Tumor pH Research Articles

Tumor-specific delivery of clickable inhibitor for PD-L1 degradation and mitigating resistance of radioimmunotherapy.

Achieving selective and durable inhibition of programmed death ligand 1 (PD-L1) in tumors for T cell activation remains a major challenge in immune checkpoint blockade therapy. We herein presented a set of clickable inhibitors for spatially confined PD-L1 degradation and radioimmunotherapy of cancer. Using metabolic glycan engineering click bioorthogonal chemistry, PD-L1 expressed on tumor cell membranes was labeled with highly active azide groups. This enables covalently binding of the clickable inhibitor with PD-L1 and subsequent PD-L1 degradation. A pH-activatable nanoparticle responding to extracellular acidic pH of tumor was subsequently used to deliver the clickable PD-L1 inhibitor into extracellular tumor microenvironment for depleting PD-L1 on the surface of tumor cell and macrophage membranes in vivo. We further demonstrated that a combination of the clickable PD-L1 inhibitor with radiotherapy (RT) eradicated the established tumor by inhibiting RT-up-regulated PD-L1 in the tumor tissue. Therefore, selective PD-L1 blockade in tumors via the clickable PD-L1 inhibitor offers a versatile approach to promote cancer immunotherapy.

PH sensitive lipid polymeric hybrid nanoparticle (LPHNP) of paclitaxel and curcumin for targeted delivery in breast cancer

Objective The study aimed at designing a pH sensitive Lipid polymeric Hybrid nanoparticle (LPHNP) for targeted release of Paclitaxel (PTX) and Curcumin (CUR) in breast cancer. Significance Such systems shall result in controlled triggered release in acidic microenvironment of tumor cells with improved pharmacokinetic profile. Methods Chitosan-coated CUR and PTX coloaded pH-sensitive LPHNPs were synthesized employing nanoprecipitation technique. The synthesized NPs were characterized in terms of particle size, polydispersity index (PDI), zeta potential, and morphology. Results LPHNPs co-loaded with curcumin (CUR) and paclitaxel (PTX) were successfully formulated, achieving a size of 146 nm, a PDI of 0.18, and an entrapment efficiency exceeding 90%. In vitro release studies demonstrated controlled release of CUR and PTX under tumor pH conditions showing 1.6 fold and 1.7 fold higher release in ABS pH 5 in comparison to PBS 7.4 for PTX and CUR respectively. MTT-assay studies revealed enhanced cytotoxicity of CUR and PTX as LPHNPs showing IC50 value of free CUR & PTX 480.06 µg/mL decreasing to 282.97 µg/mL for CS-CUR-PTX-LPHNPs. In vivo pharmacokinetic evaluations in rats confirmed significantly improved bioavailability, with a 3.8-fold increase in AUC for CUR and a 6.6-fold increase for PTX. Additionally, the LPHNPs demonstrated controlled release and prolonged retention, evidenced by a 2.2-fold increase in the half-life (t1/2) of CUR and a 1.3-fold increase in the half-life of PTX. Conclusions: The results underscores potential of chitosan-coated LPHNP as a promising delivery platform, offering high drug loading, optimal size for cellular penetration, and prolonged blood circulation for cancer.

Synthesis and Optimization of Ethylenediamine-Based Zwitterion on Polymer Side Chain for Recognizing Narrow Tumorous pH Windows.

Polyzwitterions that show the alternation of net charge in response to external stimuli have attracted great attention as a new class of surface-polymers on nanomedicines. However, the correlation between their detailed molecular structures and expression of antifouling properties under physiological condition remain controversial. Herein, we synthesized a series of ethylenediamine-based polyzwitterions with carboxy groups/sulfonic groups and ethylene, propylene, and butylene spacers as potential surface-polymers for nanomedicines, allowing sensitive recognition of tumor acidic environments (pH = 6.5-5.5). Then, we evaluated their structure-based characteristics, including pH-dependent cellular uptakes and intracellular distributions. Additionally, the role of conformation stability, i.e., Gibbs free energy changes, was to induce an intramolecular electrostatic interaction in the zwitterionic moieties. These results highlight the practicality of fine-tuning the design of zwitterionic moieties on polymers for the future development of nanomedicines that can recognize the narrow pH window in tumor acidic environments.

