Combined Photothermal Chemotherapy for Effective Treatment Against Breast Cancer in Mice Model.

Introduction: Breast cancer ranks among the most prevalent cancers in women, characterized by significant morbidity, disability, and mortality. Presently, chemotherapy is the principal clinical approach for treating breast cancer; however, it is constrained by limited targeting capability and an inadequate therapeutic index. Photothermal therapy, as a non-invasive approach, offers the potential to be combined with chemotherapy to improve tumor cellular uptake and tissue penetration. In this research, a mesoporous polydopamine-coated gold nanorod nanoplatform, encapsulating doxorubicin (Au@mPDA@DOX), was developed. Methods: This nanoplatform was constructed by surface coating mesoporous polydopamine (mPDA) onto gold nanorods, and doxorubicin (DOX) was encapsulated in Au@mPDA owing to π-π stacking between mPDA and DOX. The dynamic diameter, zeta potential, absorbance, photothermal conversion ability, and drug release behavior were determined. The cellular uptake, cytotoxicity, deep penetration, and anti-tumor effects were subsequently investigated in 4T1 cells. After that, fluorescence imaging, photothermal imaging and pharmacodynamics studies were utilized to evaluate the anti-tumor effects in tumor-bearing mice model. Results: This nanoplatform exhibited high drug loading capacity, excellent photothermal conversion and, importantly, pH/photothermal dual-responsive drug release behavior. The in vitro results revealed enhanced photothermal-facilitated cellular uptake, drug release and tumor penetration of Au@mPDA@DOX under near-infrared irradiation. In vivo studies confirmed that, compared with monotherapy with either chemotherapy or photothermal therapy, the anti-tumor effects of Au@mPDA@DOX are synergistically improved. Conclusion: Together with good biosafety and biocompatibility, the Au@mPDA@DOX nanoplatform provides an alternative method for safe and synergistic treatment of breast cancer.

Combined Chemo- and Photothermal Therapies of Non-Small Cell Lung Cancer Using Polydopamine/Au Hollow Nanospheres Loaded with Doxorubicin.

Purpose: The chemotherapeutic agent doxorubicin (DOX) is limited by its cardiotoxicity, posing challenges in its application for non-small cell lung cancer (NSCLC). This study aims to explore the efficacy of polydopamine/Au nanoparticles loaded with DOX for chemotherapy and photothermal therapy in NSCLC to achieve enhanced efficacy and reduced toxicity. Methods: Hollow polydopamine (HPDA)/Au@DOX was synthesized via polydopamine chemical binding sacrificial template method. Morphology was characterized using transmission electron microscopy, particle size and potential were determined using dynamic light scattering, and photothermal conversion efficiency was assessed using near-infrared (NIR) thermal imaging. Drug loading rate and in vitro drug release were investigated. In vitro, anti-tumor experiments were conducted using CCK-8 assay, flow cytometry, and live/dead cell staining to evaluate the cytotoxicity of HPDA/Au@DOX on A549 cells. Uptake of HPDA/Au@DOX by A549 cells was detected using the intrinsic fluorescence of DOX. The in vivo anti-metastasis and anti-tumor effects of HPDA/Au@DOX were explored in mouse lung metastasis and subcutaneous tumor models, respectively. Results: HPDA/Au@DOX with a particle size of (164.26±3.25) nm, a drug loading rate of 36.31%, and an encapsulation efficiency of 90.78% was successfully prepared. Under 808 nm laser irradiation, HPDA/Au@DOX accelerated DOX release and enhanced uptake by A549 cells. In vitro photothermal performance assessment showed excellent photothermal conversion capability and stability of HPDA/Au@DOX under NIR laser irradiation. Both in vitro and in vivo experiments demonstrated that the photothermal-chemotherapy combination group (HPDA/Au@DOX+NIR) exhibited stronger anti-metastatic and anti-tumor activities compared to the monotherapy group (DOX). Conclusion: HPDA/Au@DOX nanosystem demonstrated excellent photothermal effect, inhibiting the growth and metastasis of A549 cells. This nanosystem achieves the combined effect of chemotherapy and photothermal, making it promising for NSCLC treatment.

