dose-dependent accumulation and cytotoxicity in PSMA+ PC3 PIP cells, and also showed growth inhibition of the corresponding tumors. PT-DDC did not accumulate in PSMA- PC3 flu tumors and did not inhibit their growth. Ctrl-DDC did not show PSMA specificity. Conclusion: In this study, we synthesized a multimodal theranostic agent capable of delivering DM1 and a radionuclide to PSMA+ tumors. This approach holds promise for enhancing image-guided treatment of aggressive, metastatic subtypes of prostate cancer.

Multiphysics Modeling of Low-Intensity Pulsed Ultrasound Induced Chemotherapeutic Drug Release from the Surface of Gold Nanoparticles.

Currently, no numerical model for low-intensity pulsed ultrasound (LIPUS)-triggered anticancer drug release from gold nanoparticle (GNP) drug carriers exists in the literature. In this work, LIPUS-induced doxorubicin (DOX) release from GNPs was achieved in an ex vivo tissue model. Transmission electronic microscopy (TEM) imaging was performed before and after LIPUS exposure, and significant aggregation of the GNPs was observed upon DOX release. Subsequently, GNP surface potential was determined before and after LIPUS-induced DOX release, using a Zetasizer. A numerical model was then created to predict GNP aggregation, and the subsequent DOX release, via combining a thermal field simulation by solving the bioheat transfer equation (in COMSOL) and the Derjaguin, Landau, Verwey, and Overbeek (DLVO) total interaction potential (in MATLAB). The DLVO model was applied to the colloidal DOX-loaded GNPs by summing the attractive van der Waals and electrostatic repulsion interaction potentials for any given GNP pair. DLVO total interaction potential was found before and after LIPUS exposure, and an energy barrier for aggregation was determined. The DLVO interaction potential peak amplitude was found to drop from 1.36 kBT to 0.24 kBT after LIPUS exposure, translating to an 82.4% decrease in peak amplitude value. It was concluded that the interaction potential energy threshold for GNP aggregation (and, as a result, DOX release) was equal to 0.24 kBT.

Enzyme prodrug therapy: cytotoxic potential of paracetamol turnover with recombinant horseradish peroxidase.

Targeted cancer treatment is a promising, less invasive alternative to chemotherapy as it is precisely directed against tumor cells whilst leaving healthy tissue unaffected. The plant-derived enzyme horseradish peroxidase (HRP) can be used for enzyme prodrug cancer therapy with indole-3-acetic acid or the analgesic paracetamol (acetaminophen). Oxidation of paracetamol by HRP in the presence of hydrogen peroxide leads to N-acetyl-p-benzoquinone imine and polymer formation via a radical reaction mechanism. N-acetyl-p-benzoquinone imine binds to DNA and proteins, resulting in severe cytotoxicity. However, plant HRP is not suitable for this application since the foreign glycosylation pattern is recognized by the human immune system, causing rapid clearance from the body. Furthermore, plant-derived HRP is a mixture of isoenzymes with a heterogeneous composition. Here, we investigated the reaction of paracetamol with defined recombinant HRP variants produced in E. coli, as well as plant HRP, and found that they are equally effective in paracetamol oxidation at a concentration ≥ 400 µM. At low paracetamol concentrations, however, recombinant HRP seems to be more efficient in paracetamol oxidation. Yet upon treatment of HCT-116 colon carcinoma and FaDu squamous carcinoma cells with HRP-paracetamol no cytotoxic effect was observed, neither in the presence nor absence of hydrogen peroxide. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00706-021-02848-x.

Multifunctional Nanoparticles in Precise Cancer Treatment: Considerations in Design and Functionalization of Nanocarriers.