Developing a Photoacoustic Probe for in vivo Tumor pH Detection by Gaussian calculation

pH dysregulation is a major feature of cancer, and the development of advanced photoacoustic probes capable of monitoring pH is important for both diagnosis and treatment of cancer. Previous work (done by Tijana Jokic’s group) found that aza-BODIPY molecule has better photoacoustic properties and this was investigated in depth, leading to the development of new pH probes, but the functionality of the molecule can be upgraded again if the photoacoustic properties of the molecule can be further expanded, while the maximum wavelength of the molecule can be further extended to fit the commercial range. This study optimized the previous molecule based on the Gaussian program, and the new molecule with NO2 attached to R4 showed the best properties in which the maximum excitation wavelength reached 770.85 nm.

Photosensitizing metal–organic framework nanoparticles combined with tumor-sensitization strategies can enhance the phototherapeutic effect upon medullary thyroid carcinoma

Photodynamic therapy (PDT) utilizing metal-organic frameworks (MOFs) has developed as a new and efficacious treatment for malignant tumors located on the surface of the human body. In order to achieve more effective PDT treatment outcomes, the traditional method has been to increase the intensity of the laser irradiation, but this approach can easily lead to tissue burns. In this study, we developed a new type of nanoparticle, F68-PKI@PCN224, aims to achieve effective PDT upon medullary thyroid carcinoma (MTC) which is an uncommon form of thyroid cancer that originates in the parafollicular cells of the thyroid and the therapeutic outlook for patients with MTC remains unsatisfactory. F68-PKI@PCN224 combines the antitumor features of PDT with mammalian target of rapamycin (mTOR) inhibitor PKI-587 (PKI). The tumor sensitization, slow release, and pH response features of F68-PKI@PCN224 was demonstrated by a series of in vitro and in vivo experiments / assays. F68-PKI@PCN224 achieved the long-term activation and slow releasing of PKI and TCPP in MTC tumor tissues. During the process of generating PDT effects, F68-PKI@PCN224 enhanced the tumor's sensitivity to PDT, direct laser irradiation of MTC cells or subcutaneous tumor tissues. As a result, low-dose phototherapy achieves a higher anti-tumor effect upon F68-PKI@PCN224 compared with TCPP. This study reveals the synergistic effect between tumor sensitization by mTOR inhibitor and PDT and initially unveils the mechanism of action of these nanoparticles.

Autophagic cell death induced by pH modulation for enhanced iron-based chemodynamic therapy

Iron-based chemodynamic therapy (CDT) exhibits commendable biocompatibility and selectivity, but its efficacy is constrained by the intracellular pH of tumors. To overcome this obstacle, we constructed a silica delivery platform loaded with autophagy-inducing reagents (rapamycin, RAPA) and iron-based Fenton reagents (Fe3O4). This platform was utilized to explore a novel strategy that leverages autophagy to decrease tumor acidity, consequently boosting the effectiveness of CDT. Both in vitro and in vivo experiments revealed that RAPA prompted the generation of acidic organelles (e.g., autophagic vacuoles and autophagosomes), effectively changing the intracellular pH in the tumor microenvironment. Furthermore, RAPA-induced tumor acidification significantly amplified the efficacy of Fe3O4-based Fenton reactions, consequently increasing the effectiveness of Fe3O4-based CDT. This innovative approach, which leverages the interplay between autophagy induction and iron-based CDT, shows promise in overcoming the limitations posed by tumor pH, thus offering a more efficient approach to tumor treatments.