Switchable PAMAM megamers for deep tumor penetration and enhanced cell uptake.

Nanoparticles fabricated to deliver anticancer drugs are usually designed to present optimized tumor penetration and cell internalization. However, there are some barriers and difficulties with most current technologies. Herein, size and charge switchable polyamidoamine (PAMAM) megamers (SChPMs) were prepared for the delivery of doxorubicin (DOX). SChPMs were fabricated by connecting PAMAM dendrimers with pH-sensitive bonds and surface PEGylation. At pH 7.4, the size and surface charge of these nanocarriers were approximately 100 nm and + 0.75 mV, but at the acidic extracellular pH of tumor cells (pH 6.5), their size were reduced dramatically (15 nm) and their surface charge increased to +6.7 mV. Cell studies confirmed that alteration of the size and surface charge enhanced their penetration into multicellular spheroids and cell internalization. These megamers, in addition to delivering the drug to the deeper areas of the tumor, could powerfully overcome physiological resistance to anthracycline-based drugs. The nanocarrier revealed enhanced antitumoral activity in animal studies. Toxicology studies and histopathological assessments of vital tissues of 4 T1 tumor bearing mice indicated minimal tissue damage when DOX-loaded SChPMs (DSChPMs) were used. It can be concluded that the versatile and agile nanocarriers developed in this study could be considered for further investigations into their clinical application.

Milk-derived extracellular vesicles enable gut-to-tumor oral delivery of tumor-activated doxorubicin prodrugs.

Rationale: Oral chemotherapy has been emerging as a hopeful therapeutic regimen for the treatment of various cancers because of its high safety and convenience, lower costs, and high patient compliance. Despite the current advancements in nanoparticle-mediated drug delivery, numerous anticancer drugs susceptible to the hostile gastrointestinal (GI) environment exhibit poor permeability across the intestinal epithelium, rendering them ineffective in providing therapeutic benefits. In this paper, we focus on harnessing milk-derived extracellular vesicles (mEVs) for gut-to-tumor oral drug delivery by leveraging their high bioavailability. Methods: The tumor-activated prodrug (a cathepsin B-specific cleavable FRRG peptide and doxorubicin, FDX) is used as a model drug and is complexed with mEVs, resulting in FDX@mEVs. To verify stability in the GI tract, prolonged intestinal retention, and enhanced trans-epithelial transport via neonatal Fc receptor (FcRn)-mediated transcytosis, intestinal transport evaluation is conducted using in vitro intestinal barrier model and mouse model. Results: FDX@mEVs form a stable nanostructure with an average diameter of 131.1 ± 70.5 nm and complexation processes do not affect the inherent properties of FDX. Orally administered FDX@mEVs show significantly improved bioavailability compared to uncomplexed FDX via FcRn-mediated transcytosis of mEVs resulting in increased tumor accumulation of FDX in tumor-bearing mouse model. Conclusions: After oral administration of FDX@mEVs, it is observed that remarkable antitumor efficacy in colon tumor-bearing mice without adverse effects, such as body weight loss, liver/kidney dysfunction, and cardiotoxicity.

Impact of formulation parameters and circulation time on PEGylated liposomal doxorubicin related hand-foot syndrome.

PEGylated liposomal doxorubicin (PLD) has effectively reduced the cardiac toxicity of free doxorubicin (DOX) due to its unique nanoscale properties. However, an unexpected accumulation of PLD in the skin has led to hand-foot syndrome (HFS), negatively impacting quality of life and psychological well-being. In this study, self-limiting HFS rat models were created to mimic human symptoms through varying dosing schedules and intensities of PLD. The effects of PLD formulation parameters on HFS were also investigated. The results demonstrated that replacing ammonium sulfate with citric buffer, increasing liposome size, or reducing DSPE-mPEG2000 modification density alleviated HFS. Additionally, liposomes without DSPE-mPEG2000 modification completely avoided HFS, suggesting that PEGylated phospholipid was the key formulation parameter contributing to PLD-induced HFS. Furthermore, the correlation between liposome pharmacokinetics and HFS indicated that PEGylation, rather than the extended circulation time of liposomes, may mediated PLD-related HFS. Better understanding of the formulation parameters that trigger HFS can guide reformulation strategies to mitigate or prevent this syndrome.

