Payload Release Research Articles

Action Programmed Nanoantibiotics with pH-Induced Collapse and Negative-Charged-Surface-Induced Deformation against Antibiotic-Resistant Bacterial Peritonitis.

The incorporation of well-designed antibiotic nanocarriers, along with an antibiotic adjuvant effect, in combination with various antibiotics, offers an opportunity to combat drug-resistant strains. However, precise control over morphology and encapsulated payload release can significantly impact their antibacterial efficacy and synergistic effects when used alongside antibiotics. Here, this study focuses on developing lipopeptide-based nanoantibiotics, which demonstrate an antibiotic adjuvant effect by inducing pH-induced collapse and negative-charged-surface-induced deformation. This enhances the disruption of the bacterial outer membrane and facilitates drug penetration, effectively boosting the antimicrobial activity against drug-resistant strains. The modulation regulations of the lipopeptide nanocarriers with modular design are governed by the authors. The nanoantibiotics, made from lipopeptide and ciprofloxacin (Cip), have a drug loading efficiency of over 80%. The combination with Cip results in a significantly low fractional inhibitory concentration index of 0.375 and a remarkable reduction in the minimum inhibitory concentration of Cip against multidrug-resistant (MDR) Escherichia coli (clinical isolated strains) by up to 32-fold. The survival rate of MDR E. coli peritonitis treated with nanoantibiotics is significantly higher, reaching over 87%, compared to only 25% for Cip and no survival for the control group. Meanwhile, the nanoantibiotic shows no obvious toxicity to major organs.

Update of antibody-drug conjugates for hematological malignancies.

Antibody-drug conjugates (ADCs), consisting of monoclonal antibodies (mAbs) covalently linked to cytotoxic drugs via chemical linkers, are a kind of promising tumor immunotherapy. ADCs also face a number of challenges, including unavoidable adverse effects, drug resistance, tumor targeting and payload release. To address these issues, in addition to optimizing the individual components of ADCs, such as new payloads, linkage sites and new targets, and using bispecific antibodies to increase precision, attention should be paid to optimizing the dosage of ADCs. There are currently 7 ADCs approved for marketing by the Food and Drug Administration (FDA) for hematological malignancies, and dozens of other ADCs are either in clinical trials or in the process of applying for marketing. In recent clinical studies targeting ADCs in hematologic malignancies, in addition to validating effectiveness in different indications, researchers have attempted to combine ADCs with other chemotherapeutic agents in anticipation of increased therapeutic efficacy. Furthermore, the availability of bispecific antibodies may increase the safety and efficacy of ADCs. This review summarized the progress of research on ADCs in hematological malignancies, the challenges being faced, and possible future directions to improve the efficacy of ADCs, which can provide novel insight into the future exploration of ADCs in the treatment of hematological malignancies.

Feature-Enhanced Artificial Neutrophils for Dual-Modal MR/NIR Imaging-Guided Cancer Therapy

Neutrophils release neutrophil elastase (ELANE) to kill a wide range of cancer cells through proteolytically liberating the CD95 death domain (DD) and initiating apoptotic pathway in cancer cells. However, current neutrophil-inspired strategies are restricted to single reactive oxygen species (ROS)-based killing and rarely involve coordinated multi-path tumor killing. Herein, we develop feature-enhanced artificial neutrophils (aNeu) to improve tumor therapy via dual-modal MR/NIR imaging-guided combined actions of cytotoxic porcine pancreatic elastase (PPE), ROS and the triggered protective immunity. We construct aNeu by loading PPE and NIR-responsive IR780 into glutathione-unlocked hollow MnO2 nanoparticles and then coating with neutrophil membrane. After stimulation-responsive activation inside tumor cells, the as-prepared aNeu can exhibit robust tumor killing effect and elicit adaptive immune response to promote tumor elimination. Moreover, MR/NIR imaging enable aNeu to monitor payload release and to anticipate therapeutic outcome. This feature-enhanced aNeu offers a new paradigm for neutrophil-inspired tumor therapy.

Fibrin Hydrogels Reinforced by Reactive Microgels for Stimulus-Triggered Drug Administration.