BJS 2 - Tumour targeted oxygen-generating nanoparticles for enhanced radiotherapy in the treatment of pancreatic cancer

Abstract Aim To determine if novel oxygen-generating nanoparticles, encased in a pH-sensitive polymethacrylate polymer (SOG-01), can enhance radiotherapy-based treatment in a preclinical pancreatic cancer model. SOG-01 nanoparticles are stable in circulation and, at the lower pH in hypoxic tumours, the polymer coating dissolves to expose a solid peroxide core, capable of generating oxygen in the tumour microenvironment. Since hypoxia reduces the efficacy of radiotherapy, this particle could potentially be employed to enhance radiotherapy-based approaches for the treatment of pancreatic cancer. Methods A human xenograft pancreatic cancer model (BxPC-3) in mice was employed as a target. SOG-01 was administered systemically and animals (n=6 per experimental group) were subsequently treated with radiation (a single dose of 6 Gy) using a Gulmay (160kV) AGO HS-MP1 X-Ray generator. Control animals were either untreated, treated with SOG-01 alone, or radiation alone. Tumour size and survival were employed as a measure of therapeutic efficacy. Results When the mean tumour size of groups treated with SOG-01 or radiation alone was compared with that of the untreated group at day 23 no statistically significant decrease was observed. However, a dramatic 89% and statistically significant decrease (p = 0.001; α = 0.05) was observed for tumours treated with combination of SOG-01 and radiation. Additionally, Kaplan Meier analysis demonstrated enhanced survival to 65 days when compared with 38 day survival for the group treated with radiation alone. Conclusions The data suggest that SOG-01 may play a role in enhancing radiotherapy-based approaches for the treatment of pancreatic cancer.

A novel Nav1.5-dependent feedback mechanism driving glycolytic acidification in breast cancer metastasis

Solid tumours have abnormally high intracellular [Na+]. The activity of various Na+ channels may underlie this Na+ accumulation. Voltage-gated Na+ channels (VGSCs) have been shown to be functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood. Here, we show that protein expression of the Nav1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts. Knockdown of Nav1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Nav1.5 activity increases ATP demand and glycolysis in breast cancer cells, likely by upregulating activity of the Na+/K+ ATPase, thus promoting H+ production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis. In turn, acidic extracellular pH elevates persistent Na+ influx through Nav1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and the movement of Na+ into cancer cells which can facilitate invasion. These results highlight the clinical significance of Nav1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment.

Development and Validation of Four Different Methods to Improve MRI-CEST Tumor pH Mapping in Presence of Fat.

CEST-MRI is an emerging imaging technique suitable for various in vivo applications, including the quantification of tumor acidosis. Traditionally, CEST contrast is calculated by asymmetry analysis, but the presence of fat signals leads to wrong contrast quantification and hence to inaccurate pH measurements. In this study, we investigated four post-processing approaches to overcome fat signal influences and enable correct CEST contrast calculations and tumor pH measurements using iopamidol. The proposed methods involve replacing the Z-spectrum region affected by fat peaks by (i) using a linear interpolation of the fat frequencies, (ii) applying water pool Lorentzian fitting, (iii) considering only the positive part of the Z-spectrum, or (iv) calculating a correction factor for the ratiometric value. In vitro and in vivo studies demonstrated the possibility of using these approaches to calculate CEST contrast and then to measure tumor pH, even in the presence of moderate to high fat fraction values. However, only the method based on the water pool Lorentzian fitting produced highly accurate results in terms of pH measurement in tumor-bearing mice with low and high fat contents.

Electric Field-Responsive Gold Nanoantennas for the Induction of a Locoregional Tumor pH Change Using Electrolytic Ablation Therapy.

Electrolytic ablation (EA) is a burgeoning treatment for solid tumors, in which electrical energy catalyzes a chemical reaction to generate reactive species that can eradicate cancer cells. However, the application of this technique has been constrained owing to the limited spatial effectiveness and complexity of the electrode designs. Therefore, the incorporation of nanotechnology into EA is anticipated to be a significant improvement. Herein, we present a therapeutic approach based on difructose dianhydride IV-conjugated polyethylenimine-polyethylene glycol-modified gold nanorods as electric nanoantennas and nanoelectrocatalysts for EA. We demonstrate that square-wave direct current (DC) fields trigger a reaction between water molecules and chloride ions on the gold nanorod surface, generating electrolytic products including hydrogen, oxygen, and chlorine gases near the electrodes, changing the pH, and inducing cell death. These electric nanoantennas showed significant efficacy in treating colorectal cancer both in vitro and in vivo after DC treatment. These findings clearly indicate that gold nanoantennas enhance the effectiveness of EA by creating a localized electric field and catalyzing electrolytic reactions for the induction of locoregional pH changes within the tumor. By overcoming the limitations of traditional EA and offering an enhanced level of tumor specificity and control, this nanotechnology-integrated approach advances further innovations in cancer therapies.