Hybrid Liposome-MSN System with Co-Delivering Potential Effective Against Multidrug-Resistant Tumor Targets in Mice Model.

Introduction: RNA interference (RNAi) stands as a widely employed gene interference technology, with small interfering RNA (siRNA) emerging as a promising tool for cancer treatment. However, the inherent limitations of siRNA, such as easy degradation and low bioavailability, hamper its efficacy in cancer therapy. To address these challenges, this study focused on the development of a nanocarrier system (HLM-N@DOX/R) capable of delivering both siRNA and doxorubicin for the treatment of breast cancer. Methods: The study involved a comprehensive investigation into various characteristics of the nanocarrier, including shape, diameter, Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), encapsulation efficiency, and drug loading. Subsequently, in vitro and in vivo studies were conducted on cytotoxicity, cellular uptake, cellular immunofluorescence, lysosome escape, and mouse tumor models to evaluate the efficacy of the nanocarrier in reversing tumor multidrug resistance and anti-tumor effects. Results: The results showed that HLM-N@DOX/R had a high encapsulation efficiency and drug loading capacity, and exhibited pH/redox dual responsive drug release characteristics. In vitro and in vivo studies showed that HLM-N@DOX/R inhibited the expression of P-gp by 80%, inhibited MDR tumor growth by 71% and eliminated P protein mediated multidrug resistance. Conclusion: In summary, HLM-N holds tremendous potential as an effective and targeted co-delivery system for DOX and P-gp siRNA, offering a promising strategy for overcoming MDR in breast cancer.

LC-MS/MS method for simultaneous Doxorubicin and Baicalein estimation: formulation and pharmacokinetic applications.

Aim & objective: Combinatorial delivery of Doxorubicin (DOX) and Baicalein (BAC) has a potential to improve breast cancer treatment by mitigating the cardiotoxicity induced by DOX. The nanoformulation has been optimized and subjected to pharmacokinetic studies using LC-MS/MS.Materials & methods: Nanoformulation bearing DOX and BAC was optimized using quality by design approach and method validation was done following USFDA guidelines.Results: The particle size, PDI and zeta potential of developed nanoformulation were 162.56 ± 2.21 nm, 0.102 ± 0.03 and -16.5 ± 1.21 mV, respectively. DOX-BAC-SNEDDs had a higher AUC0-t values of 6128.84 ± 68.71 and 5896.62 ± 99.31 ng/mL/h as compared with DOX-BAC suspension.Conclusion: These findings hold promise for advancing breast cancer treatment and facilitating therapeutic drug monitoring.

[Box: see text].

Starch-based "smart" nanomicelles: Potential delivery systems for doxorubicin.

Vesicular nanosystems are a cornerstone to the contemporary drug delivery paradigm owing to their ability to encapsulate a variety of drug molecules, which improves the overall pharmacokinetics and bioavailability of the cargo drug. These systems have proven potential in the delivery of hydrophobic chemotherapeutic "Doxorubicin" (DOX), which faces frequent challenge relating to its nonspecific interactions, dose-limiting toxicity (myelosuppression being the most common manifestation), and short half-life (distribution half-life of 5 min, terminal half-life of 20-48 h), which limit its overall clinical effectiveness. "Smart" nanomicelles with stimuli-responsive linkages take advantage of tumor microenvironment for deploying the cargo drug at the target site, which prevents nonspecific distribution and, hence, low toxicity. Similarly, those with stealth properties evade protein response, which triggers the immunogenic response. The nanomicelles co-loaded with magnetic nanoparticles provide additional utility such as contrast enhancement agents in theranostics. Overall, the starch-based nanomicelles prove to be an excellent delivery system for overcoming the limitations associated with the conventional DOX delivery regime.

Physicochemical profiling of nanomedicines using centrifugal field flow fractionation.