Tissue engineering is a steadily growing field of research due to its wide-ranging applicability in the field of regenerative medicine. Application-dependent mechanical properties of a scaffold material as well as its biocompatibility and tailored functionality represent particular challenges. Here the properties of fibrin-based hydrogels reinforced by functional cytocompatible poly(N-vinylcaprolactam)-based (PVCL) microgels are studied and evaluated. The employment of temperature-responsive microgels decorated by epoxy groups for covalent binding to the fibrin is studied as a function of cross-linking degree within the microgels, microgel concentration, as well as temperature. Rheology reveals a strong correlation between the mechanical properties of the reinforced fibrin-based hydrogels and the microgel rigidity and concentration. The incorporated microgels serve as cross-links, which enable temperature-responsive behavior of the hydrogels, and slow down the hydrogel degradation. Microgels can be additionally used as carriers for active drugs, as demonstrated for dexamethasone. The microgels' temperature-responsiveness allows for triggered release of payload, which is monitored using a bioassay. The cytocompatibility of the microgel-reinforced fibrin-based hydrogels is demonstrated by LIVE/DEAD staining experiments using human mesenchymal stem cells. The microgel-reinforced hydrogels are a promising material for tissue engineering, owing to their superior mechanical performance and stability, possibility of drug release, and retained biocompatibility.

Quantitative Factors Introduced in the Feasibility Analysis of Reactive Oxygen Species (ROS)‐Sensitive Triggers

AbstractReactive oxygen species (ROS) are critical for cellular signaling. Various pathophysiological conditions are also associated with elevated levels of ROS. Hence, ROS‐sensitive triggers have been extensively used for selective payload delivery. Such applications are predicated on two key functions: (1) a sufficient magnitude of concentration difference for the interested ROS between normal tissue/cells and intended sites and (2) appropriate reaction kinetics to ensure a sufficient level of selectivity for payload release. Further, ROS refers to a group of species with varying reactivity, which should not be viewed as a uniform group. In this review, we critically analyze data on the concentrations of different ROS species under various pathophysiological conditions and examine how reaction kinetics affect the success of ROS‐sensitive linker chemistry. Further, we discuss different ROS linker chemistry in the context of their applications in drug delivery and imaging. This review brings new insights into research in ROS‐triggered delivery, highlights factors to consider in maximizing the chance for success and discusses pitfalls to avoid.

Quantitative Factors Introduced in the Feasibility Analysis of Reactive Oxygen Species (ROS)-Sensitive Triggers.

Reactive oxygen species (ROS) are critical for cellular signaling. Various pathophysiological conditions are also associated with elevated levels of ROS. Hence, ROS-sensitive triggers have been extensively used for selective payload delivery. Such applications are predicated on two key functions: (1) a sufficient magnitude of concentration difference for the interested ROS between normal tissue/cells and intended sites and (2) appropriate reaction kinetics to ensure a sufficient level of selectivity for payload release. Further, ROS refers to a group of species with varying reactivity, which should not be viewed as a uniform group. In this review, we critically analyze data on the concentrations of different ROS species under various pathophysiological conditions and examine how reaction kinetics affect the success of ROS-sensitive linker chemistry. Further, we discuss different ROS linker chemistry in the context of their applications in drug delivery and imaging. This review brings new insights into research in ROS-triggered delivery, highlights factors to consider in maximizing the chance for success and discusses pitfalls to avoid.

An open-label phase 1 study to investigate SGNCEACAM5C/SAR445953 in adults with advanced solid tumors (SGNCEA5C-001).

