Synergistic Combination Therapy Research Articles

Abstract PO2-04-09: Combination of the PLK1 Inhibitor Onvansertib and the PI3Kα Inhibitor Alpelisib Overcomes Palbociclib Resistance in PIK3CA-mutated HR+ Breast Cancer

Abstract In the 1st line setting of hormone receptor-positive HER2 negative (HR+/HER2-) metastatic breast cancer, cyclin dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, abemaciclib and ribociclib) are typically used in combination with endocrine therapy. Though initially effective, acquired resistance to either CDK4/6 inhibitors or endocrine therapy eventually leads to disease relapse in most patients. Activating mutations in PIK3CA, the gene encoding alpha catalytic subunit of phosphatidylinositol-4,5-bisphosphat 3-kinase (PI3K) are found in approximately 40% of HR+ breast cancer patients and have been implicated in mediating resistance to CDK4/6 inhibitors. The PI3Kα inhibitor alpelisib is currently approved for PI3KCA-mutant HR+ breast cancer after progression on CDK4/6 inhibitors. However, drug-associated resistance mechanisms may limit its clinical benefit. Synergistic combination therapies have the potential to improve efficacy and overcome resistance mechanisms. Polo-like kinase 1 (PLK1) is a serine-threonine-protein kinase, key cell cycle regulator that controls G2/M entry and mitotic progression, and that has been shown to mediate resistance to palbociclib in HR+ breast cancer. Onvansertib is an oral and highly specific PLK1 inhibitor currently on clinical development in solid tumors and hematological malignancies. Here we evaluated the potential of onvansertib to increase the activity of alpelisib in PIK3CA-mutant HR+ breast cancer preclinical models. The combination of onvansertib and alpelisib synergistically inhibited cell viability and/or colony formation in three PI3KCA-mutant HR+ breast cancer cell lines, MCF-7 (PIK3CA E545K), EFM-19 (PIK3CA H1047L), and T-47D (PIK3CA 1047R). A significant increase in apoptosis was observed in cells treated with the combination compared to either agent alone. We next tested the combination of onvansertib and alpelisib in patient-derived xenograft (PDX) models. For this purpose, palbociclib-resistant PIK3CA-mutant HR+ breast cancer PDXs were established from primary breast tumor (PDX HBCx-86, PIK3CA E545K) or from metastatic bone biopsies of patients who had progressed on endocrine therapy plus palbociclib (HBCx-180, PIK3CA H1047R) or on PI3Kα inhibitor (HBCx-134palboR31, PIK3CA H1047R). PDX tumors were grafted subcutaneously in nude mice and mice were treated with vehicle, onvansertib (45 mg/kg, oral, 5 days a week), alpelisib (25mg/kg, oral, 5 days a week) or the combination. The combination was well tolerated and showed superior anti-tumor activity than the single agents in the 3 PDX models. In the HBCx-86 PDX, although none of the single agents showed activity, the combination induced potent tumor growth inhibition. In the metastasis-derived PDX HBCx-134palboR31, the combination treatment induced pronounced tumor regression in 62% of mice (5/8), with complete response in 25% (2/8), while mice treated with the single agents showed tumor progression. Finally, in the HBCx-180 PDX, established from a patient with primary resistance to palbociclib, the efficacy of the combination was greater and more durable, with significant survival advantage, compared to the monotherapies. Collectively, our preclinical findings suggest that co-targeting PLK1 and PI3Kα with onvansertib and alpelisib respectively, may constitute a promising therapeutic combination strategy for patients with PIK3CA-mutant HR+ breast cancer failing to respond to first-line standard of care therapies. Citation Format: Sreeja Sreekumar, Pierre Painsec, Davis Klein, Dalia Gonzalez, Laura Sourd, Elodie Montaudon, Tod Smeal, Elisabetta Marangoni, Maya Ridinger. Combination of the PLK1 Inhibitor Onvansertib and the PI3Kα Inhibitor Alpelisib Overcomes Palbociclib Resistance in PIK3CA-mutated HR+ Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-09.