Nanomedicines comprise multiple components, and particle density is considered an important property that regulates the biodistribution of administered nanomedicines. The density of nanoparticles is characterized by centrifugal methods, such as analytical ultracentrifugation. Particle size and distribution are key physicochemical and quality attributes of nanomedicines. In this study, we developed a novel profiling method applicable to liposomes and lipid nanoparticles (LNPs), based on particle size and density, using centrifugal field-flow fractionation (CF3). We evaluated the elution profiles of PEGylated liposomes of different sizes with various doxorubicin (DOX)-loading amounts using CF3. This method was applied to evaluate the drug release of DOX-loaded liposomes, intra- and inter-batch variability, reconstitution reproducibility of AmBisome®, and elution characteristics of LNPs in COVID-19 vaccines (Comirnaty® and SpikevaxTM). The data obtained in the present study underscore the significance of the proposed methodology and highlight the importance of profiling and characterizing liposomes and LNPs using CF3 fractograms and a multi-angle light-scattering detector.

ROS-Responsive Nanoprobes for Bimodal Imaging-Guided Cancer Targeted Combinatorial Therapy.

Purpose: Chemotherapy mediated by Reactive oxygen species (ROS)-responsive drug delivery systems can potentially mitigate the toxic side effects of chemotherapeutic drugs and significantly enhance their therapeutic efficacy. However, achieving precise targeted drug delivery and real-time control of ROS-responsive drug release at tumor sites remains a formidable challenge. Therefore, this study aimed to describe a ROS-responsive drug delivery system with specific tumor targeting capabilities for mitigating chemotherapy-induced toxicity while enhancing therapeutic efficacy under guidance of Fluorescence (FL) and Magnetic resonance (MR) bimodal imaging. Methods: Indocyanine green (ICG), Doxorubicin (DOX) prodrug pB-DOX and Superparamagnetic iron oxide (SPIO, Fe3O4) were encapsulated in poly(lactic-co-glycolic acid) (PLGA) by double emulsification method to prepare ICG/ pB-DOX/ Fe3O4/ PLGA nanoparticles (IBFP NPs). The surface of IBFP NPs was functionalized with mammaglobin antibodies (mAbs) by carbodiimide method to construct the breast cancer-targeting mAbs/ IBFP NPs (MIBFP NPs). Thereafter, FL and MR bimodal imaging ability of MIBFP NPs was evaluated in vitro and in vivo. Finally, the combined photodynamic therapy (PDT) and chemotherapy efficacy evaluation based on MIBFP NPs was studied. Results: The multifunctional MIBFP NPs exhibited significant targeting efficacy for breast cancer. FL and MR bimodal imaging clearly displayed the distribution of the targeting MIBFP NPs in vivo. Upon near-infrared laser irradiation, the MIBFP NPs loaded with ICG effectively generated ROS for PDT, enabling precise tumor ablation. Simultaneously, it triggered activation of the pB-DOX by cleaving its sensitive moiety, thereby restoring DOX activity and achieving ROS-responsive targeted chemotherapy. Furthermore, the MIBFP NPs combined PDT and chemotherapy to enhance the efficiency of tumor ablation under guidance of bimodal imaging. Conclusion: MIBFP NPs constitute a novel dual-modality imaging-guided drug delivery system for targeted breast cancer therapy and offer precise and controlled combined treatment options.

A multi-nozzle nebuliser does not improve tissue drug delivery during PIPAC.

BACKGROUND: Multi-nozzle nebulisers for pressurised intraperitoneal aerosol chemotherapy (PIPAC) are implemented in clinical practice to improve the homogeneity of tissue drug delivery. Nonetheless, the advantages of such devices over one-nozzle nebulisers have not been demonstrated thus far. In this study, we compared the performance of multi- and one-nozzle nebulisers by conducting physical and ex vivo pharmacological experiments. METHODS: The one-nozzle nebuliser Capnopen® and the multi-nozzle nebuliser were the subjects of this study. In physical experiments, the aerosol droplet size was measured by laser diffraction spectroscopy. Spatial spray patterns were depicted on blotting paper. Pharmacological experiments were performed on the enhanced inverted bovine urinary bladder model, demonstrating real-time tissue drug delivery, aerosol sedimentation and homogeneity of doxorubicin and cisplatin tissue distribution. RESULTS: The multi-nozzle nebuliser had a sixfold greater aerosolisation flow and a threefold greater angle of aerosolisation than Capnopen®. The aerosol particle size and distribution range were higher than that of Capnopen®. Spray patterns on blotting paper were more extensive with the multi-nozzle nebuliser. Real-time tissue drug delivery with the multi-nozzle nebuliser was over 100 ml within 1 min, and the aerosol sedimentation was 48.9% ± 21.2%, which was not significantly different from that of Capnopen®. The doxorubicin and cisplatin tissue concentrations were greater with Capnopen®. Although there was no significant difference in the homogeneity of doxorubicin distribution between the two devices, the homogeneity of cisplatin distribution was significantly higher with Capnopen®. CONCLUSION: The multi-nozzle PIPAC nebuliser did not fulfil expectations. Even though the surface spray patterns were broader with the multi-nozzle nebuliser, the tissue drug homogeneity and concentration were greater with Capnopen®.

