Specific Targeting Of Cancer Cells Research Articles

Functionalized Calcium Carbonate-Based Microparticles as a Versatile Tool for Targeted Drug Delivery and Cancer Treatment

Functionalized Calcium Carbonate-Based Microparticles as a Versatile Tool for Targeted Drug Delivery and Cancer Treatment

Functionalization of β-cyclodextrin metal-organic frameworks with gelatin and glutamine for drug delivery of curcumin to cancerous cells

Beta-cyclodextrin Metal-Organic Framework (β-CD-MOF) is a unique class of porous materials that merges the inherent properties of cyclodextrins with the structural advantages of metal-organic frameworks (MOFs). When combined with the concept of MOFs, which are crystalline structures composed of metal ions or clusters linked by organic ligands, the resulting β-CD-MOF holds immense potential for various applications, especially in the field of drug delivery. In this study, biocompatible metal-organic frameworks (MOFs) synthesized using β-Cyclodextrin (β-CD) and potassium enabled drug delivery of curcumin (CCM) to cancerous cells. Functionalizing β-CD-MOF with l-glutamine (glutamine-β-CD-MOF) enhanced cancer cell-specific targeting due to glutamine's essential role in cancer cell proliferation and energy pathways. Amino group functionalization provided further functionalization opportunities. Gelatin coating (gelatin@β-CD-MOF) facilitated controlled drug release in an acidic medium. High drug loading capacities (52.38–55.63 %) were achieved for β-CD-MOF@CCM and glutamine-β-CD-MOF@CCM, leveraging the high porosity and affinity of amine and phenol groups of curcumin. The MTT assay highlighted the specificity and differentiation of glutamine-β-CD-MOF in targeting cancerous over normal cells. These functionalized β-CD MOFs efficiently encapsulate curcumin, ensuring controlled drug release and enhanced therapeutic efficacy, particularly in cancer therapy.

Folate-modified liposomes mediate the co-delivery of cisplatin with miR-219a-5p for the targeted treatment of cisplatin-resistant lung cancer

Cisplatin (DDP) resistance, often leading to first-line chemotherapy failure in non-small cell lung cancer (NSCLC), poses a significant challenge. MiR-219a-5p has been reported to enhance the sensitivity of human NSCLC to DDP. However, free miR-219a-5p is prone to degradation by nucleases in the bloodstream, rendering it unstable. In light of this, our study developed an efficient nanodrug delivery system that achieved targeted delivery of DDP and miR-219a-5p by modifying liposomes with folate (FA). Based on the results of material characterization, we successfully constructed a well-dispersed and uniformly sized (approximately 135.8 nm) Lipo@DDP@miR-219a-5p@FA nanodrug. Agarose gel electrophoresis experiments demonstrated that Lipo@DDP@miR-219a-5p@FA exhibited good stability in serum, effectively protecting miR-219a-5p from degradation. Immunofluorescence and flow cytometry experiments revealed that, due to FA modification, Lipo@DDP@miR-219a-5p@FA could specifically bind to FA receptors on the surface of tumor cells (A549), thus enhancing drug internalization efficiency. Safety evaluations conducted in vitro demonstrated that Lipo@DDP@miR-219a-5p@FA exhibited no significant toxicity to non-cancer cells (BEAS-2B) and displayed excellent blood compatibility. Cellular functional experiments, apoptosis assays, and western blot demonstrated that Lipo@DDP@miR-219a-5p@FA effectively reversed DDP resistance in A549 cells, inhibited cell proliferation and migration, and further promoted apoptosis. In summary, the Lipo@DDP@miR-219a-5p@FA nanodrug, through specific targeting of cancer cells and reducing their resistance to DDP, significantly enhanced the anti-NSCLC effects of DDP in vitro, providing a promising therapeutic option for the clinical treatment of NSCLC.

