bims-drudre 2021-04-18 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2021–04–18
sixteen papers selected by
Ceren Kimna, Technical University of Munich

Cheerios Effect Inspired Microbubbles as Suspended and Adhered Oral Delivery Systems.
Programmable protein circuit design.
Immunogenic Cell Death Inducing Fluorinated Mitochondria-Disrupting Helical Polypeptide Synergizes with PD-L1 Immune Checkpoint Blockade.
Tailor-Made Nanomaterials for Diagnosis and Therapy of Pancreatic Ductal Adenocarcinoma.
Enhanced tumour penetration and prolonged circulation in blood of polyzwitterion-drug conjugates with cell-membrane affinity.
Tumor cell membrane-based peptide delivery system targeting the tumor microenvironment for cancer immunotherapy and diagnosis.
Nanostructured Dense Collagen-Polyester Composite Hydrogels as Amphiphilic Platforms for Drug Delivery.
Compartmenting poly-adenine-based spherical nucleic acids for efficient live-cell microRNA capture.
Metabolic Control by Heat Stress Determining Cell Fate to Ferroptosis for Effective Cancer Therapy.
Inflammatory tumor microenvironment responsive neutrophil exosomes-based drug delivery system for targeted glioma therapy.
Bacteria-Based Cancer Immunotherapy.
Structure-guided engineering of adenine base editor with minimized RNA off-targeting activity.
Computational modelling of perivascular-niche dynamics for the optimization of treatment schedules for glioblastoma.
Engineered Protein Photo-Thermal Hydrogels for Outstanding In Situ Tongue Cancer Therapy.
Targeted apoptosis of macrophages and osteoclasts in arthritic joints is effective against advanced inflammatory arthritis.
An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications.

Adv Sci (Weinh). 2021 Apr;8(7): 2004184

Cheerios Effect Inspired Microbubbles as Suspended and Adhered Oral Delivery Systems.

Cheng Zhao, Lijun Cai, Min Nie, Luoran Shang, Yongan Wang, Yuanjin Zhao.

  Oral drug administration has an important role in medical treatment. Attempts to develop drug microcarriers with desired features for extended duration and improved absorption is highly sought. Herein, inspired by the physical phenomenon of the Cheerios effect, a novel microfluidic electrospray microbubble carrier is presented that can suspend and actively adhere to the stomach for durable oral delivery. Compared with conventional fabrication methods, the present strategy shows stability and controllability of the product. Benefiting from their uniform hollow structure, the resultant microbubbles present the same behavior of the Cheerios and can float in the gastric juice, adhere and remain to the stomach wall, which thus enhance the duration and absorption of the loaded drugs. Based on these, it is demonstrated as a proof of concept that the dexamethasone-loaded hollow microbubbles can be applied to oral administration and remain suspended and adhered to the stomach of murine for more than 1 d, showing good therapeutic effect in treating lupus erythematosus. Thus, it is believed that the microbubbles floating system will find important values in long-term oral administration.

Keywords:  Cheerios effect; drug delivery; microbubble; microfluidics; systemic lupus erythematosus

DOI:  https://doi.org/10.1002/advs.202004184
Cell. 2021 Apr 05. pii: S0092-8674(21)00292-0. [Epub ahead of print]

Programmable protein circuit design.

Zibo Chen, Michael B Elowitz.

  A fundamental challenge in synthetic biology is to create molecular circuits that can program complex cellular functions. Because proteins can bind, cleave, and chemically modify one another and interface directly and rapidly with endogenous pathways, they could extend the capabilities of synthetic circuits beyond what is possible with gene regulation alone. However, the very diversity that makes proteins so powerful also complicates efforts to harness them as well-controlled synthetic circuit components. Recent work has begun to address this challenge, focusing on principles such as orthogonality and composability that permit construction of diverse circuit-level functions from a limited set of engineered protein components. These approaches are now enabling the engineering of circuits that can sense, transmit, and process information; dynamically control cellular behaviors; and enable new therapeutic strategies, establishing a powerful paradigm for programming biology.

