Photodynamic-Chemodynamic Cascade Reactions for Efficient Drug Delivery and Enhanced Combination Therapy.

Nanomedicines with photodynamic therapy and reactive oxygen species (ROS)-triggered drug release capabilities are promising for cancer therapy. However, most of the nanomedicines based on ROS-responsive nanocarriers still suffer from serious ROS consumption during the triggered drug release process. Herein, a photodynamic-chemodynamic cascade strategy for the design of drug delivery nanosystem is proposed. A doxorubicin hydrochloride-loaded ROS-responsive polymersome (DOX-RPS) is prepared via the self-assembly of amphiphilic poly(ethylene glycol)-poly(linoleic acid) and poly(ethylene glycol)-(2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-α)-iron chelate (PEG-HPPH-Fe). The RPS can effectively deliver a drug to tumor site through passive targeting effect. Upon laser irradiation, the photosensitizer HPPH can efficiently generate ROS, which further causes in situ oxidation of linoleic acid chain and subsequent RPS structural destruction, permitting triggered drug release. Intriguingly, catalyzed by HPPH-Fe, ROS will be regenerated from linoleic acid peroxide through a chemodynamic process. Therefore, ROS-triggered drug release can be achieved without ROS over-consumption. The in vitro and in vivo results confirmed ROS generation, triggered drug release behavior, and potent antitumor effect of the DOX-RPS. This photodynamic-chemodynamic cascade strategy provides a promising approach for enhanced combination therapy.

Biphasic synthesis of biodegradable urchin-like mesoporous organosilica nanoparticles for enhanced cellular internalization and precision cascaded therapy.

It is widely accepted that a small particle size and rough surface can enhance tumor tissue accumulation and tumor cellular uptake of nanoparticles, respectively. Herein, sub-50 nm urchin-inspired disulfide bond-bridged mesoporous organosilica nanoparticles (UMONs) featured with a spiky surface and glutathione (GSH)-responsive biodegradability were successfully synthesized by a facile one-pot biphasic synthesis strategy for enhanced cellular internalization and tumor accumulation. l-Arginine (LA) is encapsulated into the mesopores of UMONs, whose outer surface is capped with the gatekeeper of ultrasmall gold nanoparticles, i.e., UMONs-LA-Au. On the one hand, the mild acidity-activated uncapping of ultrasmall gold can realize a tumor microenvironment (TME)-responsive release of LA. On the other hand, the unique natural glucose oxidase (GOx)-mimicking catalytic activity of ultrasmall gold can catalyze the decomposition of intratumoral glucose to produce acidic hydrogen peroxide (H2O2) and gluconic acid. Remarkably, these products can not only further facilitate the release of LA, but also catalyze the LA-H2O2 reaction for an increased nitric oxide (NO) yield, which realizes synergistic catalysis-enhanced NO gas therapy for tumor eradication. The judiciously fabricated UMONs-LA-Au present a paradigm of TME-responsive nanoplatforms for both enhanced cellular uptake and tumor-specific precision cascaded therapy, which broadens the range of practical biomedical applications and holds a significant promise for the clinical translation of silica-based nanotheranostics.

A hybrid semiconducting organosilica-based O2 nanoeconomizer for on-demand synergistic photothermally boosted radiotherapy.

The outcome of radiotherapy is significantly restricted by tumor hypoxia. To overcome this obstacle, one prevalent solution is to increase intratumoral oxygen supply. However, its effectiveness is often limited by the high metabolic demand for O2 by cancer cells. Herein, we develop a hybrid semiconducting organosilica-based O2 nanoeconomizer pHPFON-NO/O2 to combat tumor hypoxia. Our solution is twofold: first, the pHPFON-NO/O2 interacts with the acidic tumor microenvironment to release NO for endogenous O2 conservation; second, it releases O2 in response to mild photothermal effect to enable exogenous O2 infusion. Additionally, the photothermal effect can be increased to eradicate tumor residues with radioresistant properties due to other factors. This "reducing expenditure of O2 and broadening sources" strategy significantly alleviates tumor hypoxia in multiple ways, greatly enhances the efficacy of radiotherapy both in vitro and in vivo, and demonstrates the synergy between on-demand temperature-controlled photothermal and oxygen-elevated radiotherapy for complete tumor response.