Tumor-targeting and activatable biomimetic nanococktails synergistically regulate immune responses for spatiotemporal immunotherapy of low immunogenic solid tumors

Cancer immunotherapy is generally limited by the low immunogenicity of tumor microenvironments (TME). Thus, regulating immune responses in low immunogenic solid tumors is critical for improving immunotherapeutic outcomes. Here, the tumor-targeting and activatable biomimetic nanococktails have been engineered to synergistically and systemically activate a cascade of immune responses and downregulate immunosuppressive T cells for spatiotemporal immunotherapy of low immunogenic solid tumors. The nanococktails had core-shell structures, where the photosensitizers, STING agonists and indoleamine 2,3-dioxygen-ase 1 (IDO1) inhibitors were encapsulated within the core, which can disassociate when responding to the low pH in tumors to disrupt the particle shells and cellular membranes for precision drug delivery and release. The ligands anchored on the shell of nanococktails could efficiently target the receptors that were identified to be highly expressed in the breast cancer cells, facilitating efficient intracellular drug delivery and synergistically inducing anticancer immunity and mitochondrial damage. By intravenous (i.v.) injection, the nanococktails demonstrated high accumulation in triple-negative breast cancer (TNBC), endowing precision diagnosis and effective elimination of primary TNBC tumors. The synergistic effects of STING activation and metalloimmunotherapy induced by nanococktails can amplify systemic immune responses and downregulate immunosuppressive regulatory T cells (Tregs) in primary tumors, lymph nodes and distant tumors, which spatiotemporally inhibited distant tumors and lung metastasis of TNBC with promoted survival rates. This study presents a promising strategy for leveraging nanococktails to regulate immune responses for effective immunotherapy.

Synthesis and toxicity assessment of Coffea arabica extract-derived gold nanoparticles loaded with doxorubicin in lung cancer cell cultures.

Cancer is the second leading cause of death worldwide, despite the many treatments available, cancer patients face side effects that reduce their quality of life. Therefore, there is a need to develop novel strategies to increase the efficacy of treatments. In this study, gold nanoparticles obtained by green synthesis with Coffea arabica green bean extract were loaded with Doxorubicin, (a highly effective but non-specific drug) by direct interaction and using commercial organic ligands that allow colloidal dispersion at physiological and tumor pH. Conjugation of these components resulted in stable nanohybrids at physiological pH and a tumor pH release dependent, with a particle size less than 40nm despite having the ligands and Doxorubicin loaded on their surface, which gave them greater specificity and cytotoxicity in H69 tumor cells.

Design, Synthesis, and Acid-Responsive Disassembly of Shell-Sheddable Block Copolymer Labeled with Benzaldehyde Acetal Junction.