Keywords:  ▪▪▪

DOI:  https://doi.org/10.1016/j.cell.2021.03.007
Adv Sci (Weinh). 2021 Apr;8(7): 2001308

Immunogenic Cell Death Inducing Fluorinated Mitochondria-Disrupting Helical Polypeptide Synergizes with PD-L1 Immune Checkpoint Blockade.

Seong Dong Jeong, Bo-Kyeong Jung, Hyo Min Ahn, DaeYong Lee, JongHoon Ha, Ilkoo Noh, Chae-Ok Yun, Yeu-Chun Kim.

  Immunogenic cell death (ICD) is distinguished by the release of tumor-associated antigens (TAAs) and danger-associated molecular patterns (DAMPs). This cell death has been studied in the field of cancer immunotherapy due to the ability of ICD to induce antitumor immunity. Herein, endoplasmic reticulum (ER) stress-mediated ICD inducing fluorinated mitochondria-disrupting helical polypeptides (MDHPs) are reported. The fluorination of the polypeptide provides a high helical structure and potent anticancer ability. This helical polypeptide destabilizes the mitochondrial outer membrane, leading to the overproduction of intracellular reactive oxygen species (ROS) and apoptosis. In addition, this oxidative stress triggers ER stress-mediated ICD. The in vivo results show that cotreatment of fluorinated MDHP and antiprogrammed death-ligand 1 antibodies (αPD-L1) significantly regresses tumor growth and prevents metastasis to the lungs by activating the cytotoxic T cell response and alleviating the immunosuppressive tumor microenvironment. These results indicate that fluorinated MDHP synergizes with the immune checkpoint blockade therapy to eliminate established tumors and to elicit antitumor immune responses.

Keywords:  combination cancer immunotherapy; immune checkpoint blockade; immunogenic cell death; mitochondrial membrane destabilization; α‐helical polypeptide

DOI:  https://doi.org/10.1002/advs.202001308
Adv Sci (Weinh). 2021 Apr;8(7): 2002545

Tailor-Made Nanomaterials for Diagnosis and Therapy of Pancreatic Ductal Adenocarcinoma.

Xi Hu, Fan Xia, Jiyoung Lee, Fangyuan Li, Xiaoyang Lu, Xiaozhen Zhuo, Guangjun Nie, Daishun Ling.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide due to its aggressiveness and the challenge to early diagnosis and treatment. In recent decades, nanomaterials have received increasing attention for diagnosis and therapy of PDAC. However, these designs are mainly focused on the macroscopic tumor therapeutic effect, while the crucial nano-bio interactions in the heterogeneous microenvironment of PDAC remain poorly understood. As a result, the majority of potent nanomedicines show limited performance in ameliorating PDAC in clinical translation. Therefore, exploiting the unique nature of the PDAC by detecting potential biomarkers together with a deep understanding of nano-bio interactions that occur in the tumor microenvironment is pivotal to the design of PDAC-tailored effective nanomedicine. This review will introduce tailor-made nanomaterials-enabled laboratory tests and advanced noninvasive imaging technologies for early and accurate diagnosis of PDAC. Moreover, the fabrication of a myriad of tailor-made nanomaterials for various PDAC therapeutic modalities will be reviewed. Furthermore, much preferred theranostic multifunctional nanomaterials for imaging-guided therapies of PDAC will be elaborated. Lastly, the prospects of these nanomaterials in terms of clinical translation and potential breakthroughs will be briefly discussed.

Keywords:  diagnosis; imaging‐guided therapy; nanomaterials; pancreatic ductal adenocarcinoma; therapy

DOI:  https://doi.org/10.1002/advs.202002545
Nat Biomed Eng. 2021 Apr 15.

Enhanced tumour penetration and prolonged circulation in blood of polyzwitterion-drug conjugates with cell-membrane affinity.

Siqin Chen, Yin Zhong, Wufa Fan, Jiajia Xiang, Guowei Wang, Quan Zhou, Jinqiang Wang, Yu Geng, Rui Sun, Zhen Zhang, Ying Piao, Jianguo Wang, Jianyong Zhuo, Hailin Cong, Haiping Jiang, Jun Ling, Zichen Li, Dingding Yang, Xin Yao, Xiao Xu, Zhuxian Zhou, Jianbin Tang, Youqing Shen.