177Lu-DOTA-EB-TATE, a Radiolabeled Analogue of Somatostatin Receptor Type 2, for the Imaging and Treatment of Thyroid Cancer.

PURPOSE: The goal of this study was to analyze the role of somatostatin receptor type 2 (SSTR2) as a molecular target for the imaging and treatment of thyroid cancer through analysis of SSTR2 expression and its epigenetic modulation and testing tumor uptake of different radiolabeled SSTR2 analogues. EXPERIMENTAL DESIGN: We analyzed SSTR2 expression by immunostaining of 92 thyroid cancer tissue samples and quantified standard uptake values (SUVmax) of SSTR2 analogue, 68Ga-DOTA-TATE, by PET/CT imaging in 25 patients with metastatic thyroid cancer. We utilized human thyroid cancer cell lines characterized by differential SSTR2 expression (TT, BCPAP, and FTC133) and rat pancreatic cell line (AR42J) with intrinsically high SSTR2 expression for functional in vitro studies. SSTR2-high (AR42J) and SSTR2-low (FTC133) xenograft mouse models were used to test the uptake of radiolabeled SSTR2 analogues and their therapeutic efficacy in vivo. RESULTS: Thyroid cancer had a higher SSTR2 expression than normal thyroid. Hurthle cell thyroid cancer was characterized by the highest 68Ga-DOTA-TATE uptake [median SUVmax, 16.5 (7.9-29)] than other types of thyroid cancers. In vivo studies demonstrated that radiolabeled DOTA-EB-TATE is characterized by significantly higher tumor uptake than DOTA-TATE (P < 0.001) and DOTA-JR11 (P < 0.001). Treatment with 177Lu-DOTA-EB-TATE extended survival and reduced tumor size in a mouse model characterized by high somatostatin (SST) analogues uptake (SUVmax, 15.16 ± 4.34), but had no effects in a model with low SST analogues uptake (SUVmax, 4.8 ± 0.27). CONCLUSIONS: A novel SST analogue, 177Lu-DOTA-EB-TATE, has the potential to be translated from bench to bedside for the targeted therapy of patients characterized by high uptake of SST analogues in metastatic lesions.

Peptide Receptor Radionuclide Therapy of Late-Stage Neuroendocrine Tumor Patients with Multiple Cycles of 177Lu-DOTA-EB-TATE.

