Combination Anticancer Therapy Research Articles

Dabrafenib inhibits ABCG2 and cytochrome P450 isoenzymes; potential implications for combination anticancer therapy

Dabrafenib is a BRAF inhibitor used in combination treatment of malignant melanoma and non-small cell lung carcinoma. In this study, we aimed to characterize its interactions with cytochrome P450 (CYP) isoenzymes and ATP-binding cassette (ABC) efflux transporters that have critical impact on the pharmacokinetics of drugs and play a role in drug resistance development. Using accumulation assays, we showed that dabrafenib inhibited ABCG2 and, less potently, ABCB1 transporter. We also confirmed dabrafenib as a CYP2C8, CYP2C9, CYP3A4, and CYP3A5 inhibitor. Importantly, inhibition of ABCG2 and CYP3A4 by dabrafenib led to the potentiation of cytotoxic effects of mitoxantrone and docetaxel toward respective resistant cell lines in drug combination studies. On the contrary, the synergistic effect was not consistently observed in ABCB1-expressing models. We further demonstrated that mRNA levels of ABCB1, ABCG2, ABCC1, and CYP3A4 were increased after 24 h and 48 h exposure to dabrafenib. Overall, our data confirm dabrafenib as a drug frequently and potently interacting with ABC transporters and CYP isoenzymes. This feature should be addressed with caution when administering dabrafenib to patients with polypharmacy but also could be utilized advantageously when designing new dabrafenib-containing drug combinations to improve the therapeutic outcome in drug-resistant cancer.

Oxaliplatin inhibits angiogenin proliferative and cell migration effects in prostate cancer cells

Angiogenin (Ang) is a potent angiogenic protein that is overexpressed in many types of cancer at concentration values correlated to the tumor aggressiveness. Here, by means of an integrated multi-technique approach based on crystallographic, spectrometric and spectroscopic analyses, we demonstrate that the anti-cancer drug oxaliplatin efficiently binds angiogenin. Microscopy cellular studies, carried out on the prostate cancer cell (PC-3) line , show that oxaliplatin inhibits the angiogenin prompting effect on cell proliferation and migration, which are typical features of angiogenesis process. Overall, our findings point to angiogenin as a possible target of oxaliplatin, thus suggesting a potential novel mechanism for the antineoplastic activity of this platinum drug and opening the avenue to novel approaches in the combined anti-cancer anti-angiogenic therapy.

Atorvastatin-mediated rescue of cancer-related cognitive changes in combined anticancer therapies.

Acute administration of trastuzumab (TZB) may induce various forms of cognitive impairment. These cancer-related cognitive changes (CRCC) are regulated by an adverse biological process involving cancer stem cells (CSCs) and IL-6. Recent studies have reported that atorvastatin (ATV) may change the dynamic of cognitive impairment in a combination (TZB+ATV) therapy. In this study, we investigate the mutual interactions between cancer stem cells and the tumor cells that facilitate cognitive impairment during long term TZB therapy by developing a mathematical model that involves IL-6 and the key apoptotic regulation. These include the densities of tumor cells and CSCs, and the concentrations of intracellular signaling molecules (NFκB, Bcl-2, BAX). We apply the mathematical model to a single or combination (ATV+TZB) therapy used in the experiments to demonstrate that the CSCs can enhance CRCC by secreting IL-6 and ATV may interfere the whole regulation. We show that the model can both reproduce the major experimental observation on onset and prevention of CRCC, and suggest several important predictions to guide future experiments with the goal of the development of new anti-tumor and anti-CRCC strategies. Moreover, using this model, we investigate the fundamental mechanism of onset of cognitive impairment in TZB-treated patients and the impact of alternating therapies on the anti-tumor efficacy and intracellular response to different treatment schedules.

Biomimetic Cascade Polymer Nanoreactors for Starvation and Photodynamic Cancer Therapy.

