Synergistic Combination Of Chemotherapy Research Articles

Fe3+-DOX-mediated self-assembled nanolipids for tumor microenvironment activated synergistic ferroptotic-chemo therapy assisted with MR-imaging

Chemotherapy is often plagued by side-effects, development of drug resistance, difficulty of targeted delivery, and limited effectiveness. Here, we tackle these issues by rationally designing a nanolipid system with the capabilities of selective accumulation in tumor tissues, responsiveness to tumor microenvironment (TME), synergistic combination of chemotherapy with ferroptosis, magnetic resonance (MR) imaging to monitor the uptake kinetics and therapeutic process. Specifically, a tumor-responsive nanolipid encapsulated with Fe3+-DOX nanocomplexes is devised. DOX is only released inside the tumor cells and subsequently induces apoptosis after the nanolipids are selectively accumulated in tumor tissues, readily uptaken by tumor cells, and finally disassembled by overexpressed glutathione (GSH). Free Fe2+ ions reduced from Fe3+ by GSH catalyze the excess H2O2 in tumor cells into cytotoxic ·OH radicals, which in turn cause lipid peroxidation and consequently ferroptosis. Intracellularly released Fe3+-DOX nanocomplexes emit strong MR signal, indicating successful internalization of the therapeutics and initiation of the ferroptotic-chemotherapy. Such MR imaging-monitored, highly targeted, synergistic therapy offers high therapeutic efficacy, low side-effects, and immunity to drug resistance.

Co-delivery of curcumin and si-STAT3 with a bioinspired tumor homing for polydopamine nanoparticles for synergistic osteosarcoma therapy

PurposeOwing to the complexity of cancer, a synergistic combination of chemotherapy and gene therapy can be a promising therapeutic strategy. This study aimed to use stem cell membrane (SCM)-camouflaged polydopamine nanoparticles for simultaneous delivery of curcumin (CUR) and siRNA-targeting STAT3 (CPDA/siSTAT3@SCM NPs) for osteosarcoma (OS).MethodsTransmission electron microscopy, UV–Vis absorbance spectra, zeta potential, cell co-localization, and Coomassie bright blue staining were used to characterize CPDA/siSTAT3@SCM NPs constructed by the self-assembly method. Drug release, cellular uptake, cell proliferation, apoptosis, wound healing, and transwell assays were evaluated in vitro. The expression levels of epithelial–mesenchymal transition (EMT)- and apoptosis-related proteins were measured by western blotting. Furthermore, the biodistribution, antitumor efficacy, and biosafety of CPDA/siSTAT3@SCM NPs in an MG63 xenograft mouse model were evaluated.ResultsCPDA/siSTAT3@SCM NPs were successfully synthesized to deliver CUR and siRNA simultaneously, and they showed osteosarcoma-targeting ability. Furthermore, it showed high cellular uptake and excellent synergistic antitumor effects in vitro. CPDA/siSTAT3@SCM NPs suppressed OS cell proliferation, migration, invasion, and EMT progression, and promoted the apoptotic process. In tumor-bearing mice, the treatment with CPDA/siSTAT3@SCM NPs showed an excellent antitumor effect with no side effects in major organs.ConclusionThis study revealed that CPDA/siSTAT3@SCM NPs can target drug delivery by biomimetic multifunctional nanoparticles to treat OS through chemo-gene combined therapy.

A Sequential Dual-Model Strategy Based on Photoactivatable Metallopolymer for On-Demand Release of Photosensitizers and Anticancer Drugs.

The synergistic combination of chemotherapy and photodynamic therapy has attracted considerable attention for its enhanced antitumoral effects; however, it remains challenging to successfully delivery photosensitizers and anticancer drugs while minimizing drug leakage at off‐target sites. A red‐light‐activatable metallopolymer, Poly(Ru/PTX), is synthesized for combined chemo‐photodynamic therapy. The polymer has a biodegradable backbone that contains a photosensitizer Ru complex and the anticancer drug paclitaxel (PTX) via a singlet oxygen (1O2) cleavable linker. The polymer self‐assembles into nanoparticles, which can efficiently accumulate at the tumor sites during blood circulation. The distribution of the therapeutic agents is synchronized because the Ru complex and PTX are covalently conjugate to the polymer, and off‐target toxicity during circulation is also mostly avoided. Red light irradiation at the tumor directly cleaves the Ru complex and produces 1O2 for photodynamic therapy. Sequentially, the generated 1O2 triggers the breakage of the linker to release the PTX for chemotherapy. Therefore, this novel sequential dual‐model release strategy creates a synergistic chemo‐photodynamic therapy while minimizing drug leakage. This study offers a new platform to develop smart delivery systems for the on‐demand release of therapeutic agents in vivo.

Selectively targeting tumor-associated macrophages and tumor cells with polymeric micelles for enhanced cancer chemo-immunotherapy

Tumor-associated macrophage (TAM)-related immunotherapy is a greatly promising strategy that involves altering the immunosuppressive tumor microenvironment with the immunomodulator imiquimod (R837) for enhanced cancer therapy. However, the function of R837 is seriously limited due to poor water solubility and a lack of targeting ability. Here, we developed two types of targeting polymer micelles to separately deliver R837 and the anticancer drug doxorubicin (DOX) to TAMs and tumor cells via intratumoral injection and intravenous injection, respectively, for enhanced cancer chemo-immunotherapy against breast cancer. After these micelles accumulated in the tumor tissues, the immunostimulating micelles released R837, which bound to the TLR-7 receptor on the lysosomal membrane within the TAM, stimulating the maturation of the TAM, thereby causing an antitumor immune response and relieving the immunosuppressive effect in the tumor microenvironment. Simultaneously, the chemotherapeutic micelles released DOX in the cytoplasm of the tumor cells, directly inducing cell death. As a result, a synergistic combination of chemotherapy and immunotherapy was achieved through these nanomedicines, which separately activated the antitumor immune response and inhibited tumor cell growth. Therefore, this strategy is a new avenue for the development of targeting nanomedicines for combination chemo-immunotherapy against malignant cancer.

