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The drug camptothecin has a wide range of antitumor effects in cancers including gastric cancer, rectal and colon cancer, liver cancer, and lung cancer. Camptothecin-based drugs inhibit topoisomerase 1 (Topo 1), leading to destruction of DNA, and are currently being used as important chemotherapeutic agents in clinical antitumor treatment. However,...
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... Due to its poor water solubility and bioavailability, combined with high levels of toxicity, camptothecin cannot be administered clinically and is a prime candidate for drug repositioning, 23 particularly via covalent caging strategies that render camptothecin inactive. 19,[24][25][26] Therefore, Camptothecin was previously incorporated within various drug delivery systems, 27 including polymer-drug conjugates MAG-CPT (N-(hydroxypropyl) methacrylamide), 28 CT-2106 ( poly-L-glutamate), 29 Pegamotecan ( polyethylene glycol), 30 XMT-1001 ( poly(1-hydroxymethylethylene hydroxymethylformal)) 31 and CRLX101 (cyclodextrin-based polymer) 32 that were all used in clinical trials. Whilst these systems focused on enhanced biodistribution and sustained release, we hereby introduced an external light stimulus to trigger release, and selected for this purpose the coumarin-4-ylmethyl photocleavable unit that has been widely used for uncaging of bioactive substances, including in polymers and nanosystems. ...
A light-responsive polymer allowing the controlled release of camptothecin and the generation of reactive oxygen species (ROS) is reported. The polymer was prepared by controlled copolymerisation of water-soluble N,N-dimethyl acrylamide with a bromocoumarin methacrylate monomer. The lipophilic chemotherapy agent camptothecin was caged onto the coumarin unit via a photo-cleavable carbonate ester enabling light-triggered cargo release. The polymer showed good biocompatibility in the dark, and high cancer cell killing activity mediated both by the photo-release of camptothecin and ROS generation.
... The activity of the purified A. terreus CPT was assessed against MCF-7 and HepG-2, with IC 50 values 0.27, and 0.8 μM, respectively, comparing to the authentic CPT. The higher activity of purified A. terreus CPT against MCF-7, revealing the specific structural activity relationships of CPT to bind with the topoisomerase I, in addition to targeting another metabolic process and/or structural organelles [73,74]. ...
Fungal producing potency of camptothecin (CPT) raise the hope for their usage to be a platform for industrial production of CPT, nevertheless, attenuation of their productivity of CPT with the subculturing and preservation is the challenge. So, screening for novel endophytic fungal isolates with a reliable CPT-biosynthetic stability was the objective. Among the isolated endophytic fungi from the tested medicinal plants, Aspergillus terreus OQ642314.1, endophyte of Cinnamomum camphora, exhibits the highest yield of CPT (89.4 μg/l). From the NMR, FT-IR and LC-MS/MS analyses, the extracted CPT from A. terreus gave the same structure and molecular mass fragmentation pattern of authentic CPT (349 m/z). The putative CPT had a significant activity against MCF7 (0.27 µM) and HEPG-2 (0.8 µM), with a strong affinity to inhibits the human Topoisomerase 1 activity (IC50 0.362 μg/ml) as revealed from the Gel-based DNA relaxation assay. The purified CPT displayed a strong antimicrobial activity for various bacterial (E. coli and B. cereus) and fungal (A. flavus and A. parasiticus) isolates, ensuring the unique tertiary, and stereo-structure of A. terreus for penetrating the microbial cell walls and targeting the topoisomerase I. The higher dual activity of the purified CPT as antimicrobial and antitumor, emphasize their therapeutic efficiency, especially with growth of the opportunistic microorganisms due to the suppression of human immune system with the CPT uses in vivo. The putative CPT had an obvious activity against the tumor cell (MCF7) metastasis, and migration as revealed from the wound healing assay. The overall yield of A. terreus CPT was maximized with the Blackett-Burman design by twofolds increment (164.8 μg/l). The CPT yield by A. terreus was successively diminished with the multiple fungal subculturing, otherwise, the CPT productivity of A. terreus was restored, and increased over the zero culture upon coculturing with C. camphora microbiome (1.5% w/v), ensuring the restoring of CPT biosynthetic potency of A. terreus by the plant microbiome-derived chemical signals "microbial communication". This is the first report exploring the feasibility of A. terreus "endophyte of C. camphora" to be a preliminary platform for commercial production of CPT with a reliable sustainability upon uses of indigenous C. camphora microbiome.