The selective disruption of nutritional supplements and the metabolic routes of cancer cells offer a promising opportunity for more efficient cancer therapeutics. Herein, a biomimetic cascade polymer nanoreactor (GOx/CAT-NC) was fabricated by encapsulating glucose oxidase (GOx) and catalase (CAT) in a porphyrin polymer nanocapsule for combined starvation and photodynamic anticancer therapy. Internalized by cancer cells, the GOx/CAT-NCs facilitate microenvironmental oxidation by catalyzing endogenous H2O2 to form O2, thereby accelerating intracellular glucose catabolism and enhancing cytotoxic singlet oxygen (1O2) production with infrared irradiation. The GOx/CAT-NCs have demonstrated synergistic advantages in long-term starvation therapy and powerful photodynamic therapy (PDT) in cancer treatment, which inhibits tumor cells at more than twice the rate of starvation therapy alone. The biomimetic polymer nanoreactor will further contribute to the advancement of complementary modes of spatiotemporal control of cancer therapy.

Preparation and evaluation of dabrafenib-loaded, CD47-conjugated human serum albumin-based nanoconstructs for chemoimmunomodulation

The transmembrane proteins, CD47 and signal-regulatory protein α are overexpressed in cancer cells and macrophages, respectively, and facilitate the escape of cancer cells from macrophage-mediated phagocytosis. The immunomodulatory and targeting properties of CD47, the chemotherapeutic effects of dabrafenib (D), and the anti-programmed death-1 antibodies (PD-1) pave the way for effective chemoimmunomodulation-mediated anticancer combination therapy. In this study, CD47-conjugated, D-loaded human serum albumin (HSA) nanosystems were fabricated by modified nanoparticle albumin-bound technology. Cis-aconityl-PEG-maleimide (CA), an acid-labile linker, was used to conjugate D@HSA and CD47; the resultant CD47-CA@D@HSA exhibited tumor-specificity through receptor targeting, as well as preferential cleavage and drug release in the acidic tumor microenvironment (pH 5) compared to normal physiological pH conditions (pH 6.5, 7.4). The successful preparation of nanosized (∼220 nm), narrowly dispersed (∼0.13) CD47-CA@D@HSA was proven by physicochemical characterization. In vitro and in vivo internalization, accumulation, cytotoxicity, and apoptosis were observed to be higher with CD47-conjugated nanoconstructs, than with free D or non-targeted nanoconstructs. CD47-CA@D@HSA was found to promote the infiltration of cytotoxic T cells and tumor-associated macrophages into tumors and improve in vivo tumor inhibition. Administration in combination with PD-1 further improved antitumor efficacy by promoting immune responses that blocked the immune checkpoint. No signs of toxicity were seen in mice treated with the nanoconstructs; the formulation was, therefore, thought to be biocompatible and as having potential for clinical use. The targeted chemoimmunomodulation achieved by this combination therapy was found to combat major immunosuppressive facets, making it a viable candidate for use in the treatment of cancer.

Dimeric Artesunate-Phosphatidylcholine-Based Liposomes for Irinotecan Delivery as a Combination Therapy Approach.

In this work, dimeric artesunate-phosphatidylcholine conjugate (dARTPC)-based liposomes encapsulated with irinotecan (Ir) were developed for anticancer combination therapy. First, dARTPC featured with unique amphipathic properties formed liposomes by classical thin-film methods. After that, Ir was encapsulated into dARTPC-based liposomes (Ir/dARTPC-LP) by the triethylammonium sucrose octasulfate gradient method. Physicochemical characterization indicated that Ir/dARTPC-LP had a mean size of around 140 nm and a negative ζ potential of approximately -30 mV. Most noticeably, liposomes displayed an encapsulation efficiency of greater than 98% with a controllable drug loading of 4-22%. The in vitro release of dihydroartemisinin (DHA) and Ir from Ir/dARTPC-LP was investigated by dialysis in different media. It was found that effective release of both DHA (65.42%) and Ir (77.28%) in a weakly acidic medium (pH 5.0) after 48 h was achieved in comparison to very slow release under a neutral environment (DHA 9.90% and Ir 8.72%), indicating the controllable release of both drugs. Confocal laser scanning microscopy confirmed the improved cellular internalization of Ir/dARTPC-LP. The cytotoxicity of Ir/dARTPC-LP was evaluated in the MCF-7, A549, and HepG2 cell lines. The results showed that Ir/dARTPC-LP had significant synergistic efficacy in the loss of cell growth. In vivo anticancer evaluation was performed using a 4T1 xenograft tumor model. Ir/dARTPC-LP had a high tumor inhibition rate of 62.7% without significant toxicity in comparison with the injection of Ir solution. Taken together, dARTPC encapsulated with Ir has great potential for anticancer combination therapy.