This study aimed to evaluate the safety and efficacy of multiple cycles of 177Lu-DOTA-Evans blue (EB)-TATE peptide receptor radionuclide therapy (PRRT) at escalating doses in neuroendocrine tumors (NETs). Methods: Thirty-two NET patients were randomly divided into 3 groups and treated with escalating doses. Group A received 1.17 ± 0.09 GBq/cycle; group B, 1.89 ± 0.53 GBq/cycle; and group C, 3.97 ± 0.84 GBq/cycle. The treatment was planned for up to 3 cycles. Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Treatment response was evaluated according to the European Organisation for Research and Treatment of Cancer criteria and modified PERCIST. Results: Administration of PRRT was well tolerated, without life-threatening adverse events (CTCAE grade 4). CTCAE grade 3 hematotoxicity was recorded in 1 patient (16.6%) in group B (thrombocytopenia) and 3 patients (21.4%) in group C (thrombocytopenia in 3, anemia in 1). CTCAE grade 3 hepatotoxicity (elevated aspartate aminotransferase) was recorded in 1 patient in group A (8.3%) and 1 patient in group C (7.1%). No nephrotoxicity was observed. According to the criteria of the European Organisation for Research and Treatment of Cancer, the overall disease response rates were similar in groups A, B, and C (50.0%, 50.0%, and 42.9%, respectively), and the overall disease control rates were higher in groups B (83.3%) and C (71.5%) than in group A (66.7%). According to modified PERCIST, a lower disease response rate but a similar disease control rate were found. When a comparable baseline SUVmax ranging from 15 to 40 was selected, the percentage change in SUVmax increased slightly in group A (2.1% ± 40.8%) but decreased significantly in groups B and C (-38.7% ± 10.0% and -14.7% ± 20.0%, respectively) after the first PRRT (P = 0.001) and decreased in all 3 groups after the third PRRT (groups A, B, and C: -6.9% ± 42.3%, -49.2% ± 30.9%, -11.9% ± 37.9%, respectively; P = 0.044). Conclusion: Dose escalations of up to 3.97 GBq/cycle seem to be well tolerated for 177Lu-DOTA-EB-TATE. 177Lu-DOTA-EB-TATE doses of 1.89 and 3.97 GBq/cycle were effective in tumor control and more effective than 1.17 GBq/cycle.

Reactive Oxygen Species Activatable Heterodimeric Prodrug as Tumor-Selective Nanotheranostics.

Nanotheranostics based on tumor-selective small molecular prodrugs could be more advantageous in clinical translation for cancer treatment, given its defined chemical structure, high drug loading efficiency, controlled drug release, and reduced side effects. To this end, we have designed and synthesized a reactive oxygen species (ROS)-activatable heterodimeric prodrug, namely, HRC, and nanoformulated it for tumor-selective imaging and synergistic chemo- and photodynamic therapy. The prodrug consists of the chemodrug camptothecin (CPT), the photosensitizer 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH), and a thioketal linker. Compared to CPT- or HPPH-loaded polymeric nanoparticles (NPs), HRC-loaded NPs possess higher drug loading capacity, better colloidal stability, and less premature drug leakage. Interestingly, HRC NPs were almost nonfluorescent due to the strong π-π stacking and could be effectively activated by endogenous ROS once entering cells. Thanks to the higher ROS levels in cancer cells than normal cells, HRC NPs could selectively light up the cancer cells and exhibit much more potent cytotoxicity to cancer cells. Moreover, HRC NPs demonstrated highly effective tumor accumulation and synergistic tumor inhibition with reduced side effects on mice.

In Situ Polymerized Hollow Mesoporous Organosilica Biocatalysis Nanoreactor for Enhancing ROS-Mediated Anticancer Therapy.

The combination of reactive oxygen species (ROS)-involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) holds great promise for enhancing ROS-mediated cancer treatment. Herein, we reported an in situ polymerized hollow mesoporous organosilica nanoparticle (HMON) biocatalysis nanoreactor to integrate the synergistic effect of PDT/CDT for enhancing ROS-mediated pancreatic ductal adenocarcinoma treatment. HPPH photosensitizer was hybridized within the framework of HMON via an "in situ framework growth" approach. Then, the hollow cavity of HMONs was exploited as a nanoreactor for "in situ polymerization" to synthesize the polymer containing thiol groups, thereby enabling the immobilization of ultrasmall gold nanoparticles, which behave like glucose oxidase-like nanozyme, converting glucose into H2O2 to provide self-supplied H2O2 for CDT. Meanwhile, Cu2+-tannic acid complexes were further deposited on the surface of HMONs (HMON-Au@Cu-TA) to initiate Fenton-like reaction to covert the self-supplied H2O2 into •OH, a highly toxic ROS. Finally, collagenase (Col), which can degrade the collagen I fiber in the extracellular matrix (ECM), was loaded into HMON-Au@Cu-TA to enhance the penetration of HMONs and O2 infiltration for enhanced PDT. This study provides a good paradigm for enhancing ROS-mediated anti-tumor efficacy. Meanwhile, this research offers a new method to broaden the application of silica based nanotheranostics.