The synergistic effect of curcumin and mitoquinol mesylate on cognitive impairment and the neuropathology of Alzheimer's disease

Given the complexity and heterogeneity of Alzheimer's disease (AD) pathology, targeted monotherapy drugs may not be effective. Therefore, synergistic combination therapy of curcumin and Mito Q was proposed and evaluated in a triple-transgenic AD model mice (3 × Tg-AD mice). The cognitive ability was assessed using behavioral tests and typical pathological changes were observed through Western blotting and histological analysis. The results demonstrated a significant enhancement in cognitive ability along with the mitigation of typical AD pathological features such as Aβ aggregation, tau phosphorylation, and synaptic damage. Notably, the combination therapy demonstrated superior efficacy over individual drugs alone. These findings provide valuable insights for optimizing the development of AD drugs.

Dual-functional nano-carrier system based on NIR-laser-triggered dynamic Au[sbnd]Se interaction for chemo-photothermal synergistic tumor therapy

Photothermal therapy (PTT) combined with chemotherapy has been highly desirable to improve the tumor treatment efficacy. Here, we report a novel controlled release nano-carrier system named Se-PEG-Au NPs-DOX (SePAD) for achieving chemo-photothermal synergistic tumor therapy. In this system, the diselenide-containing co-polymers (mPEG-Se–Se-PEGm) were anchored onto the surface of Au NPs via AuSe interactions and the soluble chemotherapeutic doxorubicin (Dox) was loaded into the monolayers. This structure is proved to be stable in a high biological thiols environment. Strikingly, the SePAD presents an ideal efficient photothermal capability and a controllable Dox release behavior by dynamic AuSe interaction in GSH-rich tumor cells when irradiated under 808 nm NIR laser. Following, the results of in vitro and in vivo experiments all demonstrat the superior antitumor properties of SePAD in murine breast cancer. Thus, this system provides a promising strategy to realize chemo-photothermal synergistic combination therapy for breast tumors.

Synergistic combination therapy using cowpea mosaic virus intratumoral immunotherapy and Lag-3 checkpoint blockade

Immune checkpoint therapy (ICT) for cancer can yield dramatic clinical responses; however, these may only be observed in a minority of patients. These responses can be further limited by subsequent disease recurrence and resistance. Combination immunotherapy strategies are being developed to overcome these limitations. We have previously reported enhanced efficacy of combined intratumoral cowpea mosaic virus immunotherapy (CPMV IIT) and ICT approaches. Lymphocyte-activation gene-3 (LAG-3) is a next-generation inhibitory immune checkpoint with broad expression across multiple immune cell subsets. Its expression increases on activated T cells and contributes to T cell exhaustion. We observed heightened efficacy of a combined CPMV IIT and anti-LAG-3 treatment in a mouse model of melanoma. Further, LAG-3 expression was found to be increased within the TME following intratumoral CPMV administration. The integration of CPMV IIT with LAG-3 inhibition holds significant potential to improve treatment outcomes by concurrently inducing a comprehensive anti-tumor immune response, enhancing local immune activation, and mitigating T cell exhaustion.

Designing of Polymeric Nanoparticles for Enhanced Breast Cancer Therapy: Combining Paclitaxel, Boric Acid and Tannic Acid for Controlled Drug Delivery

AbstractThis study introduces an innovative approach to enhance breast cancer treatment by combining Boric Acid (BA) and Tannic Acid (TA) with Paclitaxel (PTX) within gelatin/sodium alginate (Gel/NaAlg) nanoparticles, resulting in a synergistic combination therapy. The methodology involved integrating PTX, TA, and BA into the polymeric framework using an emulsion cross‐linking method. The resulting nanoparticles underwent rigorous characterization, confirming their suitability as a controlled release platform. Techniques such as Scanning Electron Microscope (SEM), Differential Scanning Calorimetry (DSC), X‐ray Diffractometry (XRD), and Fourier Transform Infrared Spectroscopy (FTIR) were employed for thorough analysis. The synthesized nanoparticles demonstrated a size below 204 nm, and extensive analyses confirmed their structural integrity and composition. Notably, Gel/NaAlg/PTX/BA/TA nanoparticles exhibited superior drug release kinetics compared to other formulations, offering a promising strategy for controlled release of hydrophobic drugs like PTX. Entrapment efficiency ranged from 49.84 % to 63.38 %, and drug loading capacities spanned from 49.81 to 61.42 μg/mg. This study pioneers a novel approach in breast cancer therapy by incorporating BA and TA into PTX‐loaded Gel/NaAlg nanoparticlesThese findings emphasize the importance of continued exploration in innovative drug delivery systems for more effective cancer interventions.