... Among the most common cancers, breast cancer occupies a frontline position. [61] The most common anticancer drugs employed as cargo in drug-transport vehicles are cisplatin, [62] carboplatin, [63] doxorubicin, [64] 5fluorouracil, [65] camptothecin [66] and paclitaxel. [67] Even though many anticancer drugs exist for the treatment of tumors and metastatic cancer, many of them suffer from dose limits due to toxicity. ...
... Its mode of action is to inhibit the enzyme deoxyribonucleic acid topoisomerase 1 involved in the cell cycle's S-phase and induce apoptosis (Morris and Geller 1996). Some reports suggest that CPT has some disadvantages such as poor solubility, chemical instability, and rapid metabolism, which leads to poor bioavailability (Venditto and Simanek 2010;Wen et al. 2017). There are also some other problems in delivering drugs to cancer cells such as rapid clearance and off-target delivery (Kraft et al. 2014). ...
Receptor-mediated drug delivery systems are a promising tool for targeting malignant cells to suppress/inhibit the malignancy without disturbing healthy cells. Protein-based nanocarrier systems possess numerous advantages for the delivery of variety of chemotherapeutics, including therapeutic peptides and genes. In the present work, glucose-conjugated camptothecin-loaded glutenin nanoparticles (Glu-CPT-glutenin NPs) were fabricated to deliver camptothecin to MCF-7 cells via GLUT-1 transporter protein. Initially, Glu-conjugated glutenin polymer was successfully synthesized through reductive amination reaction, and this was confirmed by FTIR and ¹³C-NMR. Then, camptothecin (CPT) was loaded into Glu-conjugated glutenin polymer forming Glu-CPT-glutenin NPs. The nanoparticles were studied for their drug releasing capacity, morphological shape, size, physical nature, and zeta potential. The fabricated Glu-CPT-glutenin NPs were found to be spherical in shape and amorphous in nature with 200-nm size range and a zeta potential of − 30 mV. Furthermore, MTT assay using Glu-CPT-glutenin NPs confirmed concentration-dependent cytotoxicity against MCF-7 cells after 24-h treatment, and IC50 was found to be 18.23 μg mL⁻¹. In vitro cellular uptake study demonstrated that the Glu-CPT-glutenin NPs had enhanced endocytosis and delivered CPT in MCF-7 cells. A typical apoptotic morphological change of condensed nuclei and distorted membrane bodies was found after treatment with IC50 concentration of NPs. The released CPT from NPs also targeted mitochondria of MCF-7 cells, significantly increasing the level of reactive oxygen species and causing the damage of mitochondrial membrane integrity. These outcomes confirmed that the wheat glutenin can positively serve as a significant delivery vehicle and enhance the anticancer potential of this drug.
Graphical Abstract
... CPT is an anticancer small molecule drug that inhibits the topoisomerase I enzyme, which has a critical role in cellular DNA functions [14], and is effective in a wide spectrum of cancers such as metastatic colon cancer, breast cancer, and small cell lung cancer. It still has not been used clinically for CRC treatment due to its physiological instability and clinical inefficacy due to its physicochemical structure and hydrolytic degradation potential [9,13,15]. While the active lactone form of CPT is present at acidic pH, it is hydrolyzed to the ineffective carboxylate form at basic pH, resulting in decreased clinical efficacy and increased drug-related toxicity. ...
Colorectal cancer (CRC) is the third most diagnosed cancer type globally and ranks second in cancer-related deaths. With the current treatment possibilities, a definitive, safe, and effective treatment approach for CRC has not been presented yet. However, new drug delivery systems show promise in this field. Amphiphilic cyclodextrin-based nanocarriers are innovative and interesting formulation approaches for targeting the colon through oral administration. In our previous studies, oral chemotherapy for colon tumors was aimed and promising results were obtained with formulation development studies, mucin interaction, mucus penetration, cytotoxicity, and permeability in 2D cell culture, and furthermore in vivo antitumoral and antimetastatic efficacy in early and late-stage colon cancer models and biodistribution after single dose oral administration. This study was carried out to further elucidate oral camptothecin (CPT)-loaded amphiphilic cyclodextrin nanoparticles for the local treatment of colorectal tumors in terms of their drug release behavior and efficacy in 3-dimensional tumor models to predict the in vivo efficacy of different nanocarriers. The main objective was to build a bridge between formulation development and in vitro phase and animal studies. In this context, CPT-loaded polycationic-β-cyclodextrin nanoparticles caused reduced cell viability in CT26 and HT29 colon carcinoma spheroid tumors of mice and human origin, respectively. In addition, the release profile, which is one of the critical quality parameters in new drug delivery systems, was investigated mathematically by release kinetic modeling for the first time. The overall findings indicated that the strategy of orally targeting anticancer drugs such as CPT with positively charged poly-β-CD-C6 nanoparticles to colon tumors for local and/or systemic efficacy is a promising approach.