Hydrogen-bonded cytosine-endowed supramolecular polymeric nanogels: Highly efficient cancer cell targeting and enhanced therapeutic efficacy

We demonstrate that cytosine moieties within physically cross-linked supramolecular polymers not only manipulate drug delivery and release, but also confer specific targeting of cancer cells to effectively enhance the safety and efficacy of chemotherapy—and thus hold significant potential as a new perspective for development of drug delivery systems. Herein, we successfully developed physically cross-linked supramolecular polymers (PECH-PEG-Cy) comprised of hydrogen-bonding cytosine pendant groups, hydrophilic poly(ethylene glycol) side chains, and a hydrophobic poly(epichlorohydrin) main chain. The polymers spontaneously self-assemble into a reversibly hydrogen-bonded network structure induced by cytosine and directly form spherical nanogels in aqueous solution. Nanogels with a high hydrogen-bond network density (i.e., a higher content of cytosine moieties) exhibit outstanding long-term structural stability in cell culture substrates containing serum, whereas nanogels with a relatively low hydrogen-bond network density cannot preserve their structural integrity. The nanogels also exhibit numerous unique physicochemical characteristics in aqueous solution, such as a desirable spherical size, high biocompatibility with normal and cancer cells, excellent drug encapsulation capacity, and controlled pH-responsive drug release properties. More importantly, in vitro experiments conclusively indicate the drug-loaded PECH-PEG-Cy nanogels can selectively induce cancer cell-specific apoptosis and cell death via cytosine receptor-mediated endocytosis, without significantly harming normal cells. In contrast, control drug-loaded PECH-PEG nanogels, which lack cytosine moieties in their structure, can only induce cell death in cancer cells through non-specific pathways, which significantly inhibits the induction of apoptosis. This work clearly demonstrates that the cytosine moieties in PECH-PEG-Cy nanogels confer selective affinity for the surface of cancer cells, which enhances their targeted cellular uptake, cytotoxicity, and subsequent induction of programmed cell death in cancer cells.

Abstract 1341: SM2235: A bispecific EGFR x CD16A innate immune cell engager for enhanced treatment of EGFR-expressing solid tumors, regardless of RAS mutation status

Abstract Background: Monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) are frontline therapies for numerous EGFR-dependent epithelial tumors. However, their efficacy faces challenges due to on-target skin toxicity and intrinsic or acquired resistance. Within the tumor microenvironment, innate immune cells, including macrophages and natural killer (NK) cells, play a significant role but are hindered by the lack of specific cancer cell targeting and a suppressive microenvironment. To enhance innate immune cell cytotoxicity, we have developed SM2235, a humanized tetravalent bispecific VHH antibody. SM2235 partially blocks EGFR and EGF interaction while conditionally activating innate immune cells through CD16A upon engagement with cancer cells. Methods: SM2235 was engineered by combining a partially blocking EGFR single-domain antibody with a high-affinity CD16A-activating single-domain antibody on an inactivated human IgG1 Fc backbone. The binding affinity and specificity were confirmed using bio-layer interferometry and ELISA with recombinant proteins, followed by flow cytometry with EGFR+ human cancer cell lines and CD16A+ primary NK cells. SM2235's efficacy in blocking EGFR-EGF interaction and downstream signaling was assessed through competitive ELISA and proliferation assays in both EGFR-dependent and independent cancer cell lines. Its ability to induce target-dependent NK cell and macrophage activation was evaluated through activation markers as well as cytotoxicity and phagocytosis assays. In vivo efficacy of SM2235 against EGFR+ human tumors was measured using xenograft assays in NSG mice, covering cetuximab-sensitive and resistant cancer cell lines. Preliminary pharmacokinetics and safety studies were conducted in cynomolgus monkeys. Results: SM2235 exhibits sub-nanomolar affinity for EGFR+ human cancer cell lines and CD16A+ primary human NK cells. It partially inhibits EGFR-dependent cancer cell proliferation. Compared to cetuximab, SM2235 significantly enhances target-dependent CD16A-mediated NK cell and macrophage activation and cytotoxicity against EGFR+ cancer cells in ADCC and ADCP assays in vitro. SM2235 effectively inhibits EGFR+ xenograft tumors in vivo, irrespective of KRAS mutation status. In cynomolgus monkeys, SM2235 demonstrates excellent tolerance with a 20-hour serum half-life of approximately 20 hours and no dose-dependent skin toxicity. Conclusions: Preclinical characterization of SM2235 shows promising in vivo efficacy against EGFR+ human cancers, regardless of KRAS mutation, with a favorable safety profile marked by minimal skin toxicity. Citation Format: Huiqin Geng, Wenjing Song, Xiaodan Liu, Shihao Lu, Hong Zhou, Simin Yang, Siyao Xie, Yi Wei, Xing Zhang, Sheila Zhou, Yanbin Liang. SM2235: A bispecific EGFR x CD16A innate immune cell engager for enhanced treatment of EGFR-expressing solid tumors, regardless of RAS mutation status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1341.