Cascade Reactions Catalyzed by Planar Metal-Organic Framework Hybrid Architecture for Combined Cancer Therapy.

Chemical transformation in cellular environment is critical for regulating biological processes and metabolic pathways. Harnessing biocatalytic cascades to produce chemicals of interest has become a research focus to benefit industrial and pharmaceutic areas. Nanoreactors, which can act as artificial cell-like devices to organize cascade reactions, have been recently proposed for potential therapeutic applications for life-threatening illnesses. Among various types of nanomaterials, there is a growing interest in 2D metal-organic frameworks (MOFs). By virtue of the ultralarge specific surface area, high porosity, and structural diversity, 2D MOF nanosheets hold great promise for a broad spectrum of biomedical use. Herein, a unique planar MOF-based hybrid architecture (GMOF-LA) is introduced by incorporating ultrasmall gold nanoparticles (Au NPs) as nanozyme and l-Arginine (l-Arg) as nitric oxide (NO) donor. The prepared Au NPs enable oxidation of glucose into hydrogen peroxide, which drives biocatalytic cascades to covert l-Arg into NO. Interestingly, the well-designed nanosheets not only possess excellent catalytical activity for NO generation, resulting in gas therapeutic effect, but also serve as a desired photosensitizer for photodynamic therapy. This study establishes a good example of exploring bioinspired nanoreactors for cooperative anticancer effect, which may pave the path for future "bench-to-bedside" design of nanomedicine.

Targeted Radionuclide Therapy in Patient-Derived Xenografts Using 177Lu-EB-RGD.

Currently, most patients with non-small cell lung cancer (NSCLC) are diagnosed in advanced stages with a poor five-year survival rate. Therefore, intensive research aimed at finding novel therapeutic strategies has been ongoing; experimental models that reliably emulate NSCLC disease are greatly needed to predict responses to novel therapeutics. Therefore, we developed patient-derived xenograft (PDX) models of NSCLC, which we then used to evaluate the therapeutic efficacy of 177Lu-EB-RGD, a peptide-based radiopharmaceutical with improved pharmacokinetics that targets integrin αvß3 In this study, three different groups of NSCLC-PDXs were successfully established, all of which maintained the same IHC and genetic characteristics of the human primary tumor. The two NSCLC-PDX groups with intense and low expression of integrin αvß3 (denoted as PDXαvß3+ and PDXαvß3-) were chosen as the experimental models to evaluate the in vivo biological behavior of 177Lu-EB-RGD. In SPECT imaging and biodistribution studies, 177Lu-EB-RGD showed significantly higher accumulation in PDXαvß3+ and PDXαvß3- models than its corresponding monomer 177Lu-RGD. A single dose of 18.5 MBq 177Lu-EB-RGD was enough to completely eradicate the tumors in PDXαvß3+, with no sign of tumor recurrence during the observation period. Such treatment was also efficacious in PDXαvß3-: a single dose of 29.6 MBq 177Lu-EB-RGD led to a significant delay in tumor growth as compared with that in the control or 177Lu-RGD group. The preclinical data from the use of this model suggest that 177Lu-EB-RGD may be an effective treatment option for NSCLC and should be further evaluated in human trials.

Targeting Neutrophils for Enhanced Cancer Theranostics.