Doxorubicin-Based Ionic Nanomedicines for Combined Chemo-Phototherapy of Cancer.

Synergistic combination therapy approach offers lots of options for delivery of materials with anticancer properties, which is a very promising strategy to treat a variety of malignant lesions with enhanced therapeutic efficacy. The current study involves a detailed investigation of combination ionic nanomedicines where a chemotherapeutic drug is coupled with a photothermal agent to attain dual mechanisms (chemotherapy (chemo) and photothermal therapy (PTT)) to improve the drug's efficacy. An FDA-approved Doxorubicin hydrochloride (DOX·HCl) is electrostatically attached with a near-infrared cyanine dye (ICG, IR783, and IR820), which serves as a PTT drug using ionic liquid chemistry to develop three ionic material (IM)-based chemo-PTT drugs. Carrier-free ionic nanomedicines (INMs) are derived from ionic materials (IMs). The photophysical properties of the developed combination IMs and their INMs were studied in depth. The phototherapeutic efficiency of the combination drugs was evaluated by measuring the photothermal conversion efficiency and singlet-oxygen quantum yield. The improved photophysical properties of the combination nanomedicines in comparison to their parent compounds significantly enhanced INMs' photothermal efficiency. Cellular uptake, dark and light toxicity studies, and cell death mechanisms of the chemo-PTT nanoparticles were also studied in vitro. The combination INMs exhibited enhanced cytotoxicity compared to their respective parent compounds. Moreover, the apoptosis cell death mechanism was almost doubled for combination nanomedicine than the free DOX, which is attributed to enhanced cellular uptake. Examination of the combination index and improved in vitro cytotoxicity results revealed a great synergy between chemo and PTT drugs in the developed combination nanomedicines.

Abstract C088: Preclinical synergistic combination therapy of lurbinectedin with irinotecan and 5-fluorouracil in pancreatic cancer

Abstract Pancreatic cancer is a devastating disease with an overall five-year survival rate of ~12% according to the American Cancer Society. Novel chemotherapeutics and targeted therapies in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin (PM01183; LY-01017) received accelerated FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. Lurbinectedin is a chemotherapeutic synthetic tetrahydroisoquinoline alkaloid that inhibits active transcription by binding to guanine rich sequences in the minor groove of DNA. Lurbinectedin has been shown to reduce oncogenic transcription by stalling and degrading RNA Polymerase II and inducing breaks in DNA, causing subsequent apoptosis. We now demonstrate lurbinectedin’s highly efficient killing of pancreatic tumor cells as a single agent in PANC-1, BxPC-3, and HPAF-II cell lines, with 72-hour IC-50s ranging from 0.266 – 0.964 nM. We further demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in synergistic killing of pancreatic tumor cells in vitro. Synergism was calculated using SynergyFinder, with HSA scores exceeding 15 in every cell line (synergy scores greater than 10 are considered synergistic according to the website manufacturer). Western Blot analysis of combination therapy indicates an upregulation of γH2AX and ATR, indicating DNA damage likely plays a role in the synergistic effects of the drugs. Bcl-2 downregulation in combination therapy indicates that the Bcl-2 family proteins likely play a role in the apoptosis of the cancer cells. Cytokine profiling analysis indicates an upregulation of the Fas apoptosis-inducing ligand under lurbinectedin and irinotecan monotherapy and combination therapy. VEGF and prolactin were downregulated in combination therapy. We further demonstrate that the triple combination between lurbinectedin, irinotecan, and 5-Fluorouracil (5-FU) enhances % inhibition as each drug concentration increases, and the presence of lurbinectedin enhances the synergism between irinotecan and 5-FU. Our results are developing insights regarding molecular mechanisms underlying therapeutic efficacy of a novel combination drug treatment for pancreatic cancer. Citation Format: Tej Tummala, Arielle De La Cruz, Ash Uruchurtu, Nicholas R. Liguori, Abbas E. Abbas, Leiqing Zhang, Chistopher G. Azzoli, Lanlan Zhou, Wafik S. El-Deiry. Preclinical synergistic combination therapy of lurbinectedin with irinotecan and 5-fluorouracil in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C088.

