Efficient Cancer Therapy Research Articles

A Tumor Microenvironment-Triggered and Photothermal-Enhanced Nanocatalysis Multimodal Therapy Platform for Precise Cancer Therapy

The tumor microenvironment (TME)-triggered therapeutic strategy not only provides effective and economical methods for cancer treatment but also minimizes the side effects on normal tissues. However, anticancer species generated by TME-triggered chemical reactions in situ within cancer cells are insufficient to inhibit tumor growth. This study reports the construction of a TME-triggered and photothermal (PT)-enhanced nanocatalysis platform that is based on cancer cell (MCF-7) membrane-camouflaged hollow porous Cu7S4 nanospheres (HPCu7S4@MCF-7) for efficient cancer therapy. HPCu7S4 exhibits strong absorption in the near-infrared region with a high PT conversion efficiency (∼30%). After coating with a cell membrane, HPCu7S4@MCF-7, which possesses a high ability to recognize and target cancer cells, can not only be used as a PT agent for PT therapy (PTT) but can also catalyze the generation of •OH and H2S under TME conditions to facilitate chemodynamic therapy (CDT) and gas therapy (GT), respectively. Moreover, NIR irradiation enhances the generation of more •OH and H2S to improve the therapeutic efficiency. Both in vitro and in vivo results demonstrate a high therapeutic efficiency of HPCu7S4@MCF-7-based PTT in combination with TME-triggered and PT-enhanced CDT and GT, which will open a new approach for constructing multimodal therapeutic strategies for potential use in the clinic.

Immunostimulatory multi-interfacial bimetallic phosphide nanoparticles as photo-enhanced cascade nanozyme for cancer therapy

Nanozyme has been widely explored for tumor catalytic therapy. Nevertheless, highly efficient and specific cancer therapy with nanozyme is still challenging under the strict condition of tumor microenvironment (TME). Herein, we fabricate a bimetallic phosphide nanoparticle (CuFeP) with multiphase interfaces as a photo-enhanced cascade nanozyme for efficient immunostimulatory cancer therapy. The CuFeP has structural, atomic and electric coupling with multi-interfacial heterojunction to promote the interfacial electron transfer, and the bimetallic redox couple of Cu+/2+ and Fe0/2+/3+ to synergistically improve the cascade catalysis of peroxidase (POD) and glutathione peroxidase (GPX), thereby inducing lethal cellular oxidative damage. Moreover, the excellent photothermal efficiency of 66.9% assists in catalysis in view of thermodynamics. Finally, the synergetic catalysis triggers immune cell death (ICD) process, which promotes maturation of dendritic cells (DCs), activation of cytotoxic and helper T cells, and excretion of proinflammatory cytokines to boost antitumor immunity in vivo. This study provides an enlightenment for the design of efficient therapeutic nanozyme to conquer cancer.

Mitochondria-Targeted Nanocarriers Promote Highly Efficient Cancer Therapy: A Review.

Mitochondria are the primary organelles which can produce adenosine triphosphate (ATP). They play vital roles in maintaining normal functions. They also regulated apoptotic pathways of cancer cells. Given that, designing therapeutic agents that precisely target mitochondria is of great importance for cancer treatment. Nanocarriers can combine the mitochondria with other therapeutic modalities in cancer treatment, thus showing great potential to cancer therapy in the past few years. Herein, we summarized lipophilic cation- and peptide-based nanosystems for mitochondria targeting. This review described how mitochondria-targeted nanocarriers promoted highly efficient cancer treatment in photodynamic therapy (PDT), chemotherapy, combined immunotherapy, and sonodynamic therapy (SDT). We further discussed mitochondria-targeted nanocarriers’ major challenges and future prospects in clinical cancer treatment.

A Multifunctional Polymeric Micelle for Targeted Delivery of Paclitaxel by the Inhibition of the P-Glycoprotein Transporters.