Improving tumor accumulation and delivery efficiency is an important goal of nanomedicine. Neutrophils play a vital role in both chemically mediating inflammatory response through myeloperoxidase (MPO) and biologically promoting metastasis during inflammation triggered by the primary tumor or environmental stimuli. Herein, a novel theranostic nanomedicine that targets both the chemical and biological functions of neutrophils in tumor is designed, facilitating the enhanced retention and sustained release of drug cargos for improved cancer theranostics. 5-hydroxytryptamine (5-HT) is equipped onto nanoparticles (NPs) loaded with photosensitizers and Zileuton (a leukotriene inhibitor) to obtain MPO and neutrophil targeting NPs, denoted as HZ-5 NPs. The MPO targeting property of 5-HT modified NPs is confirmed by noninvasive positron emission tomography imaging studies. Furthermore, photodynamic therapy is used to initiate the inflammatory response which further mediated the accumulation and retention of neutrophil targeting NPs in a breast cancer model. This design renders a greatly improved theranostic nanomedicine for efficient tumor suppression, and more importantly, inhibition of neutrophil-mediated lung metastasis via the sustained release of Zileuton. This work presents a novel strategy of targeting neutrophils for improved tumor theranostics, which may open up new avenues in designing nanomedicine through exploiting the tumor microenvironment.

Zwitterionic-to-cationic charge conversion polyprodrug nanomedicine for enhanced drug delivery.

Zwitterionic surface modification is a promising strategy for nanomedicines to achieve prolonged circulation time and thus effective tumor accumulation. However, zwitterion modified nanoparticles suffer from reduced cellular internalization efficiency. Methods: A polyprodrug-based nanomedicine with zwitterionic-to-cationic charge conversion ability (denoted as ZTC-NMs) was developed for enhanced chemotherapeutic drug delivery. The polyprodrug consists of pH-responsive poly(carboxybetaine)-like zwitterionic segment and glutathione-responsive camptothecin prodrug segment. Results: The ZTC-NMs combine the advantages of zwitterionic surface and polyprodrug. Compared with conventional zwitterionic surface, the ZTC-NMs can respond to tumor microenvironment and realize ZTC surface charge conversion, thus improve cellular internalization efficiency of the nanomedicines. Conclusions: This ZTC method offers a strategy to promote the drug delivery efficiency and therapeutic efficacy, which is promising for the development of cancer nanomedicines.

Early stratification of radiotherapy response by activatable inflammation magnetic resonance imaging.

Tumor heterogeneity is one major reason for unpredictable therapeutic outcomes, while stratifying therapeutic responses at an early time may greatly benefit the better control of cancer. Here, we developed a hybrid nanovesicle to stratify radiotherapy response by activatable inflammation magnetic resonance imaging (aiMRI) approach. The high Pearson's correlation coefficient R values are obtained from the correlations between the T1 relaxation time changes at 24-48 h and the ensuing adaptive immunity (R = 0.9831) at day 5 and the tumor inhibition ratios (R = 0.9308) at day 18 after different treatments, respectively. These results underscore the role of acute inflammatory oxidative response in bridging the innate and adaptive immunity in tumor radiotherapy. Furthermore, the aiMRI approach provides a non-invasive imaging strategy for early prediction of the therapeutic outcomes in cancer radiotherapy, which may contribute to the future of precision medicine in terms of prognostic stratification and therapeutic planning.

177Lu-EB-PSMA Radioligand Therapy with Escalating Doses in Patients with Metastatic Castration-Resistant Prostate Cancer.

This study was designed to assess the safety and therapeutic response to 177Lu-labeled Evans blue-modified prostate-specific membrane antigen (PSMA) 617 (EB-PSMA-617) treatment with escalating doses in patients with metastatic castration-resistant prostate cancer. Methods: With institutional review board approval and informed consent, patients were randomly divided into 3 groups: group A (n = 10) was treated with a 1.18 ± 0.09 GBq dose of 177Lu-EB-PSMA. Group B (n = 10) was treated with a 2.12 ± 0.19 GBq dose of 177Lu-EB-PSMA. Group C (n = 8) was treated with a 3.52 ± 0.58 GBq dose of 177Lu-EB-PSMA. Eligible patients received up to 3 cycles of 177Lu-EB-PSMA therapy, at 8-wk intervals. Results: Because of disease progression or bone marrow suppression, 4 of 10, 5 of 10, and 5 of 8 patients completed 3 cycles of therapy as planned in groups A, B, and C, respectively. The prostate-specific antigen response was correlated with treatment dose, and the prostate-specific antigen disease control rates were higher in groups B (70%) and C (75%) than in group A (10%) (P = 0.007), but no correlation between groups B and C was found. 68Ga-PSMA PET/CT showed a response in all treatment groups; however, there was no significant difference among the 3 groups. A hematologic toxicity study found that platelets decreased more in groups B and C than in group A and that grade 4 thrombocytopenia occurred in 2 (25.0%) patients in group C. No serious nephritic or hepatic side effects were observed. Conclusion: This study demonstrated that a 2.12-GBq dose of 177Lu-EB-PSMA seems to be safe and adequate in tumor treatment. Further investigations with an increased number of patients are warranted.