... The primary benefits of polyester DDSs produced through drug encapsulation or adsorption are usually increased water solubility, biocompatibility, extended drug tolerance time, precise delivery and accumulation at the site of action, and reduced toxic side-effects on unimpaired cells [80]. Unfortunately, one of the major issues with polymeric DDSs characterized by controlled drug release, particularly micro and NPs, is the initial burst [81]. ...
Camptothecin (CPT) has demonstrated antitumor activity in lung, ovarian, breast, pancreas, and stomach cancers. However, this drug, like many other potent anticancer agents, is extremely water-insoluble. Furthermore, pharmacology studies have revealed that prolonged schedules must be administered continuously. For these reasons, several of its water-soluble analogues, prodrugs, and macromolecular conjugates have been synthesized, and various formulation approaches have been investigated. Biodegradable polyesters have gained popularity in cancer treatment in recent years. A number of biodegradable polymeric drug delivery systems (DDSs), designed for localized and systemic administration of therapeutic agents, as well as tumor-targeting macromolecules, have entered clinical trials, demonstrating the importance of biodegradable polyesters in cancer therapy. Biodegradable polyester-based DDSs have the potential to deliver the payload to the target while also increasing drug availability at intended site. The systemic toxicity and serious side-effects associated with conventional cancer therapies can be significantly reduced with targeted polymeric systems. This review elaborates on the use of biodegradable polyesters in the delivery of CPT and its analogues. The design of various DDSs based on biodegradable polyesters has been described, with the drug either adsorbed on the polymer’s surface or encapsulated within its macrostructure, as well as those in which a hydrolyzed chemical bond is formed between the active substance and the polymer chain. The data related to the type of DDSs, the kind of linkage, and the details of in vitro and in vivo studies are included.
... Despite the above-mentioned advantages, the reported hydrogels still have much room for improvement in controlled release of cargo. Tailored mesoporous inorganic biomaterials have been widely utilized for cargo delivery engineering in the field of biomedicine applications [22][23][24][25][26][27][28] because of their unique features, including nanoscale size, high specific surface area, controllable mesoscopic structure and physicochemical properties [29,30]. Moreover, multiple biocompatible and degradable nanoparticles (e.g., bioactive glass nanoparticles [31], mesoporous silica microrods [32], hydroxyapatite nanovehicles [33]) have been demonstrated to be effective for bone-related tissue regeneration by virtue of providing functional mineral components of tissue and precisely regulating sustained drug delivery [34][35][36]. ...
The regeneration of articular cartilage remains a great challenge due to the difficulty in effectively enhancing spontaneous healing. Recently, the combination of implanted stem cells, suitable biomaterials and bioactive molecules has attracted attention for tissue regeneration. In this study, a novel injectable nanocomposite was rationally designed as a sustained release platform for enhanced cartilage regeneration through integration of a chitosan-based hydrogel, articular cartilage stem cells (ACSCs) and mesoporous SiO2 nanoparticles loaded with anhydroicaritin (AHI). The biocompatible engineered nanocomposite acting as a novel 3D biomimetic extracellular matrix exhibited a remarkable sustained release effect due to the synergistic regulation of the organic hydrogel framework and mesopore channels of inorganic mSiO2 nanoparticles (mSiO2 NPs). Histological assessment and biomechanical tests showed that the nanocomposites exhibited superior performance in inducing ACSCs proliferation and differentiation in vitro and promoting extracellular matrix (ECM) production and cartilage regeneration in vivo. Such a novel multifunctional biocompatible platform was demonstrated to significantly enhance cartilage regeneration based on the sustained release of AHI, an efficient bioactive natural small molecule for ACSCs chondrogenesis, within the hybrid matrix of hydrogel and mSiO2 NPs. Hence, the injectable nanocomposite holds great promise for use as a 3D biomimetic extracellular matrix for tissue regeneration in clinical diagnostics.