Effective anticancer nanomedicines need to exhibit prolonged circulation in blood, to extravasate and accumulate in tumours, and to be taken up by tumour cells. These contrasting criteria for persistent circulation and cell-membrane affinity have often led to complex nanoparticle designs with hampered clinical translatability. Here, we show that conjugates of small-molecule anticancer drugs with the polyzwitterion poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate) have long blood-circulation half-lives and bind reversibly to cell membranes, owing to the negligible interaction of the polyzwitterion with proteins and its weak interaction with phospholipids. Adsorption of the polyzwitterion-drug conjugates to tumour endothelial cells and then to cancer cells favoured their transcytosis-mediated extravasation into tumour interstitium and infiltration into tumours, and led to the eradication of large tumours and patient-derived tumour xenografts in mice. The simplicity and potency of the polyzwitterion-drug conjugates should facilitate the design of translational anticancer nanomedicines.

DOI: https://doi.org/10.1038/s41551-021-00701-4
Acta Biomater. 2021 Apr 02. pii: S1742-7061(21)00206-3. [Epub ahead of print]

Tumor cell membrane-based peptide delivery system targeting the tumor microenvironment for cancer immunotherapy and diagnosis.

Xiangzhou Meng, Jiaojiao Wang, Jundong Zhou, Qingmei Tian, Bo Qie, Gan Zhou, Wei Duan, Yimin Zhu.

  The development of an effective delivery system for peptides targeting the tumor microenvironment has always been a hot topic of research in the field of cancer diagnosis and therapy. In this study, superparamagnetic iron oxide nanoparticles (SPIO NPs) were encapsulated with H460 lung cancer cell membranes (SPIO NP@M), and two peptides, namely PD-L1 inhibitory peptide (TPP1) and MMP2 substrate peptide (PLGLLG), were conjugated to the H460 membrane (SPIO NP@M-P). Homologous targeting, cytotoxicity, and pharmacokinetics of SPIO NP@M-P were evaluated. The TPP1 peptide was delivered and released to the tumor microenvironment through the homotypic effect of tumor cell membrane and specific digestion by the tumor-specific enzyme MMP2. The newly developed delivery system (SPIO NP@M-P) for the PD-L1 inhibitory peptide could effectively extend the half-life of the peptides (60 times longer than that for peptides alone) and could maintain the ability to reactivate T cells and inhibit the tumor growth both in vitro and in vivo. Furthermore, SPIO NPs in the system could be used as a tumor imaging agent and thus show the effect of peptide treatment. The SPIO NP@M might serve as a promising theranostic platform for therapeutic application of peptides in cancer therapy. STATEMENT OF SIGNIFICANCE: A multifunctional delivery system (SPIO NP@M) was constructed for effectively delivering therapeutic peptides into the tumor microenvironment for cancer diagnosis and therapy. In this paper, the TPP-1 peptide inhibiting the binding of PD-L1 and PD-1 was delivered and released into the tumor microenvironment by the homotypic targeting of H460 cell membrane and specific digestion by the MMP2 enzyme. SPIO NPs in this system were aggregated effectively at the tumor sites and were used for magnetic resonance imaging of tumors. The SPIO NP@M-P delivery system could effectively extend the half-life of the TPP-1 peptide (60 times longer than that of the free peptide) and could maintain the ability to re-activate T cells and inhibit tumor growth in vitro and in vivo. In conclusion, the SPIO NP@M system coated with lung cancer cell membrane and loaded with the PD-L1-blocking TPP-1 peptide could be a promising integrated platform for tumor diagnosis and treatment.

Keywords:  Cancer cell membrane; MR imaging; Nanocarriers; PD-L1 inhibitory peptide; SPIO NPs

DOI:  https://doi.org/10.1016/j.actbio.2021.03.056
Adv Sci (Weinh). 2021 Apr;8(7): 2004213

Nanostructured Dense Collagen-Polyester Composite Hydrogels as Amphiphilic Platforms for Drug Delivery.

Xiaolin Wang, Olivier Ronsin, Basile Gravez, Nicolette Farman, Tristan Baumberger, Frédéric Jaisser, Thibaud Coradin, Christophe Hélary.