A thermosensitive hydrogel formulation of phage and colistin combination for the management of multidrug-resistant Acinetobacter baumannii wound infections.

Chronic skin wounds are often associated with multidrug-resistant bacteria, impeding the healing process. Bacteriophage (phage) therapy has been revitalized as a promising strategy to counter the growing concerns of antibiotic resistance. However, phage monotherapy also faces several application drawbacks, such as a narrow host spectrum, the advent of resistant phenotypes and poor stability of phage preparations. Phage-antibiotic synergistic (PAS) combination therapy has recently been suggested as a possible approach to overcome these shortcomings. In the present study, we employed a model PAS combination containing a vB_AbaM-IME-AB2 phage and colistin to develop stable wound dressings of PAS to mitigate infections associated with Acinetobacter baumannii. A set of thermosensitive hydrogels were synthesized with varying amounts of Pluronic® F-127 (PF-127 at 15, 17.5 and 20 w/w%) modified with/without 3 w/w% hydroxypropyl methylcellulose (HPMC). Most hydrogel formulations had a gelation temperature around skin temperature, suitable for topical application. The solidified gels were capable of releasing the encapsulated phage and colistin in a sustained manner to kill bacteria. The highest bactericidal effect was achieved with the formulation containing 17.5% PF-127 and 3% HPMC (F5), which effectively killed bacteria in both planktonic (by 5.66 log) and biofilm (by 3 log) states and inhibited bacterial regrowth. Good storage stability of F5 was also noted with negligible activity loss after 9 months of storage at 4 °C. The ex vivo antibacterial efficacy of the F5 hydrogel formulation was also investigated in a pork skin wound infection model, where it significantly reduced the bacterial burden by 4.65 log. These positive outcomes warrant its further development as a topical PAS-wound dressing.

Overcoming the limitations of immunotherapy in pancreatic ductal adenocarcinoma: Combining radiotherapy and metabolic targeting therapy.

As a novel anticancer therapy, immunotherapy has demonstrated robust efficacy against a few solid tumors but poor efficacy against pancreatic ductal adenocarcinoma (PDAC). This poor outcome is primarily attributable to the intrinsic cancer cell resistance and T-cell exhaustion, which is also the reason for the failure of conventional therapy. The present review summarizes the current PDAC immunotherapy avenues and the underlying resistance mechanisms. Then, the review discusses synergistic combination therapies, such as radiotherapy (RT) and metabolic targeting. Research suggests that RT boosts the antigen of PDAC, which facilitates the anti-tumor immune cell infiltration and exerts function. Metabolic reprogramming contributes to restoring the exhausted T cell function. The current review will help in tailoring combination regimens to enhance the efficacy of immunotherapy. In addition, it will help provide new approaches to address the limitations of the immunosuppressive tumor microenvironment (TME) by examining the relationship among immunotherapy, RT, and metabolism targeting therapy in PDAC.

Study on pathologic mechanism and treatment of hypertension

Hypertension is a cardinal contributor to the global burden of disease due to its widespread prevalence and its insidious ability to instigate life-threatening complications such as stroke, cardiac failure, and renal injury disorders. This discourse reviewed the key drivers of hypertension pathogenesis, emphasizing the role of the renal system, particularly the interplay of angiotensin II and renal impairment. Moreover, hypertension's complex and multivalent management strategies were overviewed, illustrating the salience of lifestyle modifications, a panoply of pharmacological interventions, synergistic combination therapies, and the innovative approach of personalized medicine. Nevertheless, challenges such as medication adherence and balancing side effects remain, alongside the requirement for persistent medical oversight reflective of hypertension’s chronic nature. As lethal complications ink the finality of hypertension’s narrative, prompt identification and treatment are paramount. This comprehensive account concludes with an urge to further dissect this intricate condition and refine management strategies, propelling us towards a future with more efficacious hypertension control and diminished complication rates.