Nanotechnology has revolutionized cancer treatment in both diagnosis and therapy. Since the initial application of nanoparticles (NPs) in cancer treatment, the main objective of nanotechnology was developing effective nanosystems with high selectivity and specificity for cancer treatment and diagnosis. To achieve this, different encapsulation and conjugation strategies along with surface functionalization techniques have been developed to synthesize anticancer drugs loaded NPs with effective targeting to specific tumor cells. The unique physicochemical attributes of NPs make them promising candidates for targeted drug delivery, localized therapies, sensing, and targeting at cellular levels. However, a nanosystem for localized and targeted cancer managements should overcome several biological barriers and biomedical challenges such as endothelial barriers, blood brain barrier, reticuloendothelial system, selective targeting, biocompatibility, acute/chronic toxicity, tumor-targeting efficacy. The NPs for in vivo applications encounter barriers at system, organ, and the cellular level. To overcome these barriers, different strategies during the synthesis and functionalization of NPs should be adapted. Pharmacokinetics and cellular uptake of NPs are largely associated with physicochemical attributes of NPs, morphology, hydrodynamic size, charge, and other surface properties. These properties can be adjusted during different phases of synthesis and functionalization of the NPs. This study reviews the advances in targeted cancer treatment and the parameters influencing the efficacies of NPs as therapeutics. Different strategies for overcoming the biological barriers at cellular, organ and system levels and biomedical challenges are discussed. Moreover, the applications of NPs in preclinical and clinical practice are reviewed.

Obligate and facultative anaerobic bacteria in targeted cancer therapy: Current strategies and clinical applications.

Traditional methods for cancer therapy, including radiotherapy, chemotherapy, and immunotherapy are characterized by inherent limitations. Bacteria-mediated tumor therapy is becoming a promising approach in cancer treatment due to the ability of obligate or facultative anaerobic microorganisms to penetrate and proliferate in hypoxic regions of tumors. It is widely known that anaerobic bacteria cause the regression of tumors and inhibition of metastasis through a variety of mechanisms, including toxin production, anaerobic lifestyle and synergy with anti-cancer drugs. These features have the potential to be used as a supplement to conventional cancer treatment. To the best of our knowledge, no reports have been published regarding the most common tumor-targeting bacterial agents with special consideration of obligate anaerobes (such as Clostridium sp., Bifidobacterium sp.) and facultative anaerobes (including Salmonella sp., Listeria monocytogenes, Lactobacillus sp., Escherichia coli, Corynebacterium diphtheriae and Pseudomonas sp). In this review, we summarize the latest literature on the role of these bacteria in cancer treatment.

A perspective on magnetic core-shell carriers for responsive and targeted drug delivery systems.

Magnetic core-shell nanocarriers have been attracting growing interest owing to their physicochemical and structural properties. The main principles of magnetic nanoparticles (MNPs) are localized treatment and stability under the effect of external magnetic fields. Furthermore, these MNPs can be coated or functionalized to gain a responsive property to a specific trigger, such as pH, heat, or even enzymes. Current investigations have been focused on the employment of this concept in cancer therapies. The evaluation of magnetic core-shell materials includes their magnetization properties, toxicity, and efficacy in drug uptake and release. This review discusses some categories of magnetic core-shell drug carriers based on Fe2O3 and Fe3O4 as the core, and different shells such as poly(lactic-co-glycolic acid), poly(vinylpyrrolidone), chitosan, silica, calcium silicate, metal, and lipids. In addition, the review addresses their recent potential applications for cancer treatment.

Ovarian stimulation in young adult cancer survivors on targeted cancer therapies.

OBJECTIVE: To describe a clinical approach to and outcomes of IVF in reproductive-aged cancer survivors receiving targeted cancer therapies. DESIGN: Case report. SETTING: Not applicable. PATIENT(S): The first case is of a female patient with metastatic lung cancer receiving long-term crizotinib, an anaplastic lymphoma kinase inhibitor. The second case is of a female patient with metastatic colon cancer receiving long-term denosumab, a RANKL antibody. Both patients presented desiring fertility. INTERVENTION(S): In vitro fertilization. MAIN OUTCOME MEASURE(S): Live birth and embryo banking. RESULT(S): The potential impact of targeted therapy on oocytes and pregnancy was investigated via literature review and pharmaceutical company inquiries. After oncologic, fertility, and psychological counseling, both survivors underwent ovarian stimulation, IVF, and preimplantation genetic screening. One couple achieved live births of dizygotic twins via gestational surrogacy. The second couple froze one euploid blastocyst for future fertility. Both survivors are stable from their cancer standpoints. CONCLUSION(S): Successful fertility treatments are possible in the context of exposure to crizotinib and denosumab.