Targeted Hyperbranched Nanoparticles for Delivery of Doxorubicin in Breast Cancer Brain Metastasis.

Breast cancer brain metastases (BM) are associated with a dismal prognosis and very limited treatment options. Standard chemotherapy is challenging in BM patients because the high dosage required for an effective outcome causes unacceptable systemic toxicities, a consequence of poor brain penetration, and a short physiological half-life. Nanomedicines have the potential to circumvent off-target toxicities and factors limiting the efficacy of conventional chemotherapy. The HER3 receptor is commonly expressed in breast cancer BM. Here, we investigate the use of hyperbranched polymers (HBP) functionalized with a HER3 bispecific-antibody fragment for cancer cell-specific targeting and pH-responsive release of doxorubicin (DOX) to selectively deliver and treat BM. We demonstrated that DOX-release from the HBP carrier was controlled, gradual, and greater in endosomal acidic conditions (pH 5.5) relative to physiologic pH (pH 7.4). We showed that the HER3-targeted HBP with DOX payload was HER3-specific and induced cytotoxicity in BT474 breast cancer cells (IC50: 17.6 μg/mL). Therapeutic testing in a BM mouse model showed that HER3-targeted HBP with DOX payload impacted tumor proliferation, reduced tumor size, and prolonged overall survival. HER3-targeted HBP level detected in ex vivo brain samples was 14-fold more than untargeted-HBP. The HBP treatments were well tolerated, with less cardiac and oocyte toxicity compared to free DOX. Taken together, our HER3-targeted HBP nanomedicine has the potential to deliver chemotherapy to BM while reducing chemotherapy-associated toxicities.

In silico investigation of a novel anti-EGFR scFv-IL-24 fusion protein induces apoptosis in malignant cells.

Epidermal growth factor receptor (EGFR), a member of the HER receptor family, is over expressed in various cancer cells. Using tumor-specific antibodies to deliver cytotoxic agents directly to the tumor cells is an effective treatment strategy. Targeted therapy by fusing anti-EGFR scFv with tumor-specific cytokines promises the emergence of a new era. We designed a novel immuno-apoptotic fusion protein, anti-EGFR scFv-IL-24, consisting of a specific cancer cell targeting antibody and recombinant cytokine IL-24 to explore its anti-cancerous potential. Amino acid sequences of both anti-EGFR scFv and IL-24 were fused using a specific rigid linker. In silico characterization of the designed fusion protein like to predict the primary, secondary, physiochemical properties, quality, and structural validation using online bioinformatic tools. The newly designed fusion protein consists of 402 amino acids that showed good quality with a predicted value of 76.7% having 81.5% residues in the most favored region as predicted by ERRAT2 and Ramachandran plot analysis. Docking and simulation studies were performed using HDOCK and Desmond module of Schrodinger. All the parameters of quality, validity, interaction analysis, and stability suggested that the fused molecule is fully operational and functional. The results of the study support that the anti-EGFR scFv-IL-24 fused protein could be proved as a novel candidate to combat cancer.

Hyaluronic acid-modified metal–organic framework for two-photon imaging-guided photodynamic therapy in triple negative breast cancer

Zr-based metal–organic frameworks (MOFs) using thiazolothiazole as an organic ligand exhibit excellent two-photon excited fluorescence performance, particularly in the generation of reactive oxygen species. In this study, a ZrTc nanoMOF was designed and modified with hyaluronic acid (HA) to provide good biocompatibility and cancer cell-specific targeting. In triple negative breast cancer (TNBC), the optimized composite ZrTc@HA exhibited considerable two-photon activity and excellent light-triggered O2·− generation ability at an excitation wavelength of 780 nm. ZrTc@HA can be used as a diagnostic probe for fluorescence imaging and as a therapeutic agent for photodynamic therapy (PDT) with no remarkable toxicity in vitro or in a subcutaneous tumor model in vivo. In summary, we developed a promising two-photon-activated ZrTc@HA for PDT in TNBC, with immense potential for advancements in monotherapy and synergistic phototherapy.

A synthetic biology approach to engineering circuits in immune cells.