  Associating collagen with biodegradable hydrophobic polyesters constitutes a promising method for the design of medicated biomaterials. Current collagen-polyester composite hydrogels consisting of pre-formed polymeric particles encapsulated within a low concentrated collagen hydrogel suffer from poor physical properties and low drug loading. Herein, an amphiphilic composite platform associating dense collagen hydrogels and up to 50 wt% polyesters with different hydrophobicity and chain length is developed. An original method of fabrication is disclosed based on in situ nanoprecipitation of polyesters impregnated in a pre-formed 3D dense collagen network. Composites made of poly(lactic-co-glycolic acid) (PLGA) and poly(lactic acid) (PLA) but not polycaprolactone (PCL) exhibit improved mechanical properties compared to those of pure collagen dense hydrogels while keeping a high degree of hydration. Release kinetics of spironolactone, a lipophilic steroid used as a drug model, can be tuned over one month. No cytotoxicity of the composites is observed on fibroblasts and keratinocytes. Unlike the incorporation of pre-formed particles, the new process allows for both improved physical properties of collagen hydrogels and controlled drug delivery. The ease of fabrication, wide range of accessible compositions, and positive preliminary safety evaluations of these collagen-polyesters will favor their translation into clinics in wide areas such as drug delivery and tissue engineering.

Keywords:  collagen; composites; dense hydrogels; drug delivery system; in situ nanoprecipitation; polyesters

DOI:  https://doi.org/10.1002/advs.202004213
Angew Chem Int Ed Engl. 2021 Apr 14.

Compartmenting poly-adenine-based spherical nucleic acids for efficient live-cell microRNA capture.

Fei Wang, Kai Jiao, Qinglong Yan, Linjie Guo, Zhibei Qu, Shuting Cao, Xiaoliang Chen, Qian Li, Ying Zhu, Jiang Li, Lihua Wang, Chunhai Fan.

  Direct delivery of exogenous non-coding nucleic acids into living cells has attracted intense interest in biological applications. However, the cell entry efficiency and target capture ability remain to be improved. Here we develop a method for compartmenting poly-adenine-based spherical nucleic acids (polyA-SNAs) for efficient capture of oncogenic microRNAs (miRNAs) in living cells. We find that polyA-SNAs exhibit high cell entry efficiency insensitive to the configuration of the anti-miRNA sequences. By programming the length of polyAs, we precisely engineer the spatial configuration of the anti-miRNA sequences in polyA-SNAs. Compartmentalized polyA-SNAs bind to miRNAs with improved capture ability as compared to densely compacted SNAs. We further demonstrate that polyA-SNAs serve as high-efficacy miRNA sponges for capturing oncogenic miRNAs both in living cells and in mice. The efficient inhibition of miRNAs results in significant suppression of tumor growth.

Keywords:  DNA-AuNP; MicroRNA; RNA decoy; RNA inhibitor; RNA sponge

DOI:  https://doi.org/10.1002/anie.202017039
ACS Nano. 2021 Apr 16.

Metabolic Control by Heat Stress Determining Cell Fate to Ferroptosis for Effective Cancer Therapy.

Shaowei Xie, Wenshe Sun, Chunfu Zhang, Baijun Dong, Jingxing Yang, Mengfei Hou, Liqin Xiong, Biao Cai, Xuesong Liu, Wei Xue.