TPS3160 Background: Patients (pts) with recurrent or metastatic solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), gastric adenocarcinoma (GC), and pancreatic ductal adenocarcinoma (PDAC), have limited treatment options with short PFS and OS despite recent advances (1-3). Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is highly expressed across multiple solid tumors, such as CRC, GC, PDAC, and NSCLC. Restricted normal tissue expression and efficient lysosomal trafficking of CEACAM5 highlight its potential as an anticancer target. SGN-CEACAM5C is a novel investigational antibody-drug conjugate (ADC) directed to CEACAM5 composed of the humanized immunoglobulin G (IgG1) anti-CEACAM5 monoclonal antibody tusamitamab chemically conjugated to 8 molecules of the topoisomerase 1 inhibitor 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT). SGN-CEACAM5C selectively binds to CEACAM5 present on the cell surface and is internalized via the endo-lysosomal pathway, with subsequent release of the payload through enzymatic cleavage. Release of the cytotoxic payload induces DNA damage, cell cycle arrest in S phase, and apoptosis in tumor cells. In vitro bystander activity was observed against tumor cells without CEACAM5 surface expression. SGN-CEACAM5C is highly active in multiple patient-derived xenograft models, including CRC, GC, and NSCLC, across various levels of CEACAM5 expression (4,5). These preclinical findings justify evaluation of SGN-CEACAM5C in a clinical trial setting. Methods: SGNCEA5C-001 (NCT06131840) is a phase 1, open-label, multicenter study designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of SGN-CEACAM5C in adults with select advanced solid tumors. This study consists of dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion (Part C). Eligible pts are adults ≥18 years of age with confirmed metastatic or unresectable solid tumor malignancy, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, an ECOG PS of 0-1, and 1 of the following tumor types: CRC, GC/gastroesophageal junction adenocarcinoma (GEJ), PDAC, NSCLC (squamous/non-squamous), or SCLC. Primary endpoints include incidence of AEs, laboratory abnormalities, dose modifications due to AEs, dose-limiting toxicities, and cumulative safety. Secondary endpoints include estimates of PK parameters, incidence of antidrug antibodies, objective response rate and best response per RECIST v1.1 by investigator, duration of response, PFS, and OS. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Recruitment is ongoing for Part A in North America. 1. Bordry 2021. 2. Chakrabarti 2022. 3. Merle 2022. 4. Baudat 2023. 5. Baudat 2024. Clinical trial information: NCT06131840 .

Breaking from the paradigm of antibody-drug conjugates: Evaluation of clinical pharmacokinetics and safety of bicycle toxin conjugates (BTCs).

3088 Background: Bicycle toxin conjugates (BTCs) are chemically synthesized molecules comprising a small (~4.5 kDa) bicyclic peptide linked to a cytotoxin. BT8009 and BT5528 are BTCs linked to monomethyl auristatin E (MMAE) targeting nectin-4 and EphA2, respectively, and have shown preliminary activity. BTCs are a unique therapeutic class of small size, with corresponding pharmacokinetic (PK) properties distinct from antibody-drug conjugates (ADCs). MMAE-containing ADCs demonstrate anti-tumor efficacy but substantial safety issues attributable to the slow clearance of ADCs, which increases uptake into off-target tissues and exposure to plasma proteases (ie, payload release).To evaluate BTC PK and safety relative to ADCs, we present results of the ongoing Phase I/II trials for BT8009 (NCT04561362) and BT5528 (NCT04180371). Methods: Patients with advanced solid tumors receiving IV BT8009 (n=147) or BT5528 (n=109) monotherapy were evaluated. Doses were given as 2.5–10 mg/m2 weekly (QW), every 2 weeks (Q2W), or 2 weeks on/1 week off for BT8009 and 2.2–10 mg/m2 QW or Q2W for BT5528. Population PK (PPK) models for BT8009 and BT5528 were developed. PK exposures (Cycle 1 area under the concentration curve [AUC]) for BTCs, conjugated MMAE, and unconjugated MMAE were simulated for 5 mg/m2 QW BT8009 and BT5528 and compared with those of an MMAE-containing ADC (approved regimen, using the PPK model in the literature). Treatment-related adverse events (TRAEs) were tabulated for BT8009 and BT5528. Results: BTCparent drugs were rapidly eliminated (half-life [t1/2] <1 hour) while unconjugated MMAE exhibited persistent exposures and gradual elimination (MMAE t1/2, 1.9 days [D] for both BT8009 and BT5528), in contrast with the ADC (parent drug t1/2, 3.6 D; MMAE t1/2, 2.6 D). Conjugated MMAE exposures for the ADC were higher than for BT8009 and BT5528 (75- and 73-fold, respectively). Unconjugated MMAE exposures for BT8009 and BT5528 were comparable to the ADC (25% and 8% higher, respectively). Among the BTC regimens most thoroughly evaluated (BT8009 5 mg/m2 QW and BT5528 6.5 mg/m2 Q2W), TRAEs of interest occurred with low frequency and severity (Table). Conclusions: Preliminary data show substantial differences between BTC and ADC PK, and a promising BTC safety profile, possibly resulting from the distinct PK and selectivity (and specificity) of Bicycle peptides. These data highlight the potential value of BTCs as a platform for developing therapies against advanced malignancies. Clinical trial information: NCT04561362 and NCT04180371 . [Table: see text]

A phase 1 dose-escalation and expansion study of an intratumorally administered dual STING agonist (ONM-501) alone and in combination with cemiplimab in patients with advanced solid tumors and lymphomas.