Solvent-Assisted Self-Assembly of a Metal-Organic Framework Based Biocatalyst for Cascade Reaction Driven Photodynamic Therapy.

Biocatalytic reactions in living cells involve complex transformations in the spatially confined microenvironments. Inspired by biological transformation processes, we demonstrate effective biocatalytic cascade driven photodynamic therapy in tumor-bearing mice by the integration of an artificial enzyme (ultrasmall Au nanoparticles) with upconversion nanoparticles (NaYF4@NaYb0.92F4:Er0.08@NaYF4)zirconium/iron porphyrin metal-organic framework core-shell nanoparticles (UMOF NPs) which act as biocatalysts and nanoreactors. The construction of core-shell UMOF NPs are realized by using a unique "solvent-assisted self-assembly" method. The integration of ultrasmall AuNPs on the UMOFs matrix leads to glucose depletion, providing Au-mediated cancer therapy via glucose oxidase like catalytic activity. Meanwhile, the UMOF matrix acts as a near-infrared (NIR) light photon-activated singlet oxygen generator through a continuous supply of oxygen via hydrogen peroxide decomposition upon irradiation. Such kinds of biocatalysts offer exciting opportunities for biomedical, catalytical ,and energy applications.

Combined 68Ga-NOTA-Evans Blue Lymphoscintigraphy and 68Ga-NOTA-RM26 PET/CT Evaluation of Sentinel Lymph Node Metastasis in Breast Cancer Patients.

In this study, we applied a new strategy to identify sentinel lymph node (SLN) metastasis by combining 68Ga-NOTA-Evans Blue (68Ga-NEB) for SLN mapping and 68Ga-NOTA-RM26 for LN metastasis detection in breast cancer patients. A total of 24 female patients with breast cancer diagnosed by core biopsy or suspected by mammography or ultrasonography were recruited and provided informed consent. All patients underwent 68Ga-NEB and 68Ga-NOTA-RM26 PET/CT imaging. Visual analysis of 68Ga-NEB PET/CT images was used to determine SLNs, and then compared with the 68Ga-NOTA-RM26 results and histopathological findings. SLNs were visualized in 24 of 24 patients (100.0%) within 4.0-10.0 (5.6 ± 1.4) min. All patients were pathologically diagnosed with breast cancer, and 12 patients had ipsilateral lymph node metastasis. By combining 68Ga-NEB and 68Ga-NOTA-RM26 images, 7/12 (58.3%) patients showed mild to intense uptake of 68Ga-NOTA-RM26 in SLNs, 1/12 patient (8.3%) had moderate uptake of 68Ga-NOTA-RM26 in the non-SLNs rather than SLN, indicating possible bypass lymphatic drainage, partially accounting for the false negatives in SLN biopsy during surgery. No false positives were found. The SUVmax of 68Ga-NOTA-RM26 activity in metastatic SLNs was significantly higher than that in non-metastatic SLNs (2.2 ± 2.3 vs 0.7 ± 0.1, P = 0.047). This study manifests the value of combination of 68Ga-NEB and 68Ga-NOTA-RM26 dual tracer PET/CT in preoperative evaluation of SLN metastasis in breast cancer patients, especially in those patients with lymphatic obstruction and bypass drainage. In general, positive 68Ga-NOTA-RM26 uptake in either SLN or other lymph nodes can apply lymph node dissection rather than intraoperative SLN biopsy.