  Flexible manipulation of the fate of cancer cells through exogenous stimulation-induced metabolic reprogramming could handle the cellular plasticity-derived therapies resistance, which provides an effective paradigm for the treatment of refractory and relapsing tumors in clinical settings. Herein, we demonstrated that moderate heat (45 °C) could significantly regress the expression of antioxidants and trigger specific lipid metabolic reprogramming in cancer cells synergized with iron oxide nanoparticles (Fe3O4 NPs). This metabolic control behavior destroyed the tumor redox homeostasis and produced overwhelming lipid peroxides, consequently sensitizing the tumor to ferroptosis. Based on these findings, a heat-triggered tumor-specific ferroptosis strategy was proposed by the rational design of a polypeptide-modified and 1H-perfluoropentane (1H-PFP)-encapsulated Fe3O4-containing nanoformulation (GBP@Fe3O4). When irradiated by an 808 nm laser, the phase transition of 1H-PFP was triggered by localized moderate heat (45 °C), leading to burst release of Fe3O4 in situ to produce potent reactive oxygen species through the Fenton reaction in the tumor microenvironment. Together with the antioxidant inhibition response and distinctive lipid metabolic reprogramming by heat stress, this oxidative damage was amplified to induce tumor ferroptosis and achieve sufficient antitumor effects. Importantly, we confirmed that ACSBG1, an acyl-CoA synthetase, was the key pro-ferroptotic factor in this heat-induced ferroptosis process. Moreover, knockout of this gene could realize cancer cell death fate conversion from ferroptosis to non-ferroptotic death. This work provides mechanistic insights and practical strategies for heat-triggered ferroptosis in situ to reduce the potential side effects of direct ferroptosis inducers and highlights the key factor in regulating cell fate under heat stress.

Keywords:  cancer therapy; ferroptosis; heat stress; iron oxide nanoparticles; metabolic reprogramming

DOI:  https://doi.org/10.1021/acsnano.1c00380
Biomaterials. 2021 Mar 31. pii: S0142-9612(21)00140-X. [Epub ahead of print]273 120784

Inflammatory tumor microenvironment responsive neutrophil exosomes-based drug delivery system for targeted glioma therapy.

Jun Wang, Wei Tang, Meng Yang, Ying Yin, Hui Li, Fangfang Hu, Lin Tang, Xiaoyue Ma, Yu Zhang, Yazhou Wang.

  Clinical treatment of malignant glioma remains a major challenge due to high infiltrative growth and chemotherapeutic resistance of tumors and the presence of the blood brain barrier (BBB). Advanced nanoplatforms that can efficiently cross the BBB and target to brain tumor are urgently needed. Encouraged by the intrinsic inflammatory chemotaxis and excellent BBB-crossing capability of neutrophils, a bioinspired neutrophil-exosomes (NEs-Exos) system for delivering loaded doxorubicin (DOX) drug for glioma treatment is proposed and systematically investigated. In vivo zebrafish and C6-Luc glioma-bearing mice models show that NEs-Exos carrying the drug rapidly penetrate the BBB and migrate into the brain. Additionally, a transwell BBB model and mouse brain inflammatory study show that NEs-Exos can respond chemotactically to inflammatory stimuli and target infiltrating tumor cells in inflamed brain tumors. Moreover, intravenous injection of NEs-Exos/DOX efficiently suppress tumor growth and prolong survival time in a glioma mouse model. On the basis of these results, NEs-Exos are confirmed to have neutrophil-like chemotactic function and BBB penetration. This novel NEs-Exos/DOX delivery platform represents a promising chemotherapeutic approach for clinical treatment of glioma and other solid tumor or brain diseases.

Keywords:  Blood brain barrier; Exosomes; Glioma; Neutrophils; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.biomaterials.2021.120784
Adv Sci (Weinh). 2021 Apr;8(7): 2003572

Bacteria-Based Cancer Immunotherapy.

Xuehui Huang, Jingmei Pan, Funeng Xu, Binfen Shao, Yi Wang, Xing Guo, Shaobing Zhou.

  In the past decade, bacteria-based cancer immunotherapy has attracted much attention in the academic circle due to its unique mechanism and abundant applications in triggering the host anti-tumor immunity. One advantage of bacteria lies in their capability in targeting tumors and preferentially colonizing the core area of the tumor. Because bacteria are abundant in pathogen-associated molecular patterns that can effectively activate the immune cells even in the tumor immunosuppressive microenvironment, they are capable of enhancing the specific immune recognition and elimination of tumor cells. More attractively, during the rapid development of synthetic biology, using gene technology to enable bacteria to be an efficient producer of immunotherapeutic agents has led to many creative immunotherapy paradigms. The combination of bacteria and nanomaterials also displays infinite imagination in the multifunctional endowment for cancer immunotherapy. The current progress report summarizes the recent advances in bacteria-based cancer immunotherapy with specific foci on the applications of naive bacteria-, engineered bacteria-, and bacterial components-based cancer immunotherapy, and at the same time discusses future directions in this field of research based on the present developments.