TPS2693 Background: The Stimulator of Interferon Genes (STING) pathway has garnered significant interest as a target for anticancer interventions due to its role in driving the production of pro-inflammatory cytokines and activating tumor-specific cell killing. Cyclic dinucleotides (CDNs) such as cGAMP, the endogenous STING agonist, are not ideal clinical candidates for exogenous routes of delivery. Early trials showed limited efficacy with CDNs due to rapid clearance, degradation and/or off-target toxicity. ONM-501 is comprised of a STING-activating pH-sensitive PC7A polymer conjugated with cGAMP. At physiologic pH, ONM-501 forms a micelle, preventing degradation of cGAMP. In the acidic tumor microenvironment, ONM-501 effects STING agonism through a multi-faceted mode of action: 1) endocytosis of nanoparticles and pH-activated micelle dissociation and payload release in endolysosomes enhances intracellular delivery of cGAMP 2) the combination of cGAMP canonical binding, and PC7A polymer noncanonical binding on STING yields synergistic STING activation and 3) stabilization of STING by PC7A polymers delays its degradation and prolongs STING activation. In pre-clinical models, these factors combine to help generate a stronger and more prolonged innate immune response that more effectively translates to a robust adaptive immune response. ONM-501 is being investigated in this first-in-human Phase 1 trial as monotherapy and combination therapy with the anti-PD1 antibody, cemiplimab, for patients with solid tumors and lymphomas. Methods: ONM5001 (NCT06022029) is a first-in-human, open-label, multi-center clinical trial. Adult patients with solid tumors or lymphomas for which no standard therapy exists or for which patients decline palliative standard therapy who have at least one injectable lesion are eligible for this study. This Phase 1 study consists of three parts: monotherapy dose escalation; combination therapy dose finding; and combination therapy dose expansion in specific tumor indication(s) that will be selected based on data from mono- and combination therapy dose finding. Each dosing cycle of ONM-501 is 21 days: patients receive an intratumoral injection of ONM-501 weekly for three weeks, followed by three weeks without injection. Cemiplimab is administered intravenously during combination therapy arms according to standard administration protocol, once every three weeks. The primary endpoint is to evaluate safety of ONM-501 monotherapy as evidenced by the number of dose limiting toxicities and treatment-emergent adverse events, and to determine the recommended dose for expansion. Secondary endpoints include characterization of pharmacokinetics and pharmacodynamics, as well as initial efficacy based on RECIST evaluation criteria. Enrollment began in November 2023. Clinical trial information: NCT06022029 .

Synthetic Condensates and Cell-Like Architectures from Amphiphilic DNA Nanostructures.

Synthetic droplets and condensates are becoming increasingly common constituents of advanced biomimetic systems and synthetic cells, where they can be used to establish compartmentalization and sustain life-like responses. Synthetic DNA nanostructures have demonstrated significant potential as condensate-forming building blocks owing to their programmable shape, chemical functionalization, and self-assembly behavior. We have recently demonstrated that amphiphilic DNA "nanostars", obtained by labeling DNA junctions with hydrophobic moieties, constitute a particularly robust and versatile solution. The resulting amphiphilic DNA condensates can be programmed to display complex, multi-compartment internal architectures, structurally respond to various external stimuli, synthesize macromolecules, capture and release payloads, undergo morphological transformations, and interact with live cells. Here, we demonstrate protocols for preparing amphiphilic DNA condensates starting from constituent DNA oligonucleotides. We will address (i) single-component systems forming uniform condensates, (ii) two-component systems forming core-shell condensates, and (iii) systems in which the condensates are modified to support in vitro transcription of RNA nanostructures.

