Effective Treatment For Metastatic Cancer Research Articles

Biguanide-anchored albumin-based nanoplatform inhibits epithelial-mesenchymal transition and reduces the stemness phenotype for metastatic cancer therapy.

In clinical chemotherapy, albumin-bound paclitaxel (Abraxane) can improve the tumor targeting property and therapeutic efficacy of paclitaxel (PTX) against orthotopic malignancies. However, patients with metastatic cancer have a poor prognosis, probably due to the instability, chemoresistance, and inability of albumin-bound paclitaxel to alter the tumor microenvironment. Here we propose a new biguanide-modified albumin-based nanoplatform that encapsulates paclitaxel for the effective treatment of metastatic cancer. The PTX is encapsulated in poly (lactic-co-glycolic acid) cores coated with biguanide-modified albumin (HSA-NH). The functionalized nanoparticles (HSA-NH NPs) exhibit a remarkable stable profile with low drug release (P < 0.05 versus Abraxane), target tumor tissues, suppress epithelial-mesenchymal transition (EMT) events for anti-metastatic effects, and reduce the phenotype of cancer stem cells. As a result, HSA-NH NPs effectively prolong animal survival (55 days) by inhibiting not only primary tumor growth but also metastasis. This study provides proof of concept that the biguanide-anchored albumin-based nanoplatform encapsulating PTX is a powerful, safe, and clinically translational strategy for the treatment of metastatic cancer. STATEMENT OF SIGNIFICANCE: Albumin-bound paclitaxel (Abraxane) can increase paclitaxel's tumor targeting and therapeutic efficacy in clinical cancer treatments such as breast cancer. However, the instability, chemoresistance, and lack of tumor microenvironment modulation of albumin-bound paclitaxel may lead to poor therapeutic efficacy in metastatic cancer patients. Here we develop biguanide-anchored albumin-based nanoplatforms that encapsulate paclitaxel (HSA-NH NPs) for metastatic cancer treatment. Poly(lactic-co-glycolic acid) (PLGA) cores encapsulating paclitaxel improve the stability of HSA-NH NPs. Based on the activities of metformin, biguanide-anchored albumin adsorbed on PLGA cores improves paclitaxel efficacy, inhibits various aberrant changes during epithelial-mesenchymal transition, and reduces tumor cell stemness. The biguanide-anchored albumin-based nanoplatform encapsulating PTX can serve as a potent, safe, and clinically translational approach for metastatic cancer therapies.

A Review of Imaging Methods to Assess Ultrasound-Mediated Ablation.

Ultrasound ablation techniques are minimally invasive alternatives to surgical resection and have rapidly increased in use. The response of tissue to HIFU ablation differs based on the relative contributions of thermal and mechanical effects, which can be varied to achieve optimal ablation parameters for a given tissue type and location. In tumor ablation, similar to surgical resection, it is desirable to include a safety margin of ablated tissue around the entirety of the tumor. A factor in optimizing ablative techniques is minimizing the recurrence rate, which can be due to incomplete ablation of the target tissue. Further, combining focal ablation with immunotherapy is likely to be key for effective treatment of metastatic cancer, and therefore characterizing the impact of ablation on the tumor microenvironment will be important. Thus, visualization and quantification of the extent of ablation is an integral component of ablative procedures. The aim of this review article is to describe the radiological findings after ultrasound ablation across multiple imaging modalities. This review presents readers with a general overview of the current and emerging imaging methods to assess the efficacy of ultrasound ablative treatments.

Evaluation of diffusion coefficient of P-glycoprotein molecules labeled with green fluorescent protein in living cell membrane.