Dose escalation of an Evans blue-modified radiolabeled somatostatin analog 177Lu-DOTA-EB-TATE in the treatment of metastatic neuroendocrine tumors.

PURPOSE: To evaluate the safety and efficacy of 177Lu-DOTA-EB-TATE, a radiolabeled somatostatin analog modified by Evans blue, at escalating doses, was used to increase tumor retention in patients with progressive metastatic neuroendocrine tumors (NETs). METHODS: Thirty-three patients with metastatic NETs were prospectively enrolled into four groups: group A (n = 6, 43 ± 12 years) administered approximately 3.7 GBq (100 mCi) 177Lu-DOTATATE as controls; group B (n = 7, 55 ± 7 years) administered approximately 1.11 GBq (30 mCi) 177Lu-DOTA-EB-TATE; group C (n = 6, 55 ± 10 years) administered approximately 1.85 GBq (50 mCi) 177Lu-DOTA-EB-TATE; group D (n = 14, 50 ± 10 years) administered approximately 3.7 GBq (100 mCi) 177Lu-DOTA-EB-TATE. Treatment-related adverse events were graded according to the CTCAE v.5.0. 68Ga-DOTATATE PET/CT were performed at baseline and 2-3 months after treatment for response evaluation. RESULTS: Administration was well tolerated. No CTC 3/4 hematotoxicity, nephrotoxicity, or hepatotoxicity was observed during or after treatment in groups A-C. In group D, CTC-3 hematotoxicity was recorded in 2 patients with multicourse chemotherapy previously. After one-cycle treatment, the SUVmax decreased in group C (Δ% = - 17.4 ± 29.3%) and group D (Δ% = - 15.1 ± 39.1%), but greatly increased in group B (Δ% = 30.0 ± 68.0%) and mildly increased in group A (Δ% = 5.4 ± 45.9%). Referring to EORTC criteria, 16.7% (1/6), 0% (0/7), 50% (3/6), and 50% (7/14) were evaluated as partial response in groups A, B, C, and D, respectively. When selecting lesions with comparable baseline SUVmax ranging from 15 to 40, SUVmax showed no significant decrease in group B (Δ% = - 7.3 ± 24.5%) (P = 0.214), significant decrease in group C (Δ% = - 34.9 ± 12.4%) (P = 0.001), and in group D (Δ% = - 17.9 ± 19.7%) (P = 0.012) as compared with group A with increased SUVmax (Δ% = 8.4 ± 48.8%). SUVmax significantly decreased in the EBTATE groups (groups B-D combined) (Δ% = - 19.0 ± 21.5%) as compared with the TATE group (P = 0.045). CONCLUSION: 177Lu-DOTA-EB-TATE is well tolerated and is more effective than 177Lu-DOTATATE. Both 1.85 GBq (50 mCi) and 3.7 GBq (100 mCi) doses appear to be more effective than 1.11 GBq (30 mCi) dose. Further investigation with more cycles of 177Lu-DOTA-EB-TATE treatment and longer follow-up is warranted. TRIAL REGISTRATION: Treatment Using 177Lu-DOTA-EB-TATE in Patients with Advanced Neuroendocrine Tumors (NCT03478358). URL: https://register.clinicaltrials.gov/prs/app/action/ViewOrUnrelease?uid=U0001JRW&ts=13&sid=S0007RNX&cx=y3yqv4.

Integrin αvß3-targeted radionuclide therapy combined with immune checkpoint blockade immunotherapy synergistically enhances anti-tumor efficacy.