Stimuli-responsive azo-functionalized non-ionic amphiphiles for controlled drug delivery applications

A series of stimuli-responsive non-ionic amphiphiles have been synthesized consisting of n-alkyl/fluoroalkyl chain to impart lipophilicity, and lactose/polyethylene glycol units which confers hydrophilicity. To execute the release of encapsulated guest in a controlled manner, the azo and ester functionalities were incorporated in the synthesized amphiphiles. The ability of the azo unit to undergo trans–cis-trans spatiotemporal isomerization under UV irradiation with subsequent release of the encapsulated guest has been studied in the aqueous solution of amphiphiles at 365 and 254 nm. Furthermore, an immobilized enzyme Candida antarctica lipase (Novozym 435), a hydrolase, was observed to facilitate the cleavage of the ester moiety of the synthesized amphiphiles resulting in the gradual collapse of the nano-aggregates and subsequent release of encapsulated guest. The aggregation and guest encapsulation behaviour of synthesized azo-functionalized amphiphiles were studied by dynamic light scattering (DLS), critical micelle concentration (CMC), and transmission electron microscopy, fluorescence and UV–Vis spectroscopy. Entrapment of hydrophobic drug/dye i.e. curcumin/Nile red in the lipophilic core, their cellular uptake, and consequently the stimuli responsive release of payload demonstrated the potential of these nanostructures in controlled drug delivery applications.

A novel quadrotor carrying payload concept via PID with Feedforward terms

PurposeThis paper introduces control strategy to enhance the performance of a novel quadrotor unmanned aerial vehicle designed for medical payload delivery. The aim is to achieve precise control and stability when carrying and releasing payloads, which alter the quadrotor’s mass and inertia characteristics.Design/methodology/approachThe equations of motion specific to the payload-carrying quadrotor are derived. A feedforward-proportional-integral-derivative (FF-PID) control strategy is then proposed to address the dynamic changes during payload release. The PID components use propeller speed/orientation information for stability. FF terms based on derivatives of desired position/orientation variables enable adaptation to real-time mass fluctuations.FindingsExtensive simulations, encompassing various fault scenarios, substantiate the effectiveness of the FF-PID approach. Notably, our findings demonstrate superior performance in maintaining altitude precision and stability during critical phases such as takeoff, payload release and landing. Graphical representations of thrust and mass dynamics distinctly illustrate the payload release event. In contrast to the linear quadratic regulator (LQR) and conventional PID control, which encountered difficulties during the payload release process, our approach proves its robustness and reliability.Research limitations/implicationsThis study, primarily based on simulations, demands validation through real-world testing in diverse conditions. Uncertainties in dynamic parameters, external factors and the applicability of the proposed approach to other quadrotor configurations require further investigation. Additionally, this research focuses on controlled payload release, leaving unexplored the challenges posed by unforeseen scenarios or disturbances. Hence, adaptability and fault tolerance necessitate further exploration. While our work presents a promising approach, practical implementation, adaptability and resilience to unexpected events are vital considerations for future research in the field of autonomous aerial medical deliveries.Practical implicationsThe proposed control strategy promises enhanced efficiency, reliability and adaptability for autonomous aerial medical deliveries in critical scenarios.Social implicationsThe innovative control strategy introduced in this study holds the potential to significantly impact society by enhancing the reliability and adaptability of autonomous aerial medical deliveries. This could lead to faster and more efficient delivery of life-saving supplies to remote or disaster-affected areas, ultimately saving lives and reducing suffering. Moreover, the technology’s adaptability may have broader applications in fields like disaster relief, search and rescue missions, and industrial cargo transport. However, its successful integration into society will require careful regulation, privacy safeguards and ethical considerations to ensure responsible and safe deployment while addressing potential concerns related to noise pollution and privacy intrusion.Originality/valueWhile PID control of quadrotors is extensively studied, payload release dynamics have been overlooked. This research studies integration of FF control to enable PID adaptation for a novel payload delivery application.

Abstract PO4-14-12: Predicting Response to HER2 Tyrosine Kinase Inhibitors and Antibody Drug Conjugates in HER2 Mutant Invasive Lobular Carcinoma Using CRISPR/Cas9 Knock-in Cell lines and Patient-derived Organoids