A synthetic circuit in a biological system involves the designed assembly of genetic elements, biomolecules, or cells to create a defined function. These circuits are central in synthetic biology, enabling the reprogramming of cellular behavior and the engineering of cells with customized responses. In cancer therapeutics, engineering T cells with circuits have the potential to overcome the challenges of current approaches, for example, by allowing specific recognition and killing of cancer cells. Recent advances also facilitate engineering integrated circuits for the controlled release of therapeutic molecules at specified locations, for example, in a solid tumor. In this review, we discuss recent strategies and applications of synthetic receptor circuits aimed at enhancing immune cell functions for cancer immunotherapy. We begin by introducing the concept of circuits in networks at the molecular and cellular scales and provide an analysis of the development and implementation of several synthetic circuits in T cells that have the goal to overcome current challenges in cancer immunotherapy. These include specific targeting of cancer cells, increased T-cell proliferation, and persistence in the tumor microenvironment. By harnessing the power of synthetic biology, and the characteristics of certain circuit architectures, it is now possible to engineer a new generation of immune cells that recognize cancer cells, while minimizing off-target toxicities. We specifically discuss T-cell circuits for antigen density sensing. These circuits allow targeting of solid tumors that share antigens with normal tissues. Additionally, we explore designs for synthetic circuits that could control T-cell differentiation or T-cell fate as well as the concept of synthetic multicellular circuits that leverage cellular communication and division of labor to achieve improved therapeutic efficacy. As our understanding of cell biology expands and novel tools for genome, protein, and cell engineering are developed, we anticipate further innovative approaches to emerge in the design and engineering of circuits in immune cells.

αvβ3 Receptor-targeted acid-responsive controlled-release endosome escape doxorubicin-loaded liposomes for A549/ADR treatment

The emergence of liposomes has provided a breakthrough for the clinical use of highly toxic chemotherapeutic drugs. However, the clinical effects of conventional drug-loaded liposomes are unsatisfactory due to the lack of specific targeting of cancer cells and the inability to achieve endosome escape and controllable release in vivo. In this paper, a cRGD-PEOz-Hz-DOB (cPzD) molecule with specific targeting, endosomal escape, and endogenous acid-sensitive controlled release ability was creatively designed and synthesized to prepare drug-loaded liposomes cPzDGX encapsulating the anticancer drug Doxorubicin (DOX) in order to enhance the anticancer performance of DOX. The study found that the hydrazone bond in cPzD reached a breakage rate of 42% within 48 h at pH 5.0, so the cumulative release rate of cPzDGX at pH 5.0 for 48 h was as high as 82.9%, which was 22.5% higher than that at pH 7.4. Moreover, the uptake of cPzDGX in A549/ADR cells was increased by 62% at 2 h, and the expression of the green fluorescent protein gene EGFP was also increased by 36% relative to the targeting control group, indicating that cRGD modification could effectively improve the targeting ability of liposomes to cancer cells. In addition, it was demonstrated that PEOz modification could help drug carriers achieve endosome escape because the green fluorescent protein expression in the PEOz-modified liposome group was 60.5% higher than that in the PEG-modified group. Finally, the cell viability of the cPzDGX group decreased by 17.2% relative to the free DOX group when the DOX concentration was 1 μg/mL in the cytotoxicity assay, and the diameter reduction of 3D tumor MCs increased by 34.4%. And cPzDGX could effectively enhance the permeability of free DOX to solid tumors. The above results indicate that the DOX-loaded liposomes cPzDGX we designed have great prospects for the accurate and efficient treatment of cancer.

Biosynthesis of a VLP-type nanocarrier specific to cancer cells using the BEVS expression system for targeted drug delivery