On-Demand Sequential Release of Dual Drug from pH-Responsive Electrospun Janus Nanofiber Membranes toward Wound Healing and Infection Control.

Drugs against bacteria and abnormal cells, such as antibiotics and anticancer drugs, may save human lives. However, drug resistance is becoming more common in the clinical world. Nowadays, a synergistic action of multiple bioactive compounds and their combination with smart nanoplatforms has been considered an alternative therapeutic strategy to fight drug resistance in multidrug-resistant cancers and microorganisms. The present study reports a one-step fabrication of innovative pH-responsive Janus nanofibers loaded with two active compounds, each in separate polymer compartments for synergistic combination therapy. By dissolving one of the compartments from the nanofibers, we could clearly demonstrate a highly yielded anisotropic Janus structure with two faces by scanning electron microscopy (SEM) analysis. To better understand the distinctive attributes of Janus nanofibers, several analytical methods, such as X-ray diffraction (XRD), FTIR spectroscopy, and contact angle goniometry, were utilized to examine and compare them to those of monolithic nanofibers. Furthermore, a drug release test was conducted in pH 7.4 and 6.0 media since the properties of Janus nanofibers correlate significantly with different environmental pH levels. This resulted in the on-demand sequential codelivery of octenidine (OCT) and curcumin (CUR) to the corresponding pH stimulus. Accordingly, the antibacterial properties of Janus fibers against Escherichia coli and Staphylococcus aureus, tested in a suspension test, were pH-dependent, i.e., greater in pH 6 due to the synergistic action of two active compounds, and Eudragit E100 (EE), and highly satisfactory. The biocompatibility of the Janus fibers was confirmed in selected tests.

Research Progress on the Synergistic Anti-Tumor Effect of Natural Anti-Tumor Components of Chinese Herbal Medicine Combined with Chemotherapy Drugs.

The application of chemotherapy drugs in tumor treatment has a long history, but the lack of selectivity of drugs often leads to serious side effects during chemotherapy. The natural anti-tumor ingredients derived from Chinese herbal medicine are attracting increased attention due to their diverse anti-tumor effects, abundant resources, and minimal side effects. An effective anti-tumor strategy may lie in the combination of these naturally derived anti-tumor ingredients with conventional chemotherapy drugs. This approach could potentially inhibit tumor growth and the development of drug resistance in tumor cells while reducing the adverse effects of chemotherapy drugs. This review provides a comprehensive overview of the combined therapy strategies integrating natural anti-tumor components from Chinese herbal medicine with chemotherapy drugs in current research. We primarily summarize various compounds in Chinese herbal medicine exhibiting natural anti-tumor activities and the relevant mechanisms in synergistic anti-tumor combination therapy. The focus of this paper is on underlining that this integrative approach, combining natural anti-tumor components of Chinese herbal medicine with chemotherapy drugs, presents a novel cancer treatment methodology, thereby providing new insights for future oncological research.

An interpretable artificial intelligence framework for designing synthetic lethality-based anti-cancer combination therapies

IntroductionSynthetic lethality (SL) provides an opportunity to leverage different genetic interactions when designing synergistic combination therapies. To further explore SL-based combination therapies for cancer treatment, it is important to identify and mechanistically characterize more SL interactions. Artificial intelligence (AI) methods have recently been proposed for SL prediction, but the results of these models are often not interpretable such that deriving the underlying mechanism can be challenging. ObjectivesThis study aims to develop an interpretable AI framework for SL prediction and subsequently utilize it to design SL-based synergistic combination therapies. MethodsWe propose a knowledge and data dual-driven AI framework for SL prediction (KDDSL). Specifically, we use gene knowledge related to the SL mechanism to guide the construction of the model and develop a method to identify the most relevant gene knowledge for the predicted results. ResultsExperimental and literature-based validation confirmed a good balance between predictive and interpretable ability when using KDDSL. Moreover, we demonstrated that KDDSL could help to discover promising drug combinations and clarify associated biological processes, such as the combination of MDM2 and CDK9 inhibitors, which exhibited significant anti-cancer effects in vitro and in vivo.ConclusionThese data underscore the potential of KDDSL to guide SL-based combination therapy design. There is a need for biomedicine-focused AI strategies to combine rational biological knowledge with developed models.