Abstract Background: Activating mutations in ERBB2 (HER2) are enriched >4-fold in invasive lobular carcinoma (ILC) with a rate of up to 19% in metastatic ILC. ILC is a histologic subtype of breast cancer characterized by loss of E-cadherin (CDH1), suggesting a potential interaction between loss of CDH1 and mutations in ERBB2. Recent trials have demonstrated promising single agent efficacy using the irreversible pan-HER tyrosine kinase inhibitor (TKI), neratinib, in patients with metastatic ERBB2 mutant ILC. However, further studies on combination therapies with other anticancer agents are needed to increase response rate and progression free survival for these patients. HER2-targeted antibody drug conjugates (ADC), particularly trastuzumab deruxtecan (T-DXd), have shown great promise in HER2-low metastatic breast cancer. Yet, their efficacy as a single agent or with HER2 TKIs in HER2-low and -mutant ILC is unknown and warrants investigation. Methods: Past studies analyzing ERBB2 mutations used overexpression of ERBB2 mutant cDNA, but this approach does not faithfully recapitulate the human disease. To model ERBB2 missense mutations as found in human breast cancers, we used CRISPR-based prime editing to generate a panel of isogenic ILC cell lines and patient-derived organoids (PDO) harboring ERBB2 wild-type (WT) or ERBB2 mutations (S310F or V777L). Both of these ERBB2 mutations have been previously characterized and are known to be activating mutations. We then used them to test neratinib and other TKIs with ADCs, including T-DXd and trastuzumab emtansine (T-DM1). Results: We successfully introduced single copy, heterozygous activating ERBB2 mutations (S310F or V777L) into two ERBB2-nonamplified metastatic ILC cell lines (MDA-MB-134 and SUM44PE) and one ERBB2-nonamplified metastatic ILC PDO (IPM-BO-053). Positive clones carrying the mutations were verified by Sanger sequencing and droplet digital PCR and subsequently pooled together. We further demonstrated that these mutations hyperactivated HER2 and downstream signaling pathways. ILC cell lines harboring these mutations showed enhanced sensitivity to HER2 TKIs but not ADCs. In contrary, ERBB2 mutations did not alter responses of IPM-BO-053 PDOs to HER2 TKIs but significantly increased responses to ADCs. Interestingly, we also observed accelerated HER2 protein degradation upon heregulin stimulation in ERBB2 mutant ILC PDOs, suggesting activating ERBB2 mutations may enhance ADC/HER2 complex internalization, degradation, and release of payloads. Lastly, we explored drug synergy between HER2 TKIs and ADCs in isogenic IPM-BO-053 PDOs and found that combination of T-DXd and neratinib or afatinib showed synergy (Combination Index < 1). Conclusions: Although the reason for the discrepancies in drug response between ILC cell lines and PDOs is not clear, we hypothesize that response in 3D PDOs might be more faithfully representing response seen in patients. We will generate additional ILC PDOs with knock-in ERBB2 mutations to validate our findings. Irreversible HER2 TKIs, such as neratinib and afatinib, showed synergy with T-DXd in ERBB2 mutant ILC PDOs. This holds important therapeutic implications in light of current treatment options for ILC. In future experiments, we will test if neratinib or afatinib increases endocytic uptake of T-DXd using a fluorescently labeled endocytosis tracker. Further, an in-depth molecular characterization of our isogenic cell lines and PDOs models is ongoing to gain mechanistic insights into how activating ERBB2 mutations increase HER2 internalization and degradation. Our in vitro studies provide a strong foundation for in vivo testing of neratinib or afatinib with T-DXd for ERBB2 mutant ILC. Citation Format: Jie Bin Liu, Danielle Tseng, Jagmohan Hooda, Daniel Brown, Adrian Lee, Steffi Oesterreich. Predicting Response to HER2 Tyrosine Kinase Inhibitors and Antibody Drug Conjugates in HER2 Mutant Invasive Lobular Carcinoma Using CRISPR/Cas9 Knock-in Cell lines and Patient-derived Organoids [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 PO4-14-12.

Near-infrared light activated rapidly separable polymeric microneedles for transdermal biologics delivery

Polymeric microneedles (PMNs) are an attractive transdermal drug delivery approach with minimal invasiveness and improved patient compliance. However, it is uncomfortable and inconvenient for patients to wear a PMN patch for hours or days until complete payload release. Here, we report a facile strategy to fabricate rapidly separable PMN arrays activated by near-infrared (NIR) light (NIR-RS-PMN) with enhanced mechanical strength through introduction of a photothermal-sensitive spacer integrating plasmonic gold nanorods into a biocompatible sodium hyaluronate matrix. Under NIR irradiation, the NIR-RS-PMN achieved rapid separation of the patch backing and microneedles within 1 min. The loaded bioactive therapeutics, e.g., insulin and RNA, were well-preserved during fabrication, NIR irradiation, and 20-day storage at room temperature. The NIR-RS-PMN was well tolerated by rats without skin irritation. Its feasibility for biologics delivery was further established by the treatment of diabetic rats with insulin encapsulated PMNs. The innovative PMNs increase ease of use and achieve effective and precise payload delivery, which may increase access to biopharmaceuticals and vaccines in remote and resource-limited communities.