T Cell-Mediated Antitumor Immunity Cooperatively Induced By TGFβR1 Antagonism and Gemcitabine Counteracts Reformation of the Stromal Barrier in Pancreatic Cancer.

The desmoplastic stroma of pancreatic cancers forms a physical barrier that impedes intratumoral drug delivery. Attempts to modulate the desmoplastic stroma to increase delivery of administered chemotherapy have not shown positive clinical results thus far, and preclinical reports in which chemotherapeutic drugs were coadministered with antistromal therapies did not universally demonstrate increased genotoxicity despite increased intratumoral drug levels. In this study, we tested whether TGFβ antagonism can break the stromal barrier, enhance perfusion and tumoral drug delivery, and interrogated cellular and molecular mechanisms by which the tumor prevents synergism with coadministered gemcitabine. TGFβ inhibition in genetically engineered murine models (GEMM) of pancreas cancer enhanced tumoral perfusion and increased intratumoral gemcitabine levels. However, tumors rapidly adapted to TGFβ-dependent stromal modulation, and intratumoral perfusion returned to pre-treatment levels upon extended TGFβ inhibition. Perfusion was governed by the phenotypic identity and distribution of cancer-associated fibroblasts (CAF) with the myelofibroblastic phenotype (myCAFs), and myCAFs which harbored unique genomic signatures rapidly escaped the restricting effects of TGFβ inhibition. Despite the reformation of the stromal barrier and reversal of initially increased intratumoral exposure levels, TGFβ inhibition in cooperation with gemcitabine effectively suppressed tumor growth via cooperative reprogramming of T regulatory cells and stimulation of CD8 T cell-mediated antitumor activity. The antitumor activity was further improved by the addition of anti-PD-L1 immune checkpoint blockade to offset adaptive PD-L1 upregulation induced by TGFβ inhibition. These findings support the development of combined antistroma anticancer therapies capable of impacting the tumor beyond the disruption of the desmoplastic stroma as a physical barrier to improve drug delivery.

Responsive polymeric drug delivery systems for combination anticancer therapy: experimental design and computational insights

Combination therapy has been designed to overcome the setbacks of traditional chemotherapy in anticancer therapy. Since combination therapy comprises a combination of anticancer agents, the different pharmacokinetics and biodistribution properties of multiple drugs are the primary concern. Stimuli-responsive polymers can vary in structure with changes in environmental conditions. Therefore, the microenvironmental differences between tumor sites and normal tissues can be utilized to achieve controlled drug release within a specific time and location range. Thus, stimuli-responsive polymers have the ability to optimize combination drug administration. This present review addresses four different strategies for preparing a polymeric combination drug delivery system. Different types of payloads, including various chemo drugs, gene drugs, and photosensitizers, that have been explored in the experiment are crucial parts of the discussion in this review. In addition, the triggering conditions of stimuli-responsive polymers used in combination therapy in recent years are summarized. Moreover, due to the investigation of drug-carrier or drug-drug interactions at the molecular level, computational chemistry provides inspiration for the rational design of novel drug delivery systems. Thus, a series of simulations to calculate the thermodynamic and kinetic properties of drug carriers are also introduced. The challenges and perspectives of nanocarrier-based combination therapy have also been discussed.

MTOR Activity and Autophagy in Senescent Cells, a Complex Partnership.