Polydopamine-Based Targeted Nanosystem for Chemo/Photothermal Therapy of Retinoblastoma in a Mouse Orthotopic Model.

Background: At present, the few photothermal/chemotherapy studies about retinoblastoma that have been reported are mainly restricted to ectopic models involving subcutaneous implantation. However, eyeball is unique physiological structure, the blood-retina barrier (BRB) hinders the absorption of drug molecules through the systemic route. Moreover, the abundant blood circulation in the fundus accelerates drug metabolism. To uphold the required drug concentration, patients must undergo frequent chemotherapy sessions. Purpose: To address these challenges above, we need to develop a secure and effective drug delivery system (FA-PEG-PDA-DOX) for the fundus. Methods: We offered superior therapeutic efficacy with minimal or no side effects and successfully established orthotopic mouse models. We evaluated cellular uptake performance and targeting efficiency of FA-PEG-PDA-DOX nanosystem and assessed its synergistic antitumor effects in vitro and vivo. Biodistribution assessments were performed to determine the retention time and targeting efficiency of the NPs in vivo. Additionally, safety assessments were conducted. Results: Cell endocytosis rates of the FA-PEG-PDA-DOX+Laser group became 5.23 times that of the DOX group and 2.28 times that of FA-PEG-PDA-DOX group without irradiation. The fluorescence signal of FA-PEG-PDA-DOX persisted for more than 120 hours at the tumor site. The number of tumor cells (17.2%) in the proliferative cycle decreased by 61.6% in the photothermal-chemotherapy group, in contrast to that of the saline control group (78.8%). FA-PEG-PDA-DOX nanoparticles(NPs) exhibited favorable biosafety and high biocompatibility. Conclusion: The dual functional targeted nanosystem, with the effects of DOX and mild-temperature elevation by irradiation, resulted in precise chemo/photothermal therapy in nude mice model.

An all-in-one nanoparticle for overcoming drug resistance: doxorubicin and elacridar co-loaded folate receptor targeted PLGA/MSN hybrid nanoparticles.

Overexpression of permeability-glycoprotein (P-gp) transporter leads to multidrug resistance (MDR) through cellular exclusion of chemotherapeutics. Co-administration of P-gp inhibitors and chemotherapeutics is a promising approach for improving the efficacy of therapy. Nevertheless, problems in pharmacokinetics, toxicity and solubility limit the application of P-gp inhibitors. Herein, we developed a novel all-in-one hybrid nanoparticle system to overcome MDR in doxorubicin (DOX)-resistant breast cancer. First, folic acid-modified DOX-loaded mesoporous silica nanoparticles (MSNs) were prepared and then loaded into PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles along with a P-gp inhibitor, elacridar. This hybrid nanoparticle system had high drug loading capacity, enabled both passive and active targeting of tumour tissues, and exhibited sequential and pH-triggered release of drugs. In vitro and in vivo studies in DOX-resistant breast cancer demonstrated the ability of the hybrid nanoparticles to reverse P-gp-mediated drug resistance. The nanoparticles were efficiently taken up by the breast cancer cells and delivered elacridar, in vitro. Biodistribution studies demonstrated substantial accumulation of the folate receptor-targeted PLGA/MSN hybrid nanoparticles in tumour-bearing mice. Moreover, deceleration of the tumour growth was remarkable in the animals administered with the DOX and elacridar co-loaded hybrid nanoparticles when compared to those treated with the marketed liposomal DOX (Caelyx®) or its combination with elacridar.