Emerging Bio‐relevant Applications of Polymer Mechanochemistry

AbstractPolymer mechanochemistry has rapidly evolved since the mid‐2000s. Recent advancements highlight the development of mechanophore platforms for the controlled release of bioactive payloads and the exploration of biocompatible activation strategies. These platforms, ranging from furan‐maleimide Diels‐Alder adducts to disulfide motifs with β‐carbonate linkages, demonstrate promising prospects in targeted drug delivery. Additionally, supramolecular assemblies and free radical‐generating mechanophores present innovative avenues for potential therapeutic applications. Biocompatible activation methods, notably high‐intensity and/or low‐intensity focused ultrasound, hold potential for in vivo applications. However, challenges persist in comprehending the fundamental physics of ultrasound and its utilization for activation. Future directions emphasize the importance of simplicity in biocompatible platforms and polymer designs, stability under physiological conditions, and precise control of mechanical activation for enhanced biomedical and clinical utility. Despite the aforementioned chemical and technical obstacles, the outlook for polymer mechanochemistry in biomedical and clinical applications remains promising, urging continued exploration and advancement. Key Scientists

Designer peptide–DNA cytoskeletons regulate the function of synthetic cells

The bottom-up engineering of artificial cells requires a reconfigurable cytoskeleton that can organize at distinct locations and dynamically modulate its structural and mechanical properties. Here, inspired by the vast array of actin-binding proteins and their ability to reversibly crosslink or bundle filaments, we have designed a library of peptide–DNA crosslinkers varying in length, valency and geometry. Peptide filaments conjoint through DNA hybridization give rise to tactoid-shaped bundles with tunable aspect ratios and mechanics. When confined in cell-sized water-in-oil droplets, the DNA crosslinker design guides the localization of cytoskeletal structures at the cortex or within the lumen of the synthetic cells. The tunable spatial arrangement regulates the passive diffusion of payloads within the droplets and complementary DNA handles allow for the reversible recruitment and release of payloads on and off the cytoskeleton. Heat-induced reconfiguration of peptide–DNA architectures triggers shape deformations of droplets, regulated by DNA melting temperatures. Altogether, the modular design of peptide–DNA architectures is a powerful strategy towards the bottom-up assembly of synthetic cells.

Stiffness Modulation and Pulsatile Release in Dual Responsive Hydrogels.

Inspired by nature, self-regulation can be introduced in synthetic hydrogels by incorporating chemo-mechanical signals or coupled chemical reactions to maintain or adapt the material's physico-chemical properties when exposed to external triggers. In this work, we present redox and light dual stimuli responsive hydrogels capable of rapidly adapting the polymer crosslinking network while maintaining hydrogel stability. Upon irradiation with UV light, polymer hydrogels containing redox responsive disulfide crosslinks and light responsive ortho-nitrobenzyl moieties show a release of payload accompanied by adaptation of the hydrogel network towards higher stiffness due to in situ crosslinking by S-nitrosylation. Whereas the hydrogel design allows the network to either become softer in presence of reducing agent glutathione or stiffer upon UV irradiation, simultaneous application of both stimuli induces network self-regulation resulting in a pulsatile form of payload release from the hydrogel. Finally, adaptive stiffness was used to make tunable hydrogels as substrates for different cell lines.

Modulation der Steifigkeit und Pulsierende Freisetzung in Dual‐Responsiven Hydrogelen

AbstractNach dem Vorbild der Natur kann Selbstregulierung synthetischer Hydrogele durch chemomechanische Signale oder chemische Reaktionsnetzwerke eingebaut werden, um die physikochemischen Eigenschaften des Materials aufrecht zu erhalten oder anzupassen, wenn sie externen Stimuli ausgesetzt werden. In dieser Arbeit stellen wir Hydrogele vor, welche auf Redox‐ und Lichtstimuli reagieren und in der Lage sind, das polymere Netzwerk schnell zu verändern und gleichzeitig die Stabilität des Hydrogels zu erhalten. Bei Bestrahlung mit UV‐Licht zeigen die Polymerhydrogele, welche redoxresponsiv über Disulfide quervernetzt sind und lichtresponsive ortho‐Nitrobenzyleinheiten tragen, eine Freisetzung ihrer Ladung mit gleichzeitiger Anpassung des Hydrogelnetzwerks zu höherer Steifigkeit aufgrund der in situ Vernetzung durch S‐Nitrosylierung. Während das Hydrogeldesign es ermöglicht, dass das Netzwerk entweder in Gegenwart des Reduktionsmittels Glutathion weicher oder bei UV‐Bestrahlung steifer wird, führt die gleichzeitige Anwendung beider Stimuli zu einer Selbstregulierung des Netzwerks, was zu einer pulsierenden Freisetzung der Ladung der Hydrogele führt. Schließlich wurde die adaptive Steifigkeit genutzt, um einstellbare Hydrogele als Substrate für verschiedene Zelllinien herzustellen.