P-glycoprotein (P-gP) efflux-mediated multidrug resistance is a fundamental aspect of chemotherapeutic failure in oncology. The current study aims to deliver paclitaxel (PTX) specifically at the target site with improved in vivo efficacy of poorly permeable PTX against solid tumors. Multifunctional polymeric micelles as targeted delivery have been devised for loading and release of PTX. Mucoadhesion, permeation enhancement, oral pharmacokinetics, biodistribution, and toxicological studies were carried out to fully elucidate the therapeutic outcomes of the polymeric micelles. Ex vivo permeation studies indicated a 7.89-fold enhancement in the permeation of PTX with mucopermeating papain functionalized thiolated redox micelles (PT-R-Ms) compared to the pure PTX. Moreover, PT-R-Ms exhibited a higher percentage of apoptotic cells (42.9 ± 0.07%) compared to pure PTX. Biodistribution studies revealed that fluorotagged PT-RMs accumulated in excised tumors and organs. The higher fluorescence intensity indicated the mucopermeation of micelles across the intestine. The orally administered PT-R-Ms efficiently overcome intestinal barriers and inhibit the P-gP efflux pump, resulting in increased bioavailability of PTX (up to 8-fold) in comparison to pure PTX. The enhanced anti-tumor efficacy and reduced toxic effects are key aspects of efficient cancer therapy. This study demonstrates that the use of mucopermeating PT-R-Ms is an encouraging approach to overwhelm the permeation barrier in cancer treatment.

Magnetic Resonance Imaging-Guided Multi-Stimulus-Responsive Drug Delivery Strategy for Personalized and Precise Cancer Treatment.

The emergence of nano-targeted controlled release liposomal drug carriers has provided a breakthrough in cancer therapy. However, their clinical efficacy is unsatisfactory, which is related to individualized differences in targeted drugs and poor in vivo release efficiency. In this paper, we prepared a class of personalized targeted and precisely controlled-release therapeutic drug carriers (GF liposomes) by co-assembling targeting and traceable o-nitrobenzyl ester lipids to propose a magnetic resonance imaging (MRI)-guided personalized in vivo targeted drug screening strategy and a multi-stimulus superimposed controlled-release strategy. Furthermore, by following the drug release process of drug-loaded liposomes (GF-D), it was found that these liposomes could rely on energy superposition to achieve more sensitive and efficient controlled drug release. In addition, the indispensable adjustment of liposome formulation for personalized MRI-based targeted therapy was verified by differential cellular uptake and in vivo magnetic resonance imaging. In the end, the 10.22-fold tumor suppression effect in the stimulus superposition group (GF-D-UV) indicates that the multi-stimulus cumulative response strategy and MRI-guided in vivo screening strategy can more effectively treat cancer. This contribution provides a concise and clever design idea for the future development of personalized precise and efficient clinical cancer therapies.

Improving anti-cancer drug delivery performance of magnetic mesoporous silica nanocarriers for more efficient colorectal cancer therapy

BackgroundImproving anti-cancer drug delivery performance can be achieved through designing smart and targeted drug delivery systems (DDSs). For this aim, it is important to evaluate overexpressed biomarkers in the tumor microenvironment (TME) for optimizing DDSs.Materials and methodsHerein, we designed a novel DDS based on magnetic mesoporous silica core–shell nanoparticles (SPION@MSNs) in which release of doxorubicin (DOX) at the physiologic pH was blocked with gold gatekeepers. In this platform, we conjugated heterofunctional polyethylene glycol (PEG) onto the outer surface of nanocarriers to increase their biocompatibility. At the final stage, an epithelial cell adhesion molecule (EpCAM) aptamer as an active targeting moiety was covalently attached (Apt-PEG-Au@NPs-DOX) for selective drug delivery to colorectal cancer (CRC) cells. The physicochemical properties of non-targeted and targeted nanocarriers were fully characterized. The anti-cancer activity, cellular internalization, and then the cell death mechanism of prepared nanocarriers were determined and compared in vitro. Finally, tumor inhibitory effects, biodistribution and possible side effects of the nanocarriers were evaluated in immunocompromised C57BL/6 mice bearing human HT-29 tumors.ResultsNanocarriers were successfully synthesized with a mean final size diameter of 58.22 ± 8.54 nm. Higher cytotoxicity and cellular uptake of targeted nanocarriers were shown in the EpCAM-positive HT-29 cells as compared to the EpCAM-negative CHO cells, indicating the efficacy of aptamer as a targeting agent. In vivo results in a humanized mouse model showed that targeted nanocarriers could effectively increase DOX accumulation in the tumor site, inhibit tumor growth, and reduce the adverse side effects.ConclusionThese results suggest that corporation of a magnetic core, gold gatekeeper, PEG and aptamer can strongly improve drug delivery performance and provide a theranostic DDS for efficient CRC therapy.Graphic abstract