RATIONALE: Radiotherapy combined with immunotherapy has revealed promising outcomes in both preclinical studies and ongoing clinical trials. Targeted radionuclide therapy (TRT) is a branch of radiotherapy concerned with the use of radioisotopes, radiolabeled molecules or nanoparticles that deliver particulate radiation to cancer cells. TRT is a promising approach in cases of metastatic disease where conventional treatments are no longer effective. The increasing use of TRT raises the question of how to best integrate TRT with immunotherapy. In this study, we proposed a novel therapeutic regimen that combined programmed death ligand 1 (PD-L1)-based immunotherapy with peptide-based TRT (177Lu as the radionuclide) in the murine colon cancer model. METHODS: To explore the most appropriate timing of immunotherapy after radionuclide therapy, the anti-PD-L1 antibody (αPD-L1 mAb) was delivered in a concurrent or sequential manner when 177Lu TRT was given. RESULTS: The results demonstrated that TRT led to an acute increase in PD-L1 expression on T cells, and TRT in combination with αPD-L1 mAb stimulated the infiltration of CD8+ T cells, which improved local tumor control, overall survival and protection against tumor rechallenge. Moreover, our data revealed that the time window for this combination therapy may be critical to outcome. CONCLUSIONS: This therapeutic combination may be a promising approach to treating metastatic tumors in which TRT can be used. Clinical translation of the result would suggest that concurrent rather than sequential blockade of the PD-1/PD-L1 axis combined with TRT improves overall survival and long-term tumor control.

Tumour microenvironment-responsive semiconducting polymer-based self-assembly nanotheranostics.

A Pt prodrug polyphenol and gadolinium ion loaded cancer theranostics nanoplatform based on mild acidic pH and thermal sensitive polymer was designed for photoacoustic (PA)/ magnetic resonance(MR)/ positron emission tomography (PET) multimodal imaging-guided chemo-photothermal combination therapy. The Pt drug release can be controlled by tumour-specific acidic pH and heat generated by external NIR irradiation. The nanoparticles were stable under normal physiological environment and released the drug under tumour acidic pH and NIR laser irradiation, which can reduce the side effect of drug to normal organs. Moreover, the MR signal can be significantly enhanced (~3-fold increase in T1 relaxivity) under the acidic tumour microenvironment, which is favorable for cancer diagnosis. The nanoparticles exhibited excellent tumour accumulation and led to complete tumour eradication with low power NIR laser irradiation. This promising approach provides a new avenue for imaging-guided combination therapy.

Polyphenol-based nanoplatform for MRI/PET dual-modality imaging guided effective combination chemotherapy.

Combination therapy with multiple chemotherapeutic agents is the main approach for cancer treatment in the clinic. Polyphenol-based materials are found in our diet, demonstrate good biocompatibility, and prevent numerous diseases. In this study, we encapsulate two drugs in a single polyphenol-based polymer with Fe3+ or Mn2+ ions as the cross-linker for cancer therapy. The combination index of two drugs is an essential parameter to evaluate drug combinations. The amphiphilic polymer poly(ethylene glycol)-block-polydopamine (PEG-PDA) was prepared by RAFT polymerization. The nanoparticles were prepared via self-assembly with Fe3+ or Mn2+ ions. Both doxorubicin (DOX) and simvastatin (SV) were encapsulated in the core of the nanoparticles. The cell viability and combination index were evaluated in vitro. The tumor accumulation of the nanoparticles was investigated by positron-emission tomography (PET) and magnetic resonance (MR) imaging. The as-prepared nanoparticles exhibited high drug loading capacity. The drug loaded nanoparticles could kill cancer cells effectively with a combination index <1. Both PET and MRI revealed that the nanoparticles showed long blood circulation time and high tumor accumulation. The nanoparticles could inhibit tumor inhibition via intravenous injection of nanoparticles. The polyphenol-based nanoplatform may serve as a promising theranostic candidate for clinical application.