Smart nanoassemblies degradable through the cleavage of acid-labile linkages have attracted significant attention because of their biological relevance found in tumor tissues. Despite their high potential to achieve controlled/enhanced drug release, a systematic understanding of structural factors that affect their pH sensitivity remains challenging, particulary in the consruction of effective acid-degradable shell-sheddable nanoassemblies. Herein, the authors report the synthesis and acid-responsive degradation through acid-catalyzed hydrolysis of three acetal and ketal diols and identify benzaldehyde acetal (BzAA) exhibiting optimal hydrolysis profiles in targeted pH ranges to be a suitable candidate for junction acid-labile linkage. The authors explore the synthesis and aqueous micellization of well-defined poly(ethylene glycol)-based block copolymer bearing BzAA linkage covalently attached to a polymethacrylate block for the formation of colloidally-stable nanoassemblies with BzAA groups at core/corona interfaces. Promisingly, the investigation on acid-catalyzed hydrolysis and disassembly shows that the formed nanoassemblies meet the criteria for acid-degradable shell-sheddable nanoassemblies: slow degradation at tumoral pH = 6.5 and rapid disassembly at endo/lysosomal pH = 5.0, while colloidal stability at physiological pH = 7.4. This work guides the design principle of acid-degradable shell-sheddable nanoassemblies bearing BzAA at interfaces, thus offering the promise to address the PEG dilemma and improve endocytosis in tumor-targeting drug delivery.

Shell‐sheddable and charge switchable magnetic nanoparticle as pH‐sensitive nanocarrier for targeted drug delivery applications

AbstractA pH‐sensitive shell‐sheddable magnetic nanocarrier was prepared based on Fe3O4@SiO2 nanoparticles coated with polyethyleneimine (PEI) and polyethyleneglycol (PEG). The PEI was coated on Fe3O4@SiO2 nanoparticles through an electrostatic attraction and the PEG chains were connected to the PEI via pH‐sensitive benzoic‐imine bonds. The synthesized products and final nanocarrier were characterized with FT‐IR, 1H NMR, dynamic light scattering (DLS), zeta‐potential, TEM, and vibrating‐sample magnetometer (VSM). The PEI, as a middle layer, was used to load the curcumin (an anticancer drug) via van der Waals interactions and the shedding of PEG as a hydrophilic corona at the tumor pH (acidic) could induce the release of the drug. The curcumin loading content was found to be ~15% and curcumin‐loaded magnetic nanoparticles (C‐LMNs) showed more triggered release at the tumor pH (5.6) than physiological pH (7.4). In comparison to pure magnetic nanoparticles (MNs), the C‐LMNs showed more cytotoxicity to human prostate cancer cell (PC‐3) and also resulted in an increased rate of late apoptotic/necrotic PC‐3 cells, assessed by flow cytometry analysis. In conclusion, the C‐LMN as pH‐ and magnetic responsive nanocarrier showed good potential for targeted curcumin delivery in therapy of prostate cancer.

Kappa-carrageenan and sodium alginate-based pH-responsive hydrogels for controlled release of methotrexate.

Despite remarkable progress in medical sciences, modern man is still fighting the battle against cancer. In 2022, only in the USA, 640 000 deaths and 2 370 000 patients were reported because of cancer. Chemotherapy is the most widely used for cancer treatments. However, chemotherapeutics have severe physicochemical side effects. Therefore, we have prepared poly(amididoamine) dendrimeric carrageenan (CG), sodium alginate (SA) and poly(vinyl alcohol) (PVA) hydrogels by using solution casting methodology. The constituents of hydrogels were cross-linked by mutable quantity of 3-aminopropyl(diethoxy)methyl silane (APDMS). Hydrogels were characterized by Fourier transform infrared spectroscopy, thermal gravimetric analysis, scanning electron microscope and atomic force microscopy. Hydrogels exhibited higher swelling volumes in 5-7 pH range. In vitro biodegradation in ribonuclease-A solution and cytocompatibility analysis against DF-1 fibroblasts established their biodegradable and non-toxic nature, which enables them as a suitable carrier for chemotherapeutic compounds. Hence, methotrexate (MTX) as a model drug was loaded on CAP-8 hydrogel and its release was detected by the UV-visible spectrophotometer in phosphate-buffered saline (PBS) solution. In 13.5 h, 81.25% and 77.23% of MTX were released at pH 7.4 (blood pH) and 5.3 (tumour pH) in PBS, respectively. MTX was released by super case II mechanism and best fitted to zero-order and Korsmeyer-Peppas model. The synthesized APDMS cross-linked CG/SA/PVA dendrimeric hydrogels could be an efficient model platform for the effective delivery of MTX in cancer treatments.

L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy.