Endogenous NO-releasing Carbon Nanodots for Tumor-specific Gas Therapy

Carbon nanodots based on L-arginine (L-Arg) were developed for enhanced nitric oxide (NO) gas therapy for cancer. The L-Arg-based carbon nanodots (Arg-dots) produced high levels of NO in the tumor environment rich in endogenous H2O2. In vitro cell experiments revealed that the Arg-dots could kill tumor cells (including human breast cancer cell line MCF-7, female gastric cancer cell line BGC-823, male lung cancer cell line A549, and female leukemic cell line K562) but did not affect the activity of normal cells (human normal lung epithelial cell line BEAS-2B). The Arg-dots produced twice the amount of NO for an equivalent amount of L-Arg. Theoretical calculations showed that the carbonization structure of the Arg-dots promoted significantly more electrons toward the guanidinium groups of L-Arg and boosted the adsorption of H2O2 molecules. In vitro and in vivo investigations confirmed that the Arg-dots reduced the multidrug resistance (MDR) effect of the tumor cells (MCF-7/ADR cells) and produced a combined antitumor efficacy with traditional chemotherapeutic drugs (adriamycin [ADR]). The fluorescence property (quantum yield, 6.88%) allows the Arg-dots to be used as a suitable fluorescent probe for fluorescence imaging of tumor cells. The ultra-small size of the Arg-dots (diameter: ca. 2.5 nm) enables them not only to penetrate deep tumors and provide enhanced antitumor activity but also to be removed through kidney filtration and have a renal clearance property. Statement of significanceNitric oxide (NO), which serves as a biological messenger, can be used in gas therapy for cancer. The development of a safe and efficient NO cancer therapy is, however, challenging because of the low NO release amount and poor tumor specificity of most NO donors. Many efforts have been made to overcome these drawbacks, but solving both these limitations through a single approach has been seldom achieved. In the present work, carbon nanodots (Arg-dots) from L-arginine were used for gas therapy of cancer. The Arg-dots produced NO in the H2O2-rich tumor environment. Theoretical calculations were consistent with the mechanism of enhanced NO release amount. The Arg-dots also reduced the multidrug resistance effect in cancer chemotherapy. In vivo and in vitro toxicity assessments confirmed that the Arg-dots have excellent biosafety.

Biomimetic nanoparticles loading with gamabutolin-indomethacin for chemo/photothermal therapy of cervical cancer and anti-inflammation

A pro-nanodrug combinational strategy for efficient cervical cancer therapy with intrinsic tumor microenvironment (TME)-responsive elements and low side effects is highly desired. Here, a pro-nanodrug complexes with GSH and NIR responsive manner is reported to boost gamabufotalin induced chemo-photothermal therapy with the assistance of reprogrammed TME by indomethacin. In addition, hybrid cell membrane was used to endow nanocomplexes with the prolonging circulation time and high accumulation of drug at tumor tissue. Indomethacin activated by the high level GSH can attenuate tumor inflammation microenvironment triggered by PTT and sensitize tumor cells to gamabufotalin through inhibiting PGE2 secretion. The released low-dose gamabufotalin with low side effects can efficiently kill tumor cells by ROS production and COX-2 low expression. In vitro and in vivo assays demonstrated that strong anti-tumor activity of nanocomplexes in tumor-bearing mice through chemo-photothermal therapy, which was reflected by the eradication of cervical tumor and significant extension of survival time of mice.