Cellular senescence is a form of proliferative arrest triggered in response to a wide variety of stimuli and characterized by unique changes in cell morphology and function. Although unable to divide, senescent cells remain metabolically active and acquire the ability to produce and secrete bioactive molecules, some of which have recognized pro-inflammatory and/or pro-tumorigenic actions. As expected, this “senescence-associated secretory phenotype (SASP)” accounts for most of the non-cell-autonomous effects of senescent cells, which can be beneficial or detrimental for tissue homeostasis, depending on the context. It is now evident that many features linked to cellular senescence, including the SASP, reflect complex changes in the activities of mTOR and other metabolic pathways. Indeed, the available evidence indicates that mTOR-dependent signaling is required for the maintenance or implementation of different aspects of cellular senescence. Thus, depending on the cell type and biological context, inhibiting mTOR in cells undergoing senescence can reverse senescence, induce quiescence or cell death, or exacerbate some features of senescent cells while inhibiting others. Interestingly, autophagy—a highly regulated catabolic process—is also commonly upregulated in senescent cells. As mTOR activation leads to repression of autophagy in non-senescent cells (mTOR as an upstream regulator of autophagy), the upregulation of autophagy observed in senescent cells must take place in an mTOR-independent manner. Notably, there is evidence that autophagy provides free amino acids that feed the mTOR complex 1 (mTORC1), which in turn is required to initiate the synthesis of SASP components. Therefore, mTOR activation can follow the induction of autophagy in senescent cells (mTOR as a downstream effector of autophagy). These functional connections suggest the existence of autophagy regulatory pathways in senescent cells that differ from those activated in non-senescence contexts. We envision that untangling these functional connections will be key for the generation of combinatorial anti-cancer therapies involving pro-senescence drugs, mTOR inhibitors, and/or autophagy inhibitors.

Jasmonate Compounds and Their Derivatives in the Regulation of the Neoplastic Processes.

Cancer is a serious problem in modern medicine, mainly due to the insufficient effectiveness of currently available therapies. There is a particular interest in compounds of natural origin, which can be used in the prophylaxis, as well as in the treatment and support of cancer treatment. One such compound is jasmonic acid (3-oxo-2-(pent-2’-enyl)cyclopentane acetic acid; isolated active form: trans-(-)-(3R,7R)- and cis-(+)-(3R,7S)-jasmonic acid) and its derivatives, which, due to their wide range of biological activities, are also proposed as potential therapeutic agents. Therefore, a review of literature data on the biological activity of jasmonates was prepared, with particular emphasis on the mechanisms of jasmonate action in neoplastic diseases. The anti-tumor activity of jasmonate compounds is based on altered cellular ATP levels; induction of re-differentiation through the action of Mitogen Activated Protein Kinases (MAPKs); the induction of the apoptosis by reactive oxygen species. Jasmonates can be used in anti-cancer therapy in combination with other known drugs, such as cisplatin, paclitaxel or doxorubicin, showing a synergistic effect. The structure–activity relationship of novel jasmonate derivatives with anti-tumor, anti-inflammatory and anti-aging effects is also shown.

A Validated LC-MS/MS Assay for the Simultaneous Quantification of the FDA-Approved Anticancer Mixture (Encorafenib and Binimetinib): Metabolic Stability Estimation.

The concurrent use of oral encorafenib (Braftovi, ENF) and binimetinib (Mektovi, BNB) is a combination anticancer therapy approved by the United States Food and Drug Administration (USFDA) for patients with BRAFV600E/V600K mutations suffering from metastatic or unresectable melanoma. Metabolism is considered one of the main pathways of drug elimination from the body (responsible for elimination of about 75% of known drugs), it is important to understand and study drug metabolic stability. Metabolically unstable compounds are not good as they required repetitive dosages during therapy, while very stable drugs may result in increasing the risk of adverse drug reactions. Metabolic stability of compounds could be examined using in vitro or in silico experiments. First, in silico metabolic vulnerability for ENF and BNB was investigated using the StarDrop WhichP450 module to confirm the lability of the drugs under study to liver metabolism. Second, we established an LC–MS/MS method for the simultaneous quantification of ENF and BNB applied to metabolic stability assessment. Third, in silico toxicity assessment of ENF and BNB was performed using the StarDrop DEREK module. Chromatographic separation of ENF, BNB, and avitinib (an internal standard) was achieved using an isocratic mobile phase on a Hypersil BDS C18 column. The linear range for ENF and BNB in the human liver microsome (HLM) matrix was 5–500 ng/mL (R2 ≥ 0.999). The metabolic stabilities were calculated using intrinsic clearance and in vitro half-life. Furthermore, ENF and BNB did not significantly influence each other’s metabolic stability or metabolic disposition when used concurrently. These results indicate that ENF and BNB will slowly bioaccumulate after multiple doses.