Magnetic hybrid nanomaterial based on a natural polymer and an amino acid as pH/temperature dual-responsive nanoplatform for the delivery of tamoxifen

Magnetic hybrid nanomaterials offer promising properties for the advancement of nanoplatforms in cancer nanomedicine, particularly in drug delivery applications. These nanoplatforms can effectively respond to various stimuli present at the tumor site, such as pH and temperature fluctuations, allowing for controlled and triggered release of therapeutic payloads. In this study, we present a straightforward methodology for the synthesis of stable hybrid magnetic nanoplatforms (HMNP) based on Fe3O4 nanoparticles, L-cysteine (L-Cys), and hyaluronic acid (HA) as key constituents for the delivery of tamoxifen (TMX). The synthesized superparamagnetic HMNP, Fe3O4-L-Cys-HA, with a size of 11 nm, was successfully loaded with TMX. The incorporation of L-Cys showed superior interaction with the surface of Fe3O4 nanoparticles compared to other L-Cys derivatives explored as ligands. Consequently, L-Cys was selected for further functionalization with HA, providing the HMNP with active targeting properties toward CD44-overexpressed receptors. High loading efficiency of TMX (75%) was achieved via electrostatic interaction between the carboxylate groups exposed by the HMNP and the ammonium group of the TMX side chain. Efficient control in the TMX release towards different receptor media was observed. Notably, the release of TMX from HMNP-TMX was triggered under acidic pH and hyperthermia conditions, showcasing its responsiveness to both stimuli. Furthermore, enhanced anticancer activity of TMX against MDA-MB-231 breast cancer cells was observed when loaded into HMNP (IC50 almost 3-fold lower for HMNP-TMX compared to free TMX), indicating improved cell uptake of TMX-loaded HMNP in comparison to the free drug. Overall, pH/temperature dual-sensitive HMNP demonstrates promising potential as a nanoplatform for cancer nanomedicine, with prospects for magnetic hyperthermia therapy.

Enhancing SN38 prodrug delivery using a self-immolative linker and endogenous albumin transport

Enhancing the delivery and release efficiency of hydroxyl agents, constrained by high pKa values and issues of release rate or unstable linkage, is a critical challenge. To address this, a self-immolative linker, composed of a modifiable p-hydroxybenzyl ether and a fast cyclization adapter (N-(ortho-hydroxyphenyl)-N-methylcarbamate) was strategically designed, for the synthesis of prodrugs. The innovative linker not only provides a side chain modification but also facilitates the rapid release of the active payloads, thereby enabling precise drug delivery. Particularly, five prodrug model compounds (J1, J2, J3, J5 and J6) were synthesized to evaluate the release rates by using β-glucuronic acid as trigger and five hydroxyl compounds as model payloads. Significantly, all prodrug model compounds could efficiently release the hydroxyl payloads under the action of β-glucuronidase, validating the robustness of the linker. And then, to assess the drug delivery and release efficiency using endogenous albumin as a transport vehicle, J1148, a SN38 prodrug modified with maleimide side chain was synthesized. Results demonstrated that J1148 covalently bound to plasma albumin through in situ Michael addition, effectively targeting the tumor microenvironment. Activated by β-glucuronidase, J1148 underwent a classical 1, 6-elimination, followed by rapid cyclization of the adapter, thereby releasing SN38. Impressively, J1148 showed excellent therapeutic efficacy against human colonic cancer xenograft model, leading to a significant reduction or even disappearance of tumors (3/6 of mice cured). These findings underscore the potential of the designed linker in the delivery system of hydroxyl agents, positioning it at the forefront of advancements in drug delivery technology.