PH-Responsive DNA nanoassembly for detection and combined therapy of tumor

We have developed a novel cancer theragnostic nanoassembly with high biocompatibility, stability and low toxicity which are activated rapidly by tumor microenvironment to realize selective fluorescence imaging, chemotherapy as well as chemoenzymatic therapy. The nanoprobes are synthesized by hybridization of fluorophore labeled hairpin DNAs containing a 5-aza-dC at hemimethylated CpG sites and pH-sensitive DNA sequence covalently conjugated with PEGylated GO. The aptamer, which is also covalently conjugated on PEGylated GO, enables to target the tumor site and the weak acid environment of tumor triggers the release of drug loaded by nanoprobes including functionalized DNA and DOXs, effectively activating fluorescence signals and selectively killing the tumor cells. The results revealed that the nanoprobe enables sensitive detection of pH changes within subcellular environment, selectively imaging and great synergy of multicombination therapeutic including chemotherapy and chemoenzymatic therapy, implying that developed pH activatable probe has considerable potential for diagnosis and efficient therapy of cancer.

Rapid Tumor Targeting of Renal-Clearable ZW800-1 Conjugate for Efficient Photothermal Cancer Therapy.

The combination of near-infrared (NIR) fluorophores and photothermal therapy (PTT) provides a new opportunity for safe and effective cancer treatment. However, the precise molecular design of functional NIR fluorophores with desired properties, such as high tumor targetability and low nonspecific uptake, remains challenging. In this study, a renal-clearable NIR fluorophore conjugate with high tumor targetability was developed for efficient photothermal cancer therapy. The isoniazid (INH)–ZW800-1 conjugate (INH–ZW) was synthesized by conjugating an antibiotic drug, INH, with a well-known zwitterionic NIR fluorophore, ZW800-1, to improve in vivo performance and fluorescence-guided cancer phototherapy. INH–ZW not only showed rapid tumor accumulation without nonspecific tissue/organ uptake within 1 h after the injection but also generated thermal energy to induce cancer cell death under NIR laser irradiation. Compared with previously reported ZW800-1 conjugates, INH–ZW preserved the ideal biodistribution of ZW800-1 and facilitated improved tumor targeting and PTT. Together, these results demonstrate that the INH–ZW conjugate has great potential to serve as an effective PTT agent capable of rapid tumor targeting and high renal clearance, with excellent photothermal efficacy.

Hyaluronan-fullerene/AIEgen nanogel as CD44-targeted delivery of tirapazamine for synergistic photodynamic-hypoxia activated therapy

The therapeutic effect of oxygen-concentration-dependent photodynamic therapy (PDT) can be diminished in the hypoxic environment of solid tumours, the effective solution to this problem is utilising hypoxic-activated bioreduction therapy (BRT). In this research, a biocompatible HA-C60/TPENH2 nanogel which can specifically bind to CD44 receptor was developed for highly efficient PDT-BRT synergistic therapy. The nanogel was degradable in acidic microenvironments of tumours and facilitated the release of biological reduction prodrug tirapazamine (TPZ). Importantly, HA-C60/TPENH2 nanogel produced reactive oxygen species and consumed oxygen content in the cell to activate TPZ, leading to higher cytotoxicity than the free TPZ did. The intracellular observation of nanogel indicated that the HA-C60/TPENH2 nanogel was self-fluorescence for cell imaging. This study applied PDT-BRT to design smart HA-based nanogel with targeted delivery, pH response, and AIEgen feature for efficient cancer therapy.

Development of Tailor-Made Dendrimer Ternary Complexes for Drug/Gene Co-Delivery in Cancer.

Cancer gene therapy, mediated by non-viral systems, remains a major research focus. To contribute to this field, in this work we reported on the development of dendrimer drug/gene ternary complexes. This innovative approach explored the great capacity of both polyamidoamine (PAMAM)-paclitaxel (PTX) conjugate and polyethylenimine (PEI) polymers to complex a p53-encoding plasmid DNA (pDNA), highlighting the utility of considering two compacting agents. The pDNA complexation capacity has been investigated as function of the nitrogen to phosphate groups ratio (N/P), which revealed to be a tailoring parameter. The physicochemical properties of the conceived ternary complexes were revealed and were found to be promising for cellular transfection. Furthermore, the formulated co-delivery systems demonstrated to be biocompatible. The ternary systems were able of cellular internalization and payload intracellular release. Confocal microscopy studies showed the co-localization of stained pDNA with the nucleus of cancer cells, after transfection mediated by these carriers. From this achievement, p53 gene expression occurred with the production of protein. Moreover, the activation of caspase-3 indicated apoptosis of cancer cells. This work represents a great progress on the design of dendrimer drug/gene co-delivery systems towards a more efficient cancer therapy. In this way, it instigates further in vitro studies concerning the evaluation of their therapeutic potential, expectedly supported by the synergistic effect, in tumoral cells.