The movement of individual molecules inside living cells has recently been resolved by single particles tracking (SPT) method which is a powerful tool for probing the organization and dynamics of the plasma membrane constituents. Effective treatment of metastatic cancers requires the toxic chemotherapy, however this therapy leads to the multidrug resistance phenomenon of the cancer cells, in which the cancer cells resist simultaneously to different drugs with different targets and chemical structures. P-glycoprotein molecules which are responsible for multidrug resistance of many cancer cells have been studied by cancer biologists during past haft of century. Recently, advances in laser and detector technologies have enabled single fluorophores to be visualized in aqueous solution. The development of the total internal reflection fluorescent microscope (TIRFM) provided means to monitor dynamic molecular localization in living cells. In this paper, P-glycoproteins (PGP) were labeled with green fluorescent protein (GFP) in living cell membrane of Madin-Darby canine kidney (MDCK) and the TIRFM method was used to characterize the dynamics of individual protein molecules on the surface of living cells. An evanescent field was produced by a totally internally reflected and a laser beam was illuminated the glass-water interface. GFP-PGP proteins that entered the evanescent field appeared as individual spots of light which were slighter than background fluorescence. We obtained high-resolution images and diffusion maps of membrane proteins on cell surface and showed the local diffusion properties of specific proteins on single cells. We also determined the diffusion coefficient, the mean square displacement and the average velocity of the tracked particles, as well as the heterogeneity of the cell environment. This study enabled us to understand single-molecule features in living cell and measure the diffusion kinetics of membrane-bound molecules.

Combining Photothermal‐Photodynamic Therapy Mediated by Nanomaterials with Immune Checkpoint Blockade for Metastatic Cancer Treatment and Creation of Immune Memory

AbstractThe pursuit of effective treatments for metastatic cancer is still one of the most intensive areas of research in the biomedical field. In a not‐so‐distant past, the scientific community has witnessed the rise of immunotherapy based on immune checkpoint inhibitors (ICIs). This therapeutic modality intends to abolish immunosuppressive interactions, re‐establishing T cell responses against metastasized cancer cells. Despite the initial enthusiasm, the ICIs were later found to be associated with low clinical therapeutic outcomes and immune‐related side effects. To address these limitations, researchers are exploring the combination of ICIs with nanomaterial‐mediated phototherapies. These nanomaterials can accumulate within the tumor and produce, upon interaction with light, a temperature increase (photothermal therapy) and/or reactive oxygen species (photodynamic therapy), causing damage to cancer cells. Importantly, these photothermal‐photodynamic effects can pave the way for an enhanced ICI‐based immunotherapy by inducing the release of tumor‐associated antigens and danger‐associated molecular patterns, as well as by relieving tumor hypoxia and triggering a pro‐inflammatory response. This progress report analyses the potential of nanomaterial‐mediated photothermal‐photodynamic therapy in combination with ICIs, focusing on their ability to modulate T cell populations leading to an anti‐metastatic abscopal effect and on their capacity to generate immune memory that prevents tumor recurrence.

Effective treatment of metastatic cancer by an innovative intratumoral alpha particle-mediated radiotherapy in combination with immunotherapy: A short review

Alpha radiation is a lethal form of radiation whose short range limits its use for cancer treatment. A unique intra-tumoral alpha radiation-based tumor ablation treatment termed Diffusing Alpha emitters Radiation Therapy (DaRT) was developed and tested for tumor ablation and stimulation of anti-tumor immunity. Radium-224 loaded wires (Alpha DaRT seeds) are inserted into the tumors and release by recoil short-lived alpha-emitting atoms. These atoms disperse in the tumor at least 5 mm from the source and spray it with highly destructive alpha radiation. DaRT was found to destroy solid malignant tumors experimental animals and in patients with cutaneous malignancies. Tumor destruction resulted in activation of specific antitumor immunity. DaRT provides, for the first time, an efficient method for treatment of the entire volume of solid tumors by alpha radiation, and could be used not only as a local treatment but also as a therapeutic strategy to induce strong systemic antitumor immune responses, which will eliminate residual disease and metastases in distant sites. This combined treatment modality holds significant potential for the treatment of non-resectable human cancers.