Dual-Drug Loaded Nanobubbles Combined with Sonodynamic and Chemotherapy for Hepatocellular Carcinoma Therapy.

Purpose: Chemotherapy remains the primary therapeutic approach for advanced Hepatocellular Carcinoma (HCC). The therapeutic effect of chemotherapy is limited and the toxic side effects are serious. The aim of this study is to develop a nanobubble that is ultrasonically responsive to reduce the toxic side effects of direct chemotherapy. Methods: We developed curcumin/doxorubicin-cis-aconitic anhydride-polyethylene glycol nanobubble (C/DCNB) surface modified with acid-sensitive polyethylene glycol (PEG). And it is loaded with curcumin (CUR) and doxorubicin (DOX), as liposomes at the nanoscale for diagnosis and therapy of tumors. Results: In this study, the acid-sensitive PEG on the surface layer of nanobubbles serves to stabilize them in the blood circulatory system and in normal tissues, while peeling off in the acidic tumor microenvironment (pH 6.8). C/DCNB can identify tumor sites through contrast-enhanced ultrasound (CEUS). And ultrasound-mediated nanobubbles promote permeability of the tumor vascular, thus improving the enhanced permeability and retention (EPR) effects in the tumor, leading to the accumulation of nanobubbles in the tumor. After endocytosis of nanobubbles, drugs are released and curcumin generates reactive oxygen species (ROS) under ultrasound conditions. CUR can enhance the sensitivity of tumor cells to DOX by inhibiting the expression of P-glycoprotein. In vitro and vivo experiments demonstrate that C/DCNB can facilitate contrast-enhanced ultrasound imaging while simultaneously delivering drugs, enabling both imaging and treatment. Conclusion: The combination of C/DCNB and ultrasound provides an effective strategy for improving the efficiency of HCC therapy and imaging.

Kupffer cells determine intrahepatic traffic of PEGylated liposomal doxorubicin.

Intrahepatic accumulation dominates organ distribution for most nanomedicines. However, obscure intrahepatic fate largely hampers regulation on their in vivo performance. Herein, PEGylated liposomal doxorubicin is exploited to clarify the intrahepatic fate of both liposomes and the payload in male mice. Kupffer cells initiate and dominate intrahepatic capture of liposomal doxorubicin, following to deliver released doxorubicin to hepatocytes with zonated distribution along the lobule porto-central axis. Increasing Kupffer cells capture promotes doxorubicin accumulation in hepatocytes, revealing the Kupffer cells capture-payload release-hepatocytes accumulation scheme. In contrast, free doxorubicin is overlooked by Kupffer cells, instead quickly distributing into hepatocytes by directly crossing fenestrated liver sinusoid endothelium. Compared to free doxorubicin, liposomal doxorubicin exhibits sustained metabolism/excretion due to the extra capture-release process. This work unveils the pivotal role of Kupffer cells in intrahepatic traffic of PEGylated liposomal therapeutics, and quantitively describes the intrahepatic transport/distribution/elimination process, providing crucial information for guiding further development of nanomedicines.

A bioinspired doxorubicin-carried albumin Nanocage against aggressive Cancer via systemic targeting of tumor and lymph node metastasis.

Cancer metastasis and recurrence are obstacles to successful treatment of aggressive cancer. To address this challenge, chemotherapy is indispensable as an essential part of comprehensive cancer treatment, particularly for subsequent therapy after surgical resection. However, small-molecule drugs for chemotherapy always cause inadequate efficacy and severe side effects against cancer metastasis and recurrence caused by lymph node metastases. Here, we developed doxorubicin-carried albumin nanocages (Dox-AlbCages) with appropriate particle sizes and pH/enzyme-responsive drug release for tumor and lymph node dual-targeted therapy by exploiting the inborn transport properties of serum albumin. Inspired by the protein-templated biomineralization and remote loading of doxorubicin into liposomes, we demonstrated the controlled synthesis of Dox-AlbCages via the aggregation or crystallization of doxorubicin and ammonium sulfate within albumin nanocages using a biomineralization strategy. Dox-AlbCages allowed efficient encapsulation of Dox in the core protected by the albumin corona shell, exhibiting favorable properties for enhanced tumor and lymph node accumulation and preferable cellular uptake for tumor-specific chemotherapy. Intriguingly, Dox-AlbCages effectively inhibited tumor growth and metastasis in orthotopic 4T1 breast tumors and prevented postsurgical tumor recurrence and lung metastasis. At the same time, Dox-AlbCages had fewer side effects than free Dox. This nanoplatform provides a facile strategy for designing tumor- and lymph node-targeted nanomedicines for suppressing cancer metastasis and recurrence.