Keywords:  bacteria; bacterial components; engineered bacteria; immunotherapy; nanomaterial

DOI:  https://doi.org/10.1002/advs.202003572
Nat Commun. 2021 Apr 16. 12(1): 2287

Structure-guided engineering of adenine base editor with minimized RNA off-targeting activity.

Jianan Li, Wenxia Yu, Shisheng Huang, Susu Wu, Liping Li, Jiankui Zhou, Yu Cao, Xingxu Huang, Yunbo Qiao.

Both adenine base editors (ABEs) and cytosine base editors (CBEs) have been recently revealed to induce transcriptome-wide RNA off-target editing in a guide RNA-independent manner. Here we construct a reporter system containing E.coli Hokb gene with a tRNA-like motif for robust detection of RNA editing activities as the optimized ABE, ABEmax, induces highly efficient A-to-I (inosine) editing within an E.coli tRNA-like structure. Then, we design mutations to disrupt the potential interaction between TadA and tRNAs in structure-guided principles and find that Arginine 153 (R153) within TadA is essential for deaminating RNAs with core tRNA-like structures. Two ABEmax or mini ABEmax variants (TadA* fused with Cas9n) with deletion of R153 within TadA and/or TadA* (named as del153/del153* and mini del153) are successfully engineered, showing minimized RNA off-targeting, but comparable DNA on-targeting activities. Moreover, R153 deletion in recently reported ABE8e or ABE8s can also largely reduce their RNA off-targeting activities. Taken together, we develop a strategy to generate engineered ABEs (eABEs) with minimized RNA off-targeting activities.

DOI: https://doi.org/10.1038/s41467-021-22519-z
Nat Biomed Eng. 2021 Apr;5(4): 346-359

Computational modelling of perivascular-niche dynamics for the optimization of treatment schedules for glioblastoma.

Amanda Randles, Hans-Georg Wirsching, Jamie A Dean, Yu-Kang Cheng, Samuel Emerson, Siobhan S Pattwell, Eric C Holland, Franziska Michor.

Glioblastoma stem-like cells dynamically transition between a chemoradiation-resistant state and a chemoradiation-sensitive state. However, physical barriers in the tumour microenvironment restrict the delivery of chemotherapy to tumour compartments that are distant from blood vessels. Here, we show that a massively parallel computational model of the spatiotemporal dynamics of the perivascular niche that incorporates glioblastoma stem-like cells and differentiated tumour cells as well as relevant tissue-level phenomena can be used to optimize the administration schedules of concurrent radiation and temozolomide-the standard-of-care treatment for glioblastoma. In mice with platelet-derived growth factor (PDGF)-driven glioblastoma, the model-optimized treatment schedule increased the survival of the animals. For standard radiation fractionation in patients, the model predicts that chemotherapy may be optimally administered about one hour before radiation treatment. Computational models of the spatiotemporal dynamics of the tumour microenvironment could be used to predict tumour responses to a broader range of treatments and to optimize treatment regimens.

DOI: https://doi.org/10.1038/s41551-021-00710-3
Adv Mater. 2021 Apr 16. e2100619

Engineered Protein Photo-Thermal Hydrogels for Outstanding In Situ Tongue Cancer Therapy.

Juanjuan Su, Shuang Lu, Shengjie Jiang, Bo Li, Bin Liu, Qiannan Sun, Jingjing Li, Fan Wang, Yan Wei.

  Surgical excision is the main choice for tongue cancer treatment. However, the physiological functions of oral and maxillofacial regions might be severely impaired and high risk of tongue tumor recurrence cannot be avoided. It is thus becoming urgently important to develop alternative strategies for tongue cancer therapy. In this regard, a new class of near-infrared (NIR) light-responsive and peritumoral injectable hydrogel is fabricated with extraordinary photothermal therapy (PTT) for in situ tongue tumors. The as-prepared soft material exhibits good biocompatibility and ultra-strong photothermal effect due to the formed network by negatively charged proteins, chitosan molecules, and Ag3 AuS2 nanoparticles (NPs). In a well-constructed in situ tongue tumor model, tumors can be efficiently eradicated by one-time PTT treatment. Importantly, there are no side effects on surrounding normal tissues and potential tumor recurrence is inhibited. In stark contrast to traditional surgical excision, such biomaterials hold great potential for clinical treatment of oral cancers.