NIR-light and GSH activated cytosolic p65-shRNA delivery for precise treatment of metastatic cancer

Despite advances in cancer therapy, metastasis remains the dominate reason for cancer-related mortality. Herein, a novel, hybrid nanocomplex, RDG/shRNA, with tumor-targeting and dual stimuli responsive properties is described for the effective treatment of metastatic cancer. This multimodal therapeutic system was prepared by complexing RDG nanovectors with p65-shRNA, an anti-NF-κB agent, via the electrostatic interactions between negatively charged shRNA and the cationic DSPEI displayed on the surface of the nanovectors. Cytosolic release of shRNA from the complex is achieved by dual-stimulation from NIR laser irradiation and high intracellular GSH concentrations, resulting in effective gene silencing of metastatic 4T1 breast cancer cells, thereby inhibiting cell proliferation and invasion. More importantly, the nanocomplex undergoes significant intratumoral accumulation due to the EPR effect and RGD-mediated endocytosis. In combination with localized NIR laser irradiation, the hybrid complex could effectively inhibit primary breast tumor growth and almost completely suppresses distant metastasis, significantly improving the therapeutic efficacy of the RDG/shRNA complex. Consequently, this NIR-light and GSH responsive complex with tumor targeting capabilities and cytosolic shRNA release is a promising nanoplatform for precise treatment of metastatic cancer.

Rational design of multimodal therapeutic nanosystems for effective inhibition of tumor growth and metastasis

Simultaneous inhibition of both tumor growth and metastasis is the key to treating metastatic cancer, yet the development of effective drug delivery systems represents a great challenge since multimodal therapeutic agents must be rationally combined to overcome the biological mechanisms underpinning tumor cell proliferation and invasion. In this context, we report a hybrid therapeutic nanoscale platform that incorporates an anti-proliferative drug, doxorubicin (DOX), and an anti-NF-κB agent, p65-shRNA, for effective treatment of metastatic breast cancer. In our design, we first conjugated DOX via an acid-labile linker onto gold nanorods that were pre-modified with the tumor targeting peptide RGD and a positively charged, disulfide cross-linked short polyethylenimines (DSPEI), and then incorporated shRNA through electrostatic complexation with DSPEI. We show that this “all in one” nanotherapeutic system (RDG/shRNA@DOX) can be effectively internalized through RGD-mediated endocytosis, followed by stimuli-responsive intracellular co-release of DOX and shRNA. Our in vitro experiments suggest that this multimodal system can significantly inhibit cell proliferation, angiogenesis, and invasion of metastatic MDA-MB-435 cancer cells. Systemic administration of RDG/shRNA@DOX into a metastatic mouse model led to enhanced tumor accumulation, and, most importantly, significant inhibition of in situ tumor growth and almost complete suppression of tumor metastasis. We believe this hybrid multimodal nanotherapeutic system provides important insight into the rational design of therapeutic systems for the effective treatment of metastatic carcinoma. Statement of SignificanceThe key to successfully treat metastatic cancer is the simultaneous inhibition of both tumor growth and metastasis. This represents a great challenge for the design of drug delivery systems since multimodal therapeutic agents must be rationally combined to overcome the respective biological mechanisms underpinning tumor cell proliferation and invasion. Toward this end, we developed a hybrid nanomedicine platform that incorporates an anti-proliferative drug, doxorubicin (DOX), and an anti-NF-κB agent, p65-shRNA, for effective treatment of metastatic breast cancer. We showed that this multimodal system (RDG/shRNA@DOX) enhanced tumor accumulation, led to prolonged circulation, and most importantly, significant inhibition of in situ tumor growth and almost complete suppression of tumor metastasis. We believe this hybrid multimodal nanotherapeutic system provides significant insight into the rational design of therapeutic systems for the effective treatment of metastatic cancer.