Abstract B026: Preclinical synergistic combination therapy of lurbinectedin with irinotecan and 5-fluorouracil in pancreatic cancer

Abstract Pancreatic cancer is a devastating disease with an overall five-year survival rate of ~12% according to the American Cancer Society. Novel chemotherapeutics and targeted therapies in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin (PM01183; LY-01017) received accelerated FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. Lurbinectedin is a chemotherapeutic synthetic tetrahydroisoquinoline alkaloid that inhibits active transcription by binding to guanine rich sequences in the minor groove of DNA. Lurbinectedin has been shown to reduce oncogenic transcription by stalling and degrading RNA Polymerase II and inducing breaks in DNA, causing subsequent apoptosis. We now demonstrate lurbinectedin’s highly efficient killing of pancreatic tumor cells as a single agent in PANC-1, BxPC-3, and HPAF-II cell lines, with 72-hour IC-50s ranging from 0.266 – 0.964 nM. We further demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in synergistic killing of pancreatic tumor cells in vitro. Synergism was calculated using SynergyFinder, with HSA scores exceeding 15 in every cell line (synergy scores greater than 10 are considered synergistic according to the website manufacturer). Western Blot analysis of combination therapy indicates an upregulation of γH2AX and ATR, indicating DNA damage likely plays a role in the synergistic effects of the drugs. Bcl-2 downregulation in combination therapy indicates that the Bcl-2 family proteins likely play a role in the apoptosis of the cancer cells. Cytokine profiling analysis indicates an upregulation of the Fas apoptosis-inducing ligand under lurbinectedin and irinotecan monotherapy and combination therapy. VEGF and prolactin were downregulated in combination therapy. We further demonstrate that the triple combination between lurbinectedin, irinotecan, and 5-Fluorouracil (5-FU) enhances % inhibition as each drug concentration increases, and the presence of lurbinectedin enhances the synergism between irinotecan and 5-FU. Our results are developing insights regarding molecular mechanisms underlying therapeutic efficacy of a novel combination drug treatment for pancreatic cancer. Citation Format: Tej Tummala, Arielle De La Cruz, Ash Uruchurtu, Nicholas R Liguori, Abbas E Abbas, Leiqing Zhang, Christopher Azzoli, Lanlan Zhou, Wafik S El-Deiry. Preclinical synergistic combination therapy of lurbinectedin with irinotecan and 5-fluorouracil in pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B026.

Macrophage-Based Microrobots for Anticancer Therapy: Recent Progress and Future Perspectives.

Macrophages, which are part of the mononuclear phagocytic system, possess sensory receptors that enable them to target cancer cells. In addition, they are able to engulf large amounts of particles through phagocytosis, suggesting a potential "Trojan horse" drug delivery approach to tumors by facilitating the engulfment of drug-hidden particles by macrophages. Recent research has focused on the development of macrophage-based microrobots for anticancer therapy, showing promising results and potential for clinical applications. In this review, we summarize the recent development of macrophage-based microrobot research for anticancer therapy. First, we discuss the types of macrophage cells used in the development of these microrobots, the common payloads they carry, and various targeting strategies utilized to guide the microrobots to cancer sites, such as biological, chemical, acoustic, and magnetic actuations. Subsequently, we analyze the applications of these microrobots in different cancer treatment modalities, including photothermal therapy, chemotherapy, immunotherapy, and various synergistic combination therapies. Finally, we present future outlooks for the development of macrophage-based microrobots.

Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer.