Keywords:  injectable hydrogels; photo-thermal therapy (PTT); tongue cancer therapy

DOI:  https://doi.org/10.1002/adma.202100619
Nat Commun. 2021 04 12. 12(1): 2174

Targeted apoptosis of macrophages and osteoclasts in arthritic joints is effective against advanced inflammatory arthritis.

Caifeng Deng, Quan Zhang, Penghui He, Bin Zhou, Ke He, Xun Sun, Guanghua Lei, Tao Gong, Zhirong Zhang.

Insufficient apoptosis of inflammatory macrophages and osteoclasts (OCs) in rheumatoid arthritis (RA) joints contributes toward the persistent progression of joint inflammation and destruction. Here, we deliver celastrol (CEL) to selectively induce apoptosis of OCs and macrophages in arthritic joints, with enzyme-responsive nanoparticles (termed PRNPs) composed of RGD modified nanoparticles (termed RNPs) covered with cleavable PEG chains. CEL-loaded PRNPs (CEL-PRNPs) dually target OCs and inflammatory macrophages derived from patients with RA via an RGD-αvβ3 integrin interaction after PEG cleavage by matrix metalloprotease 9, leading to increased apoptosis of these cells. In an adjuvant-induced arthritis rat model, PRNPs have an arthritic joint-specific distribution and CEL-PRNPs efficiently reduce the number of OCs and inflammatory macrophages within these joints. Additionally, rats with advanced arthritis go into inflammatory remission with bone erosion repair and negligible side effects after CEL-PRNPs treatment. These findings indicate potential for targeting chemotherapy-induced apoptosis in the treatment of advanced inflammatory arthritis.

DOI: https://doi.org/10.1038/s41467-021-22454-z
Proc Natl Acad Sci U S A. 2021 Apr 20. pii: e2101852118. [Epub ahead of print]118(16):

An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications.

Jacopo Millul, Gabriele Bassi, Jacqueline Mock, Abdullah Elsayed, Christian Pellegrino, Aureliano Zana, Sheila Dakhel Plaza, Lisa Nadal, Andreas Gloger, Eleonore Schmidt, Ilaria Biancofiore, Etienne J Donckele, Florent Samain, Dario Neri, Samuele Cazzamalli.

  We describe the development of OncoFAP, an ultra-high-affinity ligand of fibroblast activation protein (FAP) for targeting applications with pan-tumoral potential. OncoFAP binds to human FAP with affinity in the subnanomolar concentration range and cross-reacts with the murine isoform of the protein. We generated various fluorescent and radiolabeled derivatives of OncoFAP in order to study biodistribution properties and tumor-targeting performance in preclinical models. Fluorescent derivatives selectively localized in FAP-positive tumors implanted in nude mice with a rapid and homogeneous penetration within the neoplastic tissue. Quantitative in vivo biodistribution studies with a lutetium-177-labeled derivative of OncoFAP revealed a preferential localization in tumors at doses of up to 1,000 nmol/kg. More than 30% of the injected dose had already accumulated in 1 g of tumor 10 min after intravenous injection and persisted for at least 3 h with excellent tumor-to-organ ratios. OncoFAP also served as a modular component for the generation of nonradioactive therapeutic products. A fluorescein conjugate mediated a potent and FAP-dependent tumor cell killing activity in combination with chimeric antigen receptor (CAR) T cells specific to fluorescein. Similarly, a conjugate of OncoFAP with the monomethyl auristatin E-based Vedotin payload was well tolerated and cured tumor-bearing mice in combination with a clinical-stage antibody-interleukin-2 fusion. Collectively, these data support the development of OncoFAP-based products for tumor-targeting applications in patients with cancer.

Keywords:  FAP; small molecule therapeutics; tumor targeting

DOI:  https://doi.org/10.1073/pnas.2101852118