Tumor microenvironment/NIR-responsive carbon monoxide delivery with hollow mesoporous CuS nanoparticles for MR imaging guided synergistic therapy

The synthesis of a novel versatile nanomedicine platform integrating multiple imaging and therapeutic functions has always been a great challenge for efficient cancer diagnosis and therapy. Herein, in this study, a novel versatile carbon monoxide (CO) delivery nanoplatform was constructed with hollow mesoporous CuS NPs carrying manganese carbonyl (MnCO) to realize MR imaging-guided PTT and CO combined anticancer therapy. The MnCO@CuS nanoplatform revealed superior properties in colloidal stability, photothermal conversion, H2O2/NIR-stimulated CO release and tumoral accumulation. More importantly, the enriched H2O2 in the tumor microenvironment (TME) triggered MnCO to release CO in situ, and this process was further strengthened by the NIR irradiation. Subsequently, the intermediate products MnOx was degraded into Mn2+ by the mild acidic tumor microenvironment to enable T1-weighted MR imaging. Simultaneously, the in situ-released CO combined with NIR irradiation exhibited strongest inhibition to the growth of MV3 tumor in vitro and in vivo. Moreover, the multifunctional nanoplatform also exhibited low toxicity and good biocompatibility in vitro and in vivo. Hence, these results suggested the MnCO@CuS nanoplatform possessed significant potential in realizing TME/NIR stimulated CO/Mn2+ generation and photothermal conversion for MR imaging-guided synergistic PTT and CO anticancer therapy.

GE11 Peptide Conjugated Liposomes for EGFR-Targeted and Chemophotothermal Combined Anticancer Therapy

How to actively target tumor sites manipulating the controllable release of the encapsulated anticancer drugs and photosensitizers for synergistic anticancer therapy remains a big challenge. In this study, a cancer cell-targeted, near-infrared (NIR) light-triggered and anticancer drug loaded liposome system (LPs) was developed for synergistic cancer therapy. Photosensitizer indocyanine green (ICG) and chemotherapy drug Curcumin (CUR) were coencapsulated into the liposomes, followed by the surface conjugation of GE11 peptide for epidermal growth factor receptor (EGFR) targeting on the cancer cell surface. Strictly controlled by NIR light, GE11 peptide modified and CUR/ICG-loaded LPs (GE11-CUR/ICG-LPs) could introduce hyperthermia in EGFR overexpressed A549 cancer cells for photothermal therapy, which could also trigger the increased release of CUR for enhanced cancer cell inhibition. GE11-CUR/ICG-LPs synergized photochemotherapy could induce reactive oxygen species (ROS) generation and cytoskeleton disruption to activate stronger apoptotic signaling events than the photothermal therapy or chemotherapy alone by regulating Bax/Bcl-2 and PI3K/AKT pathways. This EGFR-targeted drug-delivery nanosystem with NIR sensitivity may potentially serve in more effective anticancer therapeutics with reduced off-target effects.

Fabrication of cisplatin-loaded polydopamine nanoparticles via supramolecular self-assembly for photoacoustic imaging guided chemo-photothermal cancer therapy

Nanoscale drug delivery system (nDDS) mediated combinatorial therapy shows great promise in cancer treatment to circumvent the drawbacks of conventional monotherapy. In this study, we reported the development of a supramolecular self-assembly strategy to construct multifunctional nDDS. Cisplatin prodrug (Pt-CD) was successfully loaded onto polydopamine nanoparticles (PDA NPs) through the host-guest supramolecular self-assembly between β-cyclodextrins (β-CD) and adamantyl groups. Two cancer therapeutic modalities, photothermal therapy (PTT) and chemotherapy, were integrated into the as-designed nanoplatform (PDA-Pt NPs) to endow combinatorial anticancer capacity. The excellent photothermal performance and redox responsive cisplatin release behavior of PDA-Pt NPs was fully validated. Moreover, PDA-Pt NPs exhibited photoacoustic imaging capacity for real-time in vivo monitoring of the accumulation of the nanodrug in the tumor site and facilitated the imaging-guided PTT at the optimal treatment window. Ultimately, the combinatorial chemo-photothermal therapy mediated by PDA-Pt NPs exhibited very potent anticancer activity against osteosarcoma 143B cells in vitro and complete ablation of the subcutaneous tumor xenograft in vivo. In conclusion, this study represents an innovative and facile supramolecular self-assembly strategy for fabrication of multifunctional nanotheranostics for efficient combined anticancer therapy, which could further inspire the development of other combinatorial nanotherapeutics.