Nanocarriers Used in Drug Delivery to Enhance Immune System in Cancer Therapy.

Cancer, a group of diseases responsible for the second largest cause of global death, is considered one of the main public health problems today. Despite the advances, there are still difficulties in the development of more efficient cancer therapies and fewer adverse effects for the patients. In this context, nanobiotechnology, a materials science on a nanometric scale specified for biology, has been developing and acquiring prominence for the synthesis of nanocarriers that provide a wide surface area in relation to volume, better drug delivery, and a maximization of therapeutic efficiency. Among these carriers, the ones that stand out are those focused on the activation of the immune system. The literature demonstrates the importance of this system for anticancer therapy, given that the best treatment for this disease also activates the immune system to recognize, track, and destroy all remaining tumor cells.

Enhanced endosomal escape of dendrigraft poly-L-lysine polymers for the efficient gene therapy of breast cancer

Enhanced endosomal escape of dendrigraft poly-L-lysine polymers for the efficient gene therapy of breast cancer

Recent Advances in Nanomaterials Development for Nanomedicine and Cancer

Cancer is considered one of the leading causes of death, with a growing number of cases worldwide. However, the early diagnosis and efficient therapy of cancer have remained a critical challenge. The emergence of nanomedicine has opened up a promising window to address the drawbacks of cancer detection and treatment. A wide range of engineered nanomaterials and nanoplatforms with different shapes, sizes, and composition has been developed for various biomedical applications. Nanomaterials have been increasingly used in various applications in bioimaging, diagnosis, and therapy of cancers. Recently, numerous multifunctional and smart nanoparticles with the ability of simultaneous diagnosis and targeted cancer therapy have been reported. The multidisciplinary attempts led to the development of several exciting clinically approved nanotherapeutics. The nanobased materials and devices have also been used extensively to develop point-of-care and highly sensitive methods of cancer detection. In this review article, the most significant achievements and latest advances in the nanomaterials development for cancer nanomedicine are critically discussed. In addition, the future perspectives of this field are evaluated.

Hyperbaric oxygen regulates tumor microenvironment and boosts commercialized nanomedicine delivery for potent eradication of cancer stem-like cells

Cancer stem-like cells (CSCs) depend highly on hypoxia in solid tumors and represent an intractable challenge for marketed nanomedicines. Herein, we for the first time leveraged hyperbaric oxygen (HBO) therapy to help commercialized nanomedicines, including Doxil and Abraxane, eliminate CSCs in stroma-rich solid tumors, e.g., triple negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC), for efficient cancer therapy. Mechanistically, we revealed that HBO disrupted hypoxia in solid tumors, thereby directly suppressing CSCs and cancer metastasis. More importantly, we found that HBO depleted excessive extracellular matrix, such as collagen and fibronectin, and thus normalized tumor blood vessels both structurally and functionally. As a consequence, HBO augmented the delivery of commercialized nanomedicines, but not small molecule drug, into solid tumors, in terms of tumor accumulation, deep penetration and cellular internalization, leading to efficient CSCs eradication and tumor inhibition. These results demonstrate that HBO enables commercialized nanomedicines to eliminate CSCs in stroma-rich solid tumors and suggest that the combination of HBO with commercialized nanomedicines is promising for the treatment of hypoxic solid tumors in the clinics.

A Novel Recombinant Fcγ Receptor-Targeted Survivin Combines with Chemotherapy for Efficient Cancer Treatment.