Graphene oxide-wrapped PEGylated liquid crystalline nanoparticles for effective chemo-photothermal therapy of metastatic prostate cancer cells

Here, we report the preparation of PEGylated liquid crystalline nanoparticles (LCN) loaded with docetaxel (DTX) and wrapped with graphene oxide (GO), called PEG-GO/LCN/DTX, for effective chemo-photothermal therapy of metastatic prostate cancer cells. The prepared formulation exhibited a small particle size (<250 nm), high drug loading capacity (∼15%), and efficient near infrared (NIR) light-induced thermal heat. Importantly, PEG-GO/LCN/DTX successfully accumulated in prostate cancer cells and exhibited potent apoptotic and antimigration effects, mediated by the combination of the anticancer effects of DTX and the thermal heat induced by exposure of GO to NIR light. Taken together, our findings support that PEG-GO/LCN/DTX may be an effective system for treatment of metastatic prostate cancer. Moreover, the results establish a proof-of-concept for the potential chemo-photothermal functionality of PEG-GO/LCN/DTX. This hybrid system of LCN and GO could provide controlled and targeted drug delivery with enhanced NIR-induced thermal effects for effective treatment of metastatic cancers.

Radiation and immunotherapy: a synergistic combination

Immunotherapy can be an effective treatment for metastatic cancer, but a significant subpopulation will not respond, likely due to the lack of antigenic mutations or the immune-evasive properties of cancer. Likewise, radiation therapy (RT) is an established cancer treatment, but local failures still occur. Clinical observations suggest that RT may expand the therapeutic reach of immunotherapy. We examine the immunobiologic and clinical rationale for combining RT and immunotherapy, two modalities yet to be used in combination in routine practice. Preclinical data indicate that RT can potentiate the systemic efficacy of immunotherapy, while activation of the innate and adaptive immune system can enhance the local efficacy of RT.

Transcription factors that mediate epithelial–mesenchymal transition lead to multidrug resistance by upregulating ABC transporters

Development of multidrug resistance (MDR) is a major deterrent in the effective treatment of metastatic cancers by chemotherapy. Even though MDR and cancer invasiveness have been correlated, the molecular basis of this link remains obscure. We show here that treatment with chemotherapeutic drugs increases the expression of several ATP binding cassette transporters (ABC transporters) associated with MDR, as well as epithelial–mesenchymal transition (EMT) markers, selectively in invasive breast cancer cells, but not in immortalized or non-invasive cells. Interestingly, the mere induction of an EMT in immortalized and non-invasive cell lines increased their expression of ABC transporters, migration, invasion, and drug resistance. Conversely, reversal of EMT in invasive cells by downregulating EMT-inducing transcription factors reduced their expression of ABC transporters, invasion, and rendered them more chemosensitive. Mechanistically, we demonstrate that the promoters of ABC transporters carry several binding sites for EMT-inducing transcription factors, and overexpression of Twist, Snail, and FOXC2 increases the promoter activity of ABC transporters. Furthermore, chromatin immunoprecipitation studies revealed that Twist binds directly to the E-box elements of ABC transporters. Thus, our study identifies EMT inducers as novel regulators of ABC transporters, thereby providing molecular insights into the long-standing association between invasiveness and MDR. Targeting EMT transcription factors could hence serve as novel strategies to curb both metastasis and the associated drug resistance.

Targeting multidrug resistance in cancer

Effective treatment of metastatic cancers usually requires the use of toxic chemotherapy. In most cases, multiple drugs are used, as resistance to single agents occurs almost universally. For this reason, elucidation of mechanisms that confer simultaneous resistance to different drugs with different targets and chemical structures - multidrug resistance - has been a major goal of cancer biologists during the past 35 years. Here, we review the most common of these mechanisms, one that relies on drug efflux from cancer cells mediated by ATP-binding cassette (ABC) transporters. We describe various approaches to combating multidrug-resistant cancer, including the development of drugs that engage, evade or exploit efflux by ABC transporters.

Functional genomic analysis of cancer metastasis: biologic insights and clinical implications

Metastasis, the spread of cancer from primary tumors to distant vital organs, has devastating consequences. Lack of effective tools to study this complex problem has hindered the development of accurate prognostic methods and effective treatments for metastatic cancer. In the postgenomic era, the application of genomic profiling methods to the analysis of clinical metastasis samples and animal metastasis models has revolutionized the field of metastasis research. This article reviews recent breakthroughs in the functional genomic analysis of metastasis. In addition, its impacts on our understanding of the molecular basis of metastasis and on clinical practice are discussed.