Polydopamine-Based Nanoparticles for Synergistic Chemotherapy of Prostate Cancer.

Introduction: Immune regulatory small molecule JQ1 can block its downstream effector PD-L1 pathway and effectively reverse the PD-L1 upregulation induced by doxorubicin (DOX). So the synergistic administration of chemotherapeutic drug DOX and JQ1 is expected to increase the sensitivity of tumors to immune checkpoint therapy and jointly enhance the body's own immunity, thus effectively killing tumor cells. Therefore, a drug delivery system loaded with DOX and JQ1 was devised in this study. Methods: Polydopamine nanoparticles (PDA NPs) were synthesized through spontaneous polymerization. Under appropriate pH conditions, DOX and JQ1 were loaded onto the surface of PDA NPs, and the release of DOX and JQ1 were measured using UV-Vis or high performance liquid chromatography (HPLC). The mechanism of fabricated nanocomplex in vitro was investigated by cell uptake experiment, cell viability assays, apoptosis assays, and Western blot analysis. Finally, the tumor-bearing mouse model was used to evaluate the tumor-inhibiting efficacy and the biosafety in vivo. Results: JQ1 and DOX were successfully loaded onto PDA NPs. PDA-DOX/JQ1 NPs inhibited the growth of prostate cancer cells, reduced the expression of apoptosis related proteins and induced apoptosis in vitro. The in vivo biodistribution indicated that PDA-DOX/JQ1 NPs could accumulated at the tumor sites through the EPR effect. In tumor-bearing mice, JQ1 delivered with PDA-DOX/JQ1 NPs reduced PD-L1 expression at tumor sites, generating significant tumor suppression. Furthermore, PDA-DOX/JQ1 NPs could reduce the side effects, and produce good synergistic treatment effect in vivo. Conclusion: We have successfully prepared a multifunctional platform for synergistic prostate cancer therapy.

Designing Mesoporous Prussian Blue@zinc Phosphate Nanoparticles with Hierarchical Pores for Varisized Guest Delivery and Photothermally-Augmented Chemo-Starvation Therapy.

Background: With the rapid development of nanotechnology, constructing a multifunctional nanoplatform that can deliver various therapeutic agents in different departments and respond to endogenous/exogenous stimuli for multimodal synergistic cancer therapy remains a major challenge to address the inherent limitations of chemotherapy. Methods: Herein, we synthesized hollow mesoporous Prussian Blue@zinc phosphate nanoparticles to load glucose oxidase (GOx) and DOX (designed as HMPB-GOx@ZnP-DOX NPs) in the non-identical pore structures of their HMPB core and ZnP shell, respectively, for photothermally augmented chemo-starvation therapy. Results: The ZnP shell coated on the HMPB core, in addition to providing space to load DOX for chemotherapy, could also serve as a gatekeeper to protect GOx from premature leakage and inactivation before reaching the tumor site because of its degradation characteristics under mild acidic conditions. Moreover, the loaded GOx can initiate starvation therapy by catalyzing glucose oxidation while causing an upgradation of acidity and H2O2 levels, which can also be used as forceful endogenous stimuli to trigger smart delivery systems for therapeutic applications. The decrease in pH can improve the pH-sensitivity of drug release, and O2 can be supplied by decomposing H2O2 through the catalase-like activity of HMPBs, which is beneficial for relieving the adverse conditions of anti-tumor activity. In addition, the inner HMPB also acts as a photothermal agent for photothermal therapy and the generated hyperthermia upon laser irradiation can serve as an external stimulus to further promote drug release and enzymatic activities of GOx, thereby enabling a synergetic photothermally enhanced chemo-starvation therapy effect. Importantly, these results indicate that HMPB-GOx@ZnP-DOX NPs can effectively inhibit tumor growth by 80.31% and exhibit no obvious systemic toxicity in mice. Conclusion: HMPB-GOx@ZnP-DOX NPs can be employed as potential theranostic agents that incorporate multiple therapeutic modes to efficiently inhibit tumors.