... Camptothecin (CPT), a monoterpene indole alkaloid (MIA), was initially isolated and identified from Camptotheca acuminata. Later investigation showed that CPT and its derivatives could inhibit DNA topoisomerase I activity, which led to it being used as a promising anti-tumor drug for treating cancer diseases in clinical therapy [1][2][3]. However, similarly to other valuable specialized metabolites in plants, low accumulation of CPT in C. acuminata limits its supply in the market [4]. ...
Camptothecin (CPT) and its derivatives from Camptotheca acuminata have antitumor effects as a DNA topoisomerase I inhibitor. Previous studies have shown that application of exogenous abscisic acid (ABA) significantly promoted the accumulation level of CPT and induced the expression of CPT biosynthetic genes, which revealed that ABA signaling is effectively involved in regulating CPT biosynthesis in C. acuminata. In this study, an ABA transporter, CaABAT, which encodes a plasma membrane protein belonging to the ABCG subfamily, was identified in C. acuminata, and its ABA import activity was confirmed by transport assay in yeast cells. Real-time PCR analysis showed that CaABAT was predominately expressed in C. acuminata leaves and its expression could be significantly upregulated by exogenous ABA treatment. Silencing of CaABAT down-regulated the expression of ABA response genes, which indicated that translocation of ABA by CaABAT should initiate changes in plant physiological status in response to ABA signaling, thus leading to decreased expression of CPT biosynthesis pathway genes and low accumulation levels of CPT in C. acuminata.
... higher than A. flavus camptothecin against HEPG-2 (IC50, 0.9 mM), MCF7 (IC50, 1.2 µM), and HCT29 (IC50, 1.35 µM) [22]. Consistently, the IC50 values of P. chrysogenum camptothecin were similar to A. terreus camptothecin towards MCF7 (0.18 mM), LS174 T (0.29 µM), HCT29 (0.43 µM) and HEPG-2 (0.73 µM) [75][76][77]. ...
Citation: El-Sayed, A.S.A.; Hassan, W.H.B.; Sweilam, S.H.; Alqarni, M.H.S.; El Sayed, Z.I.; Abdel-Aal, M.M.; Abdelsalam, E.; Abdelaziz, S.
... higher than A. flavus camptothecin against HEPG-2 (IC50, 0.9 mM), MCF7 (IC50, 1.2 µM), and HCT29 (IC50, 1.35 µM) [22]. Consistently, the IC50 values of P. chrysogenum camptothecin were similar to A. terreus camptothecin towards MCF7 (0.18 mM), LS174 T (0.29 µM), HCT29 (0.43 µM) and HEPG-2 (0.73 µM) [75][76][77]. ...
Exploring the metabolic potency of fungi as camptothecin producers raises the hope of their usage as an industrial source of camptothecin, due to their short-life span and the feasibility of metabolic engineering. However, the tiny yield and loss of camptothecin productivity of fungi during storage and sub-culturing are challenges that counteract this approach. Marine fungi could be a novel source for camptothecin production, with higher yield and reliable metabolic sustainability. The marine fungal isolate Penicillium chrysogenum EFBL # OL597937.1 derived from the sponge “Cliona sp.” has been morphologically identified and molecularly confirmed, based on the Internal Transcribed Spacer sequence, exhibiting the highest yield of camptothecin (110 μg/L). The molecular structure and chemical identity of P. chrysogenum derived camptothecin has been resolved by HPLC, FTIR and LC-MS/MS analyses, giving the same spectroscopic profiles and mass fragmentation patterns as authentic camptothecin. The extracted camptothecin displayed a strong anti-proliferative activity towards HEP-2 and HCT-116 (IC50 values 0.33–0.35 µM). The yield of camptothecin was maximized by nutritional optimization of P. chrysogenum with a Plackett-Burman design, and the productivity of camptothecin increased by 1.8 fold (200 µg/L), compared to control fungal cultures. Upon storage at 4 °C as slope culture for 8 months, the productivity of camptothecin for P. chrysogenum was reduced by 40% compared to the initial culture. Visual fading of the mycelial pigmentation of P. chrysogenum was observed during fungal storage, matched with loss of camptothecin productivity. Methylene chloride extracts of Cliona sp. had the potency to completely restore the camptothecin productivity of P. chrysogenum, ensuring the partial dependence of the expression of the camptothecin biosynthetic machinery of P. chrysogenum on the chemical signals derived from the sponge, or the associated microbial flora. This is the first report describing the feasibility of P. chrysogenum, endozoic of Cliona sp., for camptothecin production, along with reliable metabolic biosynthetic stability, which could be a new platform for scaling-up camptothecin production.