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds to CEACAM6, a cell-surface protein that is highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Using chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) to measure the tumor extracellular pH (pHe), we confirmed that L-DOS47 raises the tumor pHe from 4 h to 96 h post injection in acidic tumors (average increase of 0.13 units). Additional studies showed that combining L-DOS47 with anti-PD1 significantly increases the efficacy of the anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.

Tumor therapy by targeting extracellular hydroxyapatite using novel drugs: A paradigm shift.

It has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth. Additionally, acidosis in the TME has been reported to play a key role in selecting for a more aggressive tumor phenotype, drug resistance and desensitization to immunotherapy for many types of cancers. TME-HAP is an attractive target for tumor detection and treatment development since HAP is generally absent from normal soft tissue. We provide strong evidence that dissolution of hydroxyapatite (HAP) within the tumor microenvironment (TME-HAP) using a novel therapeutic can be used to kill cancer cells both in vitro and in vivo with minimal adverse effects. We developed an injectable cation exchange nano particulate sulfonated polystyrene solution (NSPS) that we engineered to dissolve TME-HAP, inducing localized acute alkalosis and inhibition of tumor growth and glucose metabolism. This was evaluated in cell culture using 4T1, MDA-MB-231 triple negative breast cancer cells, MCF10 normal breast cells, and H292 lung cancer cells, and in vivo using orthotopic mouse models of cancer that contained detectable microenvironment HAP including breast (MMTV-Neu, 4T1, and MDA-MB-231), prostate (PC3) and colon (HCA7) cancer using 18 F-NaF for HAP and 18 F-FDG for glucose metabolism with PET imaging. On the other hand, H292 lung tumor cells that lacked detectable microenvironment HAP and MCF10a normal breast cells that do not produce HAP served as negative controls. Tumor microenvironment pH levels following injection of NSPS were evaluated via Chemical Exchange Saturation (CEST) MRI and via ex vivo methods. Within 24 h of adding the small concentration of 1X of NSPS (~7 μM), we observed significant tumor cell death (~ 10%, p < 0.05) in 4T1 and MDA-MB-231 cell cultures that contain HAP but ⟨2% in H292 and MCF10a cells that lack detectable HAP and in controls. Using CEST MRI, we found extracellular pH (pHe) in the 4T1 breast tumors, located in the mammary fat pad, to increase by nearly 10% from baseline before gradually receding back to baseline during the first hour post NSPS administration. in the tumors that contained TME-HAP in mouse models, MMTV-Neu, 4T1, and MDA-MB-231, PC3, and HCA7, there was a significant reduction (p<0.05) in 18 F-Na Fuptake post NSPS treatment as expected; 18 F- uptake in the tumor = 3.8 ± 0.5 %ID/g (percent of the injected dose per gram) at baseline compared to 1.8 ±0.5 %ID/g following one-time treatment with 100 mg/kg NSPS. Of similar importance, is that 18 F-FDG uptake in the tumors was reduced by more than 75% compared to baseline within 24 h of treatment with one-time NSPS which persisted for at least one week. Additionally, tumor growth was significantly slower (p < 0.05) in the mice treated with one-time NSPS. Toxicity showed no evidence of any adverse effects, a finding attributed to the absence of HAP in normal soft tissue and to our therapeutic NSPS having limited penetration to access HAP within skeletal bone. Dissolution of TME-HAP using our novel NSPS has the potential to provide a new treatment paradigm to enhance the management of cancer patients with poor prognosis.