Biodegradable Microembolics with Nanografted Polyanions Enable High-Efficiency Drug Loading and Sustained Deep-Tumor Drug Penetration for Locoregional Chemoembolization Treatment.

Transarterial chemoembolization (TACE), the mainstay treatment of unresectable primary liver cancer that primarily employs nondegradable drug-loaded embolic agents to achieve synergistic vascular embolization and locoregional chemotherapy effects, suffers from an inferior drug burst behavior lacking long-term drug release controllability that severely limits the TACE efficacy. Here we developed gelatin-based drug-eluting microembolics grafted with nanosized poly(acrylic acid) serving as a biodegradable ion-exchange platform that leverages a counterion condensation effect to achieve high-efficiency electrostatic drug loading with electropositive drugs such as doxorubicin (i.e., drug loading capacity >34 mg/mL, encapsulation efficiency >98%, and loading time <10 min) and an enzymatic surface-erosion degradation pattern (∼2 months) to offer sustained locoregional pharmacokinetics with long-lasting deep-tumor retention capability for TACE treatment. The microembolics demonstrated facile microcatheter deliverability in a healthy porcine liver embolization model, superior tumor-killing capacity in a rabbit VX2 liver cancer embolization model, and stabilized extravascular drug penetration depth (>3 mm for 3 months) in a rabbit ear embolization model. Importantly, the microembolics finally exhibited vessel remodeling-induced permanent embolization with minimal inflammation responses after complete degradation. Such a biodegradable ion-exchange drug carrier provides an effective and versatile strategy for enhancing long-term therapeutic responses of various local chemotherapy treatments.

Enhanced oral bioavailability and in vitro evaluation of cannabidiol camel milk-derived exosome formulation in resistant MDA-MB-231 and MDA-MB-468 breast cancer cells.

The potential of camel milk-derived exosomes (CMDE) to enhance the bioavailability of Cannabidiol (CBD) was investigated. CBD-CMDE formulation was prepared using an established procedure and its particle size was 138.4 ± 4.37 nm, and CBD entrapment efficiency of 56.56 ± 4.26 %. In-vitro release studies showed release of 78.27 ± 5.37 % and 46.42 ± 4.75 % CBD from CMDE and control CBD formulation respectively in pH 6.8 at 24 hr. The apparent permeability (Papp) of CBD-CMDE was found to be enhanced by 3.95-fold with Papp of 22.9*10-6 ± 0.34 cm/sec as compared to control CBD formulation with Papp of 5.8*10-6 ± 0.65 cm/sec in MDCK cells. CBD-CMDE was found to be more potent than CBD in 2D cytotoxicity assay with IC50 values of 3.6 ± 0.54 µM, 3.88 ± 0.54 µM and 7.53 ± 0.59 µM, 7.53 ± 0.59 µM against Doxorubicin (DOX) resistant MDA-MB-231 and Rapamycin (RM) resistant MDA-MB-468 breast cancer cells respectively. Moreover, 3D spheroids assay results demonstrated CBD-CMDE with IC50 values of 14 ± 0.85 µM, 15 ± 0.07 µM as compared to CBD alone with IC50 values of 25 ± 0.93 µM, 34.7 ± 0.08 µM in MDA-MB-231 DOX RT cells and MDA-MB-468 RM RT cells respectively. In-vivo PK studies showed enhanced bioavailability of CBD from CBD-exosomes with AUC(0-24h) of 1350.56 ± 187.50 h.ng/mL as compared to CBD control formulation with AUC(0-24h) of 351.95 ± 39.10 h.ng/mL with a single oral dose of 12 mg/kg. The data indicate that CMDE significantly improved the oral bioavailability of CBD. Overall, CMDE can be used to enhance the oral absorption of poorly bioavailable APIs.