Pancreatic cancer is a devastating disease with a poor prognosis. Novel chemotherapeutics in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin (PM01183; LY-01017) received FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. Lurbinectedin stalls and degrades RNA Polymerase II and introduces breaks in DNA, causing subsequent apoptosis. We now demonstrate lurbinectedin's highly efficient killing of human-derived pancreatic tumor cell lines PANC-1, BxPC-3, and HPAF-II as a single agent. We further demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in the synergistic killing of pancreatic tumor cells. Western blot analysis of combination therapy indicates an upregulation of γH2AX, a DNA damage marker, and the Chk1/ATR pathway, which is involved in replicative stress and DNA damage response. We further demonstrate that the triple combination between lurbinectedin, irinotecan, and 5-fluorouracil (5-FU) results in a highly efficient killing of tumor cells. Our results are developing insights regarding molecular mechanisms underlying the therapeutic efficacy of a novel combination drug treatment for pancreatic cancer.

PH/ROS dual stimuli-responsive anionic flexible supramolecular organic frameworks for synergistic therapy

Supramolecular organic frameworks (SOFs) have emerged as a promising class of organic porous materials with vast potential as nanocarriers for combination therapy. Here, we successfully construct an anionic flexible supramolecular organic framework (TPP-SOF) by leveraging multiple host-guest interactions. TPP-SOF is fabricated by the hierarchical orthogonal assembly between anionic water-soluble dimacrocyclic host (P5CD), porphyrin photosensitizers (TPP), and ROS-sensitive thioketal linked adamantane dimer (Ada-S-Ada). TPP-SOF exhibits pH-dependent activation of 1O2 production, which further facilitates the cleavage of Ada-S-Ada linker and promotes the disintegration of the framework. Moreover, leveraging electrostatic and hydrophobic interactions, the anionic TPP-SOF serves as an effective platform for loading cationic photosensitizer IR780 and chemotherapeutic prodrug PhenPt(IV), leading to the formation of supramolecular nanoparticles (IR780/Pt@TPP-SOF) for synergistic therapy. The obtained nanoparticles exhibit good stability, efficient generation of 1O2, and photothermal performance. In vitro and in vivo studies indicate that IR780/Pt@TPP-SOF exhibits remarkable synergistic chemo/PDT/PTT effects under 808 and 660 nm light irradiation. This study showcases a deep insight for the development of SOFs and a new approach for delivering cationic drugs and constructing synergistic combination therapy systems. Statement of SignificanceIn this work, a pH/ROS-responsive anionic flexible supramolecular organic framework, TPP-SOF, was innovatively designed by the hierarchical orthogonal assembly, to co-deliver cationic photosensitizer IR780 and prodrug PhenPt(IV) for synergistic cancer therapy. The drug-loaded TPP-SOF is termed IR780/Pt@TPP-SOF, in which the photoactivity of porphyrin within TPP-SOF could be activated under acidic conditions, the 1O2 generated by the photosensitizers could break the thioketal bonds in Ada-S-Ada, leading to the disassembly of the framework and releasing the drugs. This supramolecular drug delivery system displays good biocompatibility and exhibits remarkable synergistic chemo/PDT/PTT effects.

Antibiotic Therapy Strategies for Treating Gram-Negative Severe Infections in the Critically Ill: A Narrative Review.