Formyl peptide receptor-like 1 inhibitor (FLIPr), an Fcγ receptor (FcγR) antagonist, can be used as a carrier to guide antigen-FLIPr fusion protein to FcγR then enhances antigen-specific immune responses. Survivin, a tumor-associated antigen, is over-expressed in various types of human cancer. In this study, we demonstrate that recombinant survivin-FLIPr fusion protein (rSur-FLIPr) binds to FcγRs, and efficient uptake by dendritic cells in vivo. In addition, rSur-FLIPr alone stimulates survivin-specific immune responses, which effectively suppresses the tumor growth. The antitumor immunities are through TAP-mediated and CD8-dependent pathways. Furthermore, preexisting anti-FLIPr antibody does not abolish antitumor responses induced by rSur-FLIPr immunization. These results suggest that FLIPr is an effective antigen delivery vector and can be repeatedly used. Combination of chemotherapy with rSur-FLIPr treatment reveals a great benefit to tumor-bearing mice. Altogether, these findings suggest that rSur-FLIPr is a potential candidate for efficient cancer therapy.

Cr(V)–Cr(III) in-situ transition promotes ROS generation to achieve efficient cancer therapy

The development of metal-based anticancer drugs is of considerable interest and significance in inorganic medicine. In contrast to noble metal-based small molecules, the anticancer property of earth abundant metal-based small molecules is much less explored which are usually essential trace element for the human body. Among earth abundant metals, chromium (Cr) in the +3 valent is an essential trace element for the human body to low down the blood lipids and maintain the blood sugar; on the other hand, Cr(VI) are known to be highly toxic due to their oxidation power. To design stable high-valent Cr small molecules to construct Cr(high-valent)-Cr(III) in-situ transition system to achieve low-toxic and highly efficient anti-cancer therapy is a very desirable approach. Herein we report the Cr(V)–Cr(III) in-situ transition system promotes ROS generation to achieve efficient cancer therapy in vivo and in vitro. To the best of our knowledge, these Cr-based small molecules are the first stable Cr(V) compounds with potent anticancer efficacy, especially towards malignant cancers.

Self-assembled micelle responsive to quick NIR light irradiation for fast drug release and highly efficient cancer therapy

Upconversion nanoparticles (UCNPs) have been used for designing near infrared (NIR) light-responsive nanocarriers and controllable drug release. However, the need for long-term NIR light irradiation over hours impaired their application efficiency. Here we develop a self-assembled micelle of amphipathic polymer P-DASA which degrades via quick NIR light irradiation. UCNPs and DOX are also encapsulated in the micelle for quick drug release. P-DASA is composed of hydrophilic polyethylene glycol segment and photo-responsive hydrophobic donor–acceptor Stenhouse adduct (DASA). Only 5-min NIR irradiation causes the hydrophilicity conversion of P-DASA and the complete disruption of micelle with DOX fast release of 83.7% in 30 min to achieve highly efficient therapy. Moreover, the P-glycoprotein mediated DOX efflux is also diminished by concomitantly producing NO intracellularly. This micelle demonstrates impressive in vivo therapeutic effect, and thus provides an avenue for highly efficient cancer therapy.

Self-photo-oxidation for extending visible light absorption of carbon dots and oxidase-like activity

Carbon dots (C-dots) are attractive for their low cost, excellent optical properties, and low toxicity, but most C-dots are limited by their UV absorbance, especially for photodynamic therapy (PDT) applications. Developing rational and simple strategies to obtain C-dots with longer excitation/emission wavelengths remains a challenge. Previous work showed that C-dots can produce a high yield of reactive oxygen species (ROS) upon UV light illumination. We herein show that the produced ROS can lead to further oxidation and growth of C-dots, leading to visible light absorption (400 nm–650 nm) and extend fluorescence emission from blue to green. In addition, the light-treated C-dots showed boosted peroxidase and oxidase mimicking activity than the initial C-dots in the absence of light. In the presence of visible light, the catalytic efficiency of the light-treated C-dots is 11-fold much higher than the pristine C-dots. The light-treated C-dots can be used as a PDT agent due to the extended excitation and visible photo-oxidative activity, simultaneously providing a highly efficient cancer therapy. This study provides a simple way to modify C-dots leading to novel properties.