Acidic tumor microenvironment-activated MRI nanoprobes for modulation and visualization of anti-PD-L1 immunotherapy

Tumor acidity has emerged as a pivotal regulator of immune checkpoint blockade (ICB). However, acidity-based therapy presents challenges of low efficiency and lack of reliable imaging technology for assessing the immune response. Here we report a magnetic resonance imaging (MRI)-guided ICB therapy (MRGIT) strategy to modulate and visualize the efficacy of anti-PD-L1 in pancreatic ductal adenocarcinoma (PDAC). MRGIT was achieved by a pH responsive nanoprobe (APPAM@U-104) composed of ultrasmall iron oxide nanoparticles (USIONs) and a tumor pH regulator (U-104). Notably, the nanoprobes exhibited a T1 “ON” MR signal in acidic tumors but switched to a T2 “ON” MR signal in a neutralized tumor microenvironment, resulting in a switchable MR signal from T1 to T2 during real-time MRI monitoring. Moreover, the switch of MR signals can serve as an indicator for alleviating tumor immune suppression, thus guiding the timing of anti-PD-L1 therapy. Our results revealed that the MRGIT strategy can potentiate the antitumor efficacy of anti-PD-L1 against pancreatic tumors. Collectively, this strategy sensitively regulates and recognizes tumor acidosis, thus paving the way for the modulation and noninvasive monitoring of anti-PD-L1 efficacy in PDAC.

Metabolism-Regulating Nanozyme System for Advanced Nanocatalytic Cancer Therapy.

Nanocatalytic therapy, an emerging approach in cancer treatment, utilizes nanomaterials to initiate enzyme-mimetic catalytic reactions within tumors, inducing tumor-suppressive effects. However, the targeted and selective catalysis within tumor cells is challenging yet critical for minimizing the adverse effects. The distinctive reliance of tumor cells on glycolysis generates abundant lactate, influencing the tumor's pH, which can be manipulated to selectively activate nanozymatic catalysis. Herein, small interfering ribonucleic acid (siRNA) targeting lactate transporter-mediated efflux is encapsulated within the iron-based metal-organic framework (FeMOF) and specifically delivered to tumor cells through cell membrane coating. This approach traps lactate within the cell, swiftly acidifying the tumor cytoplasm and creating an environment for boosting the catalysis of the FeMOF nanozyme. The nanozyme generates hydroxyl radical (·OH) in the reversed acidic environment, using endogenous hydrogen peroxide (H2O2) produced by mitochondria as a substrate. The induced cytoplasmic acidification disrupts calcium homeostasis, leading to mitochondrial calcium overload, resulting in mitochondrial dysfunction and subsequent tumor cell death. Additionally, the tumor microenvironment is also remodeled, inhibiting migration and invasion, thus preventing metastasis. This groundbreaking strategy combines metabolic regulation with nanozyme catalysis in a toxic drug-free approach for tumor treatment, holding promise for future clinical applications.

Anti-tumor effect of pH-sensitive drug-loaded nanoparticles optimized via an integrated computational/experimental approach.

The acidic pH of tumor tissue has been used to trigger drug release from nanoparticles. However, dynamic interactions between tumor pH and vascularity present challenges to optimize therapy to particular microenvironment conditions. Despite recent development of pH-sensitive nanomaterials that can accurately quantify drug release from nanoparticles, tailoring release to maximize tumor response remains elusive. This study hypothesizes that a computational modeling-based platform that simulates the heterogeneously vascularized tumor microenvironment can enable evaluation of the complex intra-tumoral dynamics involving nanoparticle transport and pH-dependent drug release, and predict optimal nanoparticle parameters to maximize the response. To this end, SPNCD nanoparticles comprising superparamagnetic cores of iron oxide (Fe3O4) and a poly(lactide-co-glycolide acid) shell loaded with doxorubicin (DOX) were fabricated. Drug release was measured in vitro as a function of pH. A 2D model of vascularized tumor growth was calibrated to experimental data and used to evaluate SPNCD effect as a function of drug release rate and tissue vascular heterogeneity. Simulations show that pH-dependent drug release from SPNCD delays tumor regrowth more than DOX alone across all levels of vascular heterogeneity, and that SPNCD significantly inhibit tumor radius over time compared to systemic DOX. The minimum tumor radius forecast by the model was comparable to previous in vivo SPNCD inhibition data. Sensitivity analyses of the SPNCD pH-dependent drug release rate indicate that slower rates are more inhibitory than faster rates. We conclude that an integrated computational and experimental approach enables tailoring drug release by pH-responsive nanomaterials to maximize the tumor response.