Not enough data exist to inform the optimal duration and type of antimicrobial therapy against GN infections in critically ill patients. Narrative review based on a literature search through PubMed and Cochrane using the following keywords: "multi-drug resistant (MDR)", "extensively drug resistant (XDR)", "pan-drug-resistant (PDR)", "difficult-to-treat (DTR) Gram-negative infection," "antibiotic duration therapy", "antibiotic combination therapy" "antibiotic monotherapy" "Gram-negative bacteremia", "Gram-negative pneumonia", and "Gram-negative intra-abdominal infection". Current literature data suggest adopting longer (≥10-14 days) courses of synergistic combination therapy due to the high global prevalence of ESBL-producing (45-50%), MDR (35%), XDR (15-20%), PDR (5.9-6.2%), and carbapenemases (CP)/metallo-β-lactamases (MBL)-producing (12.5-20%) Gram-negative (GN) microorganisms (i.e., Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumanii). On the other hand, shorter courses (≤5-7 days) of monotherapy should be limited to treating infections caused by GN with higher (≥3 antibiotic classes) antibiotic susceptibility. A general approach should be based on (i) third or further generation cephalosporins ± quinolones/aminoglycosides in the case of MDR-GN; (ii) carbapenems ± fosfomycin/aminoglycosides for extended-spectrum β-lactamases (ESBLs); and (iii) the association of old drugs with new expanded-spectrum β-lactamase inhibitors for XDR, PDR, and CP microorganisms. Therapeutic drug monitoring (TDM) in combination with minimum inhibitory concentration (MIC), bactericidal vs. bacteriostatic antibiotics, and the presence of resistance risk predictors (linked to patient, antibiotic, and microorganism) should represent variables affecting the antimicrobial strategies for treating GN infections. Despite the strategies of therapy described in the results, clinicians must remember that all treatment decisions are dynamic, requiring frequent reassessments depending on both the clinical and microbiological responses of the patient.

Contribution of different mechanisms to aminoglycoside resistance in clinical isolates of Acinetobacter baumannii

The antibiotics overuse for infection treatment was the sparkle in the spreading of multi-drug resistance Acinetobacter baumannii in hospitals. In our study, we evaluated the contribution of the aminoglycoside resistance mechanisms of A. baumannii to the resistance surge in some selected Egyptian hospitals with a checkerboard assay application to retrieve the aminoglycoside activity. The resistance profile analysis of collected 200 A. baumannii isolates revealed a multidrug-resistant pattern with limited susceptibilities to aminoglycosides. Analysis of the prevalence of aminoglycoside-modifying enzyme (AMEs) genes revealed the presence of the six AMEs genes either singly or in combination in selected isolates and aph (3)-VIa gene was the predominant one. At the same time, four efflux pump genes of AdeABC and AdeKJL family showed significant (P < 0.001) up-regulation levels. Moreover, the implementation of combination strategy showed fourteen synergistic activities against two high-level aminoglycoside-resistance (HLAR) A. baumannii isolates. The findings highlighted the alarming levels of aminoglycoside resistance in A. baumannii isolates, which proved that a common enzymatic modification mechanism acts synergistically with decreased antibiotic accumulation in acquiring aminoglycoside resistance. Additionally, the study provides useful information for the promising synergistic combination therapy that reduces the therapeutic dose of aminoglycosides used and subsequently increases their clinical application.

Biocompatible Polymer-Modified Nanoplatform for Ferroptosis-Enhanced Combination Cancer Therapy.

Ferroptosis is a novel type of iron-dependent non-apoptotic pathway that regulates cell death and shows unique mechanisms including causing lipid peroxide accumulation, sensitizing drug-resistant cancers, priming immunity by immunogenic cell death, and cooperatively acting with other anticancer modalities for eradicating aggressive malignancies and tumor relapse. Recently, there has been a great deal of effort to design and develop anticancer biocompatible polymeric nanoplatforms including polypeptide and PEGylated ones to achieve effective ferroptosis therapy (FT) and synergistic combination therapies including chemotherapy (CT), photodynamic therapy (PDT), sonodynamic therapy (SDT), photothermal therapy (PTT), gas therapy (GT) including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2 S), and immunotherapy (IT). To be noted, the combo therapies such as FT-CT, FT-PTT, FT-GT, and FT-IT are attracting much efforts to fight against intractable and metastatic tumors as they can generate synergistic antitumor effects and immunogenic cell death (ICD) effects or modulate immunosuppressive tumor microenvironments to initiate strong antitumor immunity and memory effects. Meanwhile, the polymeric Fenton nano-agents with good biosafety and high anticancer efficacy would provide a guarantee for their further clinical transitions. In this review, various biocompatible polymer-modified nanoplatforms designed for FT and combo treatments are summarized for anticancer therapies and discussed for potential clinical transitions. This article is protected by copyright. All rights reserved.