Glutathione-activated DNA-Au nanomachine as targeted drug delivery platform for imaging-guided combinational cancer therapy

Multimodal therapy is a combination of different therapeutic modalities within one single platform to enhance treatment efficiency, which holds great promise in biomedical research and clinical practice. Herein, a glutathione (GSH)-activated DNA-Au nanomachine with tumor-targeting capacity has been developed for imaging-guided photodynamic/photothermal/chemo combination therapy of murine breast cancer. In this theranostic nanoplatform, G-quadruplex double-stranded DNA (G-dsDNA) containing AS1411 aptamer is served as not only the targeting unit to specifically recognize murine 4T1 breast cancer cells but also the carrier for loading photosensitizer chlorins e6 (Ce6), iron-containing porphyrin hemin and anticancer drug doxorubicin (Dox). In tumor microenvironment, the excessive GSH triggers the rupture of disulfide bridges and results in the dissociation of DNA-Au nanomachine along with the release of Dox for chemotherapy and the aggregation of AuNPs for photothermal therapy (PTT) as well as in situ imaging. Meanwhile, hemin and Ce6 delivered by G-quadruplexes alleviate the tumor hypoxia, which further promotes the generation of reactive oxygen species (ROS) for enhanced photodynamic therapy (PDT). The in vitro and in vivo assays validate that the combination of PDT/PTT/chemotherapy shows a high efficiency for targeted damage of 4T1 cells and inhibition of tumor growth. Therefore, the proposed multifunctional DNA-Au nanomachine provides a powerful and robust theranostic nanoplatform for imaging-guided combinatorial anticancer therapy.

Targeting FAK in anticancer combination therapies.

Focal adhesion kinase (FAK) is both a non-receptor tyrosine kinase and an adaptor protein that primarily regulates adhesion signalling and cell migration, but FAK can also promote cell survival in response to stress. FAK is commonly overexpressed in cancer and is considered a high-value druggable target, with multiple FAK inhibitors currently in development. Evidence suggests that in the clinical setting, FAK targeting will be most effective in combination with other agents so as to reverse failure of chemotherapies or targeted therapies and enhance efficacy of immune-based treatments of solid tumours. Here, we discuss the recent preclinical evidence that implicates FAK in anticancer therapeutic resistance, leading to the view that FAK inhibitors will have their greatest utility as combination therapies in selected patient populations.

MicroRNA-143 Sensitizes Cervical Cancer Cells to Cisplatin: a Promising Anticancer Combination Therapy.

Cisplatin-based chemotherapy is commonly used for cervical cancer treatment. However, the development of chemoresistance is considered the main obstacle to the effectiveness of this therapeutic agent. MicroRNAs are illustrated to play a major role in the regulation of cancer cell chemosensitivity. Therefore, this study was aimed to investigate the potential therapeutic role of miRNA-143 in combination with cisplatin on cervical cancer cells. Then, CaSki cell line with low expression levels of miRNA-143 was selected for functional experiments. The cells were treated with miRNA-143 and cisplatin individually or in combination. The cell viability and apoptosis induction were evaluated by MTT, Annexin V-FITC/PI, and DAPI staining tests. Cell migration was further evaluated by wound healing assay. The effect of miRNA-143 and cisplatin combination on gene expression was quantified by real-time PCR. Furthermore, the combination therapy effect on cell cycle progression and autophagy induction was also evaluated by flow cytometry. Our results showed that miRNA-143 overexpression could increase cisplatin-induced apoptosis and increase the sensitivity of CaSki cells to low doses of this chemotherapeutic agent via modulating the expression of apoptosis-related genes including Bcl-2, Bax, and caspase-9. Besides, miRNA-143 and cisplatin were demonstrated to cooperatively increase the cell cycle arrest at the sub-G1 and G2-M phases, induce autophagy activation, and via downregulation of vimentin inhibit CaSki cell migration. Moreover, c-Myc as an important regulator of cell growth was downregulated in treatment groups compared to the control. In conclusion, regarding that miRNA-143 could sensitize cervical cancer cells to cisplatin, it may be considered a promising therapeutic strategy for the treatment of this malignancy.