NIR-Activated Spatiotemporally Controllable Nanoagent for Achieving Synergistic Gene-Chemo-Photothermal Therapy in Tumor Ablation.

A rational combination of different therapeutic modalities within one single nanostructure is promising to enhance the therapeutic response, especially to achieve a synergistic therapeutic efficacy for tumor treatment. Herein, a near-infrared (NIR) photothermally activated nanoagent, which could achieve a spatially controllable codelivery of different curative molecules and a temporally controlled responsive release, was designed to perform effective gene-chemo-photothermal therapy of malignant tumors. The nanoagent consisted of a gold nanorod (AuNR) functionalized with mPEG, DNA, and small interfering RNA (siRNA). With the aid of aptamer AS1411-mediated recognition and endocytosis, the nanoagents were selectively delivered into cancer cells; subsequently, the photothermal conversion of AuNRs happened while under NIR irradiation, which successfully achieved an effective photothermal therapy, induced dehybridization of DNA duplexes, and simultaneously released doxorubicin (DOX) and siRNA. Then, the released siRNA silenced the expression of the multidrug resistance associated protein 1 (MRP1), the primary cause of the undesirable expelling of DOX in PC-3 cells, yielding a remarkable improvement in the efficiency of gene-chemo therapy. All of the results of in vitro and in vivo studies revealed that our prepared nanoagents exhibited an excellent performance in synergistic gene-chemo-photothermal therapy and successfully inhibited tumor growth. This work provides an interesting concept of a nanoscale therapeutic agent in achieving a dramatically enhanced therapeutic ability for tumor ablation, whichbenefitsfrom the spatiotemporally controllable properties and the synergistic combination of chemotherapy, gene therapy, and photothermal therapy in one single nanoagent.

Detection of Phosphatidylcholine-Coated Gold Nanoparticles in Orthotopic Pancreatic Adenocarcinoma using Hyperspectral Imaging.

Nanoparticle uptake and distribution to solid tumors are limited by reticuloendothelial system systemic filtering and transport limitations induced by irregular intra-tumoral vascularization. Although vascular enhanced permeability and retention can aid targeting, high interstitial fluid pressure and dense extracellular matrix may hinder local penetration. Extravascular diffusivity depends upon nanoparticle size, surface modifications, and tissue vascularization. Gold nanoparticles functionalized with biologically-compatible layers may achieve improved uptake and distribution while enabling cytotoxicity through synergistic combination of chemotherapy and thermal ablation. Evaluation of nanoparticle uptake in vivo remains difficult, as detection methods are limited. We employ hyperspectral imaging of histology sections to analyze uptake and distribution of phosphatidylcholine-coated citrate gold nanoparticles (CGN) and silica-gold nanoshells (SGN) after tail-vein injection in mice bearing orthotopic pancreatic adenocarcinoma. For CGN, the liver and tumor showed 26.5±8.2 and 23.3±4.1 particles/100μm2 within 10μm from the nearest source and few nanoparticles beyond 50μm, respectively. The spleen had 35.5±9.3 particles/100μm2 within 10μm with penetration also limited to 50μm. For SGN, the liver showed 31.1±4.1 particles/100μm2 within 10μm of the nearest source with penetration hindered beyond 30μm. The spleen and tumor showed uptake of 22.1±6.2 and 15.8±6.1 particles/100μm2 within 10μm, respectively, with penetration similarly hindered. CGH average concentration (nanoparticles/μm2) was 1.09±0.14 in the liver, 0.74±0.12 in the spleen, and 0.43±0.07 in the tumor. SGN average concentration (nanoparticles/μm2) was 0.43±0.07 in the liver, 0.30±0.06 in the spleen, and 0.20±0.04 in the tumor. Hyperspectral imaging of histology sections enables analysis of phosphatidylcholine-coated gold-based nanoparticles in pancreatic tumors with the goal to improve nanotherapeutic efficacy.

English

Carcinoma of the prostate gland is the most frequent malignant tumor affecting male population. While the large majority of tumors are represented by adenocarcinoma, pure squamous cell carcinoma (SCC) comprises only 0.5-1% of all prostate neoplastic lesions. We herein report a case of pure squamous cell carcinoma of the prostate. A 60 years old male presented with history of lower urinary tract symptoms. Patient was subsequently subjected for transurethral resection of prostate and histopathology of prostatic chips showed SCC of the prostate. INTRODUCTION: Primary squamous cell carcinoma (SCC) of the prostate gland is a rare (0.5-1%) condition, deemed rather more malignant than the ordinary adenocarcinoma and resistant to the usual therapy for prostate cancer. It is characterized by a high degree of malignancy, commonly metastasizing to the bone (mainly with osteolytic lesions), liver and lungs with a median survival time of 14 months. This is a report of a case controlled by a synergistic combination of chemotherapy and radiotherapy.