ObjectiveCanine parvovirus (CPV) is a small virus without an envelope that consists of three viral proteins including VP1, VP2, and VP3. Exclusively, the VP2 can form a typically CPV-sized virus-like particle (CPV-VLP) that can be used as a biological nanocarrier for diagnostic and therapeutic purposes since these VLPs can target cancer cells specially through the transferrin surface receptors (TFRs). Consequently, we aimed to produce these nanocarriers to be used for specific targeting of cancer cells. MethodsSf9 insect cells were transfected with constructed recombinant bacmid shuttle vector encoding an enhanced green fluorescent protein (EGFP) and CPV-VP2 by the cationic lipids of Cellfectin II. Subsequently, two recombinant baculoviruses expressing EGFP and VP2 were produced and expression of VP2 was increased under the optimal condition. In consequence, the CPV-VLP nanoparticles composed of recombinant VP2 subunits were extracted. The purity of VLPs was then evaluated by SDS-PAGE, and the structural integrity and quality of the final product were evaluated by TEM and HA methods. Eventually, the size distribution of the produced biological nanoparticles and their uniformity were determined by the DLS method. ResultsThe expression of EGFP protein was confirmed by fluorescent microscopy, and the expression of VP2 protein was evaluated by SDS-PAGE and western blotting. Infected Sf9 insect cells also showed cytopathic effects (CPEs), and the maximum expression of VP2 occurred at MOI of 10 (pfu/cell) at the harvest time of 72 h post-infection (hpi). After performing various stages of purification, buffer exchange, and concentration, the quality and structural integrity of the VLP product were confirmed. The results of the DLS technique showed the presence of uniform particles (PdI below 0.5) with an approximate size of 25 nm. ConclusionThe results indicate BEVS as an appropriate and efficient system for generating CPV-VLPs, and the used method based on two-stage ultracentrifugation was appropriate for purifying these nanoparticles. Produced nanoparticles can be used as the biologic nano-carriers in future studies.

LWJ-M30, a conjugate of DM1 and B6, for the targeted therapy of colorectal cancer with improved therapeutic effects.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide as well as a significant cause of mortality. The conventional treatment could cause serious side effects and induce drug resistance, recurrence and metastasis of cancers. Hence, specific targeting of cancer cells without affecting the normal tissues is currently an urgent necessity in cancer therapy. The emerging of peptide-drug conjugates (PDC) is regarded as a promising approach to address malignant tumors. LWJ-M30, a conjugate of DM1 and B6 peptide, targeted transferrin receptors (TfRs) on the surface of the CRC cells, showing a powerful anti-cancer effect. LWJ-M30 significantly inhibited the HCT116 cells proliferation and migration in vitro. LWJ-M30 also dramatically decreased the level of polymeric tubulin, while the disruption of microtubules caused the cell cycle to be arrested in the G2/M phase. LWJ-M30 induced the HCT116 cells apoptosis both in vivo and in vitro. The results in vivo demonstrated that LWJ-M30 could inhibit the HCT116 growth without affecting the mouse body weight. Taking these results together, our data indicated that LWJ-M30 could improve the therapeutic effects of DM1 while reducing the systemic toxicity in normal tissues.

Engineering Poly(ethylene glycol) Nanoparticles for Accelerated Blood Clearance Inhibition and Targeted Drug Delivery.

Surface modification with poly(ethylene glycol) (PEGylation) is an effective strategy to improve the colloidal stability of nanoparticles (NPs) and is often used to minimize cellular uptake and clearance of NPs by the immune system. However, PEGylation can also trigger the accelerated blood clearance (ABC) phenomenon, which is known to reduce the circulation time of PEGylated NPs. Herein, we report the engineering of stealth PEG NPs that can avoid the ABC phenomenon and, when modified with hyaluronic acid (HA), show specific cancer cell targeting and drug delivery. PEG NPs cross-linked with disulfide bonds are prepared by using zeolitic imidazolate framework-8 NPs as templates. The reported templating strategy enables the simultaneous removal of the template and formation of PEG NPs under mild conditions (pH 5.5 buffer). Compared to PEGylated liposomes, PEG NPs avoid the secretion of anti-PEG antibodies and the presence of anti-PEG IgM and IgG did not significantly accelerate the blood clearance of PEG NPs, indicating the inhibition of the ABC effect for the PEG NPs. Functionalization of the PEG NPs with HA affords PEG NPs that retain their stealth properties against macrophages, target CD44-expressed cancer cells and, when loaded with the anticancer drug doxorubicin, effectively inhibit tumor growth. The innovation of this study lies in the engineering of PEG NPs that can circumvent the ABC phenomenon and that can be functionalized for the improved and targeted delivery of drugs.