Endogenous mRNA Triggered DNA‐Au Nanomachine for In Situ Imaging and Targeted Multimodal Synergistic Cancer Therapy

AbstractThe development of versatile nanotheranostic platforms that integrate both diagnostic and therapeutic functions have always been an intractable challenge in precise cancer treatment. Herein, an aptamer‐tethered deoxyribonucleic acids‐gold particle (Apt‐DNA‐Au) nanomachine has been developed for in situ imaging and targeted multimodal synergistic therapy of mammary carcinoma. Upon specifically internalized into MCF‐7 cells, the tumor‐related TK1 mRNA activates the Apt‐DNA‐Au nanomachine by DNA strand displacement cascades, resulting in the release of the fluorophore and antisense DNA as well as the aggregation of AuNPs for in situ imaging, suppression of survivin expression and photothermal therapy, respectively. Meanwhile, the controlled released drugs are used for chemotherapy, while under the laser irradiation the loaded photosensitizer produces reactive oxygen species (ROS) for photodynamic therapy. The results confirm that the proposed Apt‐DNA‐Au nanomachine provides a powerful nanotheranostic platform for in situ imaging‐guided combinatorial anticancer therapy.

Endogenous mRNA Triggered DNA-Au Nanomachine for In Situ Imaging and Targeted Multimodal Synergistic Cancer Therapy.

The development of versatile nanotheranostic platforms that integrate both diagnostic and therapeutic functions have always been an intractable challenge in precise cancer treatment. Herein, an aptamer-tethered deoxyribonucleic acids-gold particle (Apt-DNA-Au) nanomachine has been developed for in situ imaging and targeted multimodal synergistic therapy of mammary carcinoma. Upon specifically internalized into MCF-7 cells, the tumor-related TK1 mRNA activates the Apt-DNA-Au nanomachine by DNA strand displacement cascades, resulting in the release of the fluorophore and antisense DNA as well as the aggregation of AuNPs for in situ imaging, suppression of survivin expression and photothermal therapy, respectively. Meanwhile, the controlled released drugs are used for chemotherapy, while under the laser irradiation the loaded photosensitizer produces reactive oxygen species (ROS) for photodynamic therapy. The results confirm that the proposed Apt-DNA-Au nanomachine provides a powerful nanotheranostic platform for in situ imaging-guided combinatorial anticancer therapy.

Combination prostate cancer therapy: Prostate-specific membranes antigen targeted, pH-sensitive nanoparticles loaded with doxorubicin and tanshinone

Prostate cancer is the second most frequently diagnosed cancer in the men population. Combination anticancer therapy using doxorubicin (DOX) and another extract of traditional Chinese medicine is one nano-sized drug delivery system promising to generate synergistic anticancer effects, maximize the treatment effect, and overcome multi-drug resistance. The purpose of this study is to construct a drug delivery system for the co-delivery of DOX and tanshinones (TAN). Lipid nanoparticles loaded with DOX and TAN (N-DOX/TAN) were prepared by emulsification and solvent-diffusion method. PSMA targeted nanoparticles loaded with DOX and TAN (P-N-DOX/TAN) were synthesized by conjugating a PSMA targeted ligand to N-DOX/TAN. We evaluate the performance of this system in vitro and in vivo. P-N-DOX/TAN has a size of 139.7 ± 4.1 nm and a zeta potential of 11.2 ± 1.6 mV. The drug release of DOX and TAN from P-N-DOX/TAN was much faster than that of N-DOX/TAN. N-DOX/TAN presented more inhibition effect on tumor growth than N-DOX and N-TAN, which is consistent with the synergistic results and successfully highlighting the advantages of combing the DOX and TAN in one system. P-N-DOX/TAN achieved higher uptake by LNCaP cells (58.9 ± 1.9%), highest tumor tissue distribution, and the most significant tumor inhibition efficiency. The novel nanomedicine offers great promise for the dual drug delivery to prostate cancer cells, showing the potential of synergistic combination therapy for prostate cancer.