Improvement of specific aiming of X-ray radiotherapy on HER2-overexpressing cancerous cell lines by targeted delivery of silver nanoparticle

Human epidermal growth factor receptor 2 (HER2) as a member of epidermal growth factor receptor (EGFR) family is expressed in various kinds of malignant cells at a level higher than normal cells. Therefore, HER2 could be consider as a target for specific chemotherapy and selective ablation of cancerous cells. ZHER2 affibody as an engineered peptide with great affinity for HER2 receptor could be employed for specific targeting of cancer cells with high HER2 expression level. On the other hand, X-ray radiotherapy is one of the most prevalent approaches in cancer therapy and nanoparticles with high atomic number could enhance its efficiency. As an outcome, targeted delivery of these nanoparticles can increase intensity and focus of X-ray radiation on cancerous cells. In the current in vitro study, silver nanoparticles (AgNPs) in conjugations with ZHER2 affibody were investigated for enhancement of X-ray radiation therapy of HER2-positive cancerous cells originated from various kinds of malignancies. Cell lines with high expression of HER2 (SK-BR-3, HN-5, SK-OV-3) and also MCF-7 cell line with normal expression of HER2 were irradiated with X-ray in the presence of various concentrations of AgNPs or AgNP-ZHER2 conjugates. Morphology and size of prepared AgNPs and AgNP-ZHER2 were examined by atomic force microscopy (AFM) and dynamic light scattering (DLS). Success of conjugation was confirmed by UV–Vis spectroscopy and viability of treated cells was assessed by MTT assay. Our results showed that while sensitivity of four examined cell lines to AgNPs, AgNP-ZHER2, and X-ray radiation is different, but presence of AgNP-ZHER2 conjugate could significantly enhance efficiency of X-ray radiation in ablation of HER2-overexpressed cells at in vitro conditions.

Construction of Red Fluorescent Dual Targeting Mechanically Interlocked Molecules for Live Cancer Cell Specific Lysosomal Staining and Multicolor Cellular Imaging.

We have designed and synthesized red fluorescent mechanically interlocked molecules with dual targeting functionality for live cancer cell specific active targeting followed by selective internalization and imaging of malignant lysosomes along with real-time tracking, 3D, and multicolor cellular imaging applications.

Two-photon responsive porphyrinic metal-organic framework involving Fenton-like reaction for enhanced photodynamic and sonodynamic therapy.

Designing new oxygenation nanomaterials by oxygen-generating or oxygen-carrying strategies in hypoxia-associated anti-tumor therapy is a high priority target yet challenge. In this work, we fabricated a nanoplatform involving Fenton-like reaction, Pd@MOF-525@HA, to relieve tumor hypoxia via oxygen-generating strategy for enhanced oxygen-dependent anti-tumor therapy. Thereinto, the porphyrinic MOF-525 can produce singlet oxygen (1O2) via light or ultrasonic irradiation for photodynamic and sonodynamic therapy. Notably, the well-dispersed Pd nanocubes within MOF-525 can convert H2O2 into O2 to mitigate the hypoxic environment for enhanced therapy outcome. Moreover, the two-photon activity and cancer cell specific targeting capability of Pd@MOF-525@HA gave rise to deeper tissue penetration and near-infrared light-induced fluorescence imaging to achieve precise guidance for cancer therapy. This work provides a feasible way in designing new oxygenation nanomaterials to relieve tumor hypoxia for enhanced cancer treatment.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s12951-022-01436-3.

Synthetic introns enable highly specific targeting of cancer cells.

Synthetic introns enable highly specific targeting of cancer cells.

Anticancer effect of selenium/chitosan/polyethylene glycol/allyl isothiocyanate nanocomposites against diethylnitrosamine-induced liver cancer in rats

BackgroundNano-based drug delivery systems have shown several advantages in cancer treatment like specific targeting of cancer cells, good pharmacokinetics, and lesser adverse effects. Liver cancer is a fifth most common cancer and third leading cause of cancer-related mortalities worldwide. ObjectiveThe present study focusses to formulate the selenium (S)/chitosan (C)/polyethylene glycol (Pg)/allyl isothiocyanate (AI) nanocomposites (SCPg-AI-NCs) and assess its therapeutic properties against the diethylnitrosamine (DEN)-induced liver cancer in rats via inhibition of oxidative stress and tumor markers. MethodologyThe SCPg-AI-NCs were synthesized by ionic gelation technique and characterized by various characterization techniques. The liver cancer was induced to the rats by injecting a DEN (200 mg/kg) on the 8th day of experiment. Then DEN-induced rats treated with 10 mg/kg of formulated SCPg-AI-NCs an hour before DEN administration for 16 weeks. The 8-hydroxy-2′ -deoxyguanosine (8-OHdG) content, albumin, globulin, and total protein were examined by standard methods. The level of glutathione (GSH), vitamin-C & -E, and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) activities were examined using assay kits. The liver marker enzymes i.e., alanine transaminase (ALT), aspartate tansaminase (AST), γ-glutamyl transaminase (GGT), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) activities, alpha fetoprotein (AFP) and carcinoembryonic antigen (CEA), Bax, and Bcl-2 levels, and caspase-3&9 activities was examined using assay kits and the liver histopathology was assessed microscopically by hematoxylin and eosin staining method. The effect of formulated SCPg-AI-NCs on the viability and apoptotic cell death on the HepG2 cells were examined using MTT and dual staining assays, respectively. ResultsThe results of different characterization studies demonstrated the formation of SCPg-AI-NCs with tetragonal shape, narrowed distribution, and size ranging from 390 to 450 nm. The formulated SCPg-AI-NCs treated liver cancer rats indicated the reduced levels of 8-OHdG, albumin, globulin, and total protein. The SCPg-AI-NCs treatment appreciably improved the GSH, vitamin-C & -E contents, and SOD, CAT, GPx, and GR activities in the serum of liver cancer rats. The SCPg-AI-NCs treatment remarkably reduced the liver marker enzyme activities in the DEN-induced rats. The SCPg-AI-NCs treatment decreased the AFP and CEA contents and enhanced the Bax and caspase 3&9 activities in the DEN-induced rats. The SCPg-AI-NCs effectively decreased the cell viability and induced apoptosis in the HepG2 cells. ConclusionThe present findings suggested that the formulated SCPg-AI-NCs remarkably inhibited the DEN-induced liver carcinogenesis in rats. These findings provide an evidence that SCPg-AI-NCs can be a promising anticancer nano-drug in the future to treat the liver carcinogenesis.

Versatility of berberine as an effective immunomodulator and chemo sensitizer against p53 mutant cell

Cancer is the leading cause of death among individuals due to its poor prognosis. Various therapeutics treatments are available in form radiation therapy, chemotherapy, or immunotherapy but major point of concern is the treatment of cancer resistant cell lines. Homozygous loss of the p53 gene is virtually present in every type of cancer. Mutation in DNA binding domain of p53 leads to formation of mutant forms having altered amino acid sequence which lacks DNA binding activity. Berberine is chemo-sensitizing isoquinoline quaternary alkaloid molecule obtained from Berberis vulgaris. Berberine has the capability to suppress the growth of broad range of tumors. It exhibits pharmacological, biochemical and anticancer properties which can potentiate the activities of the existing therapeutics available in a way that it can re-sensitize the cancer resistant clones. Berberine has an immanent potential to bind with DNA and can communicate with several cellular targets, further it also shows hormetic effect which refers to biphasic dose response curve in order to determine dose dependent stimulatory and inhibitory effect. Mode of action involved is yet not well understood but mechanistic pathway involved are autophagy, up-regulation of tumor-suppressor gene (p53) and epigenetic alterations in the viral DNA. In this review, versatility of berberine can be utilized ideally or in combination with chemotherapeutics drugs to potentiate chemo sensitization of the resistant cancer cell line. Further, cancer cell specific receptor targeting can also be employed in combination with berberine for therapeutic treatment of metastasizing cancer cells.

Current Photoactive Molecules for Targeted Therapy of Triple-Negative Breast Cancer.

Cancer is the second leading cause of death worldwide; therefore, there is an urgent need to find safe and effective therapies. Triple-negative breast cancer (TNBC) is diagnosed in ca. 15–20% of BC and is extremely aggressive resulting in reduced survival rate, which is mainly due to the low therapeutic efficacy of available treatments. Photodynamic therapy (PDT) is an interesting therapeutic approach in the treatment of cancer; the photosensitizers with good absorption in the therapeutic window, combined with their specific targeting of cancer cells, have received particular interest. This review aims to revisit the latest developments on chlorin-based photoactive molecules for targeted therapy in TNBC. Photodynamic therapy, alone or combined with other therapies (such as chemotherapy or photothermal therapy), has potential to be a safe and a promising approach against TNBC.