Antineoplastic Drug Delivery Research Articles

Co-Encapsulation of Paclitaxel and Doxorubicin in Liposomes Layer by Layer

The synergistic effect of antineoplastic drug co-encapsulation systems has made them highly regarded due to their improved pharmacological efficacy. Biopolymer-coated liposomes were evaluated for paclitaxel and doxorubicin co-encapsulation in MCF-7 and MDA-MB-231 breast cancer cell lines. These nanosystems are characterized by dynamic light scattering, transmission electron microscopy, and UV–VIS spectroscopy. The conventional and hybrid liposomal systems presented sizes of 150 to 230 nm and %EE greater than 80% for the encapsulated active ingredients. These drug-laden liposomal systems significantly decreased cell viability in both breast cancer cell lines compared with liposome-free drugs. The delivery of antineoplastic drugs in breast cancer therapy could potentially benefit from new hybrids for drug co-encapsulation.

HER2 siRNA Facilitated Gene Silencing Coupled with Doxorubicin Delivery: A Dual Responsive Nanoplatform Abrogates Breast Cancer.

The present study investigated the concurrent delivery of antineoplastic drug, doxorubicin, and HER2 siRNA through a targeted theranostic metallic gold nanoparticle designed using polysaccharide, PSP001. The as-synthesized HsiRNA@PGD NPs were characterized in terms of structural, functional, physicochemical, and biological properties. HsiRNA@PGD NPs exposed adequate hydrodynamic size, considerable ζ potential, and excellent drug/siRNA loading and encapsulation efficiency. Meticulous exploration of the biocompatible dual-targeted nanoconjugate exhibited an appealing biocompatibility and pH-sensitive cargo release kinetics, indicating its safety for use in clinics. HsiRNA@PGD NPs deciphered competent cancer cell internalization, enhanced cytotoxicity mediated via the induction of apoptosis, and excellent downregulation of the overexpressing target HER2 gene. Further in vivo explorations in the SKBR3 xenograft breast tumor model revealed the appealing tumor reduction properties, selective accumulation in the tumor site followed by significant suppression of the HER2 gene which contributed to the exclusive abrogation of breast tumor mass by the HsiRNA@PGD NPs. Compared to free drugs or the monotherapy constructs, the dual delivery approach produced a synergistic suppression of breast tumors both in vitro and in vivo. Hence the drawings from these findings implicate that the as-synthesized HsiRNA@PGD NPs could offer a promising platform for chemo-RNAi combinational breast cancer therapy.

Natural Polymers as a Carrier for the Effective Delivery of Antineoplastic Drugs.

Cancer is a broad term for a set of disorders marked by the development of physically and functionally changed cells that proliferate uncontrollably, infect neighboring tissues, and result in malignant tumours, 'neoplasm'. Cancer remains a difficult disease to treat because of the significant adverse effects and poor pharmacokinetic profile of antineoplastic drugs, despite advancements in our understanding of the features and behavior of tumor cells in recent decades. In this series, the role of natural polymers is prominent as a component of a novel delivery system of anticancer drugs. These natural polymeric drug delivery systems (NPDDS) have many advantages over synthetic polymers like controlled delivery, biodegradability, inexpensive, low toxicity profile, and easily obtainable. These polymers further modify for the targeting of tumour cells. This review discusses and critically analyses the different natural polymers, such as chitosan, cellulose, starch, albumin, dextran, fucoidan, gelatin, etc., in terms of natural ingredient-based polymeric nanocarriers specifically for cancer therapy. It also describes benefits, drawbacks, and opinions and provides insights about the efficacy of NPDDS as well as its future perspectives and tabulated recent patents and cases under clinical trials exploited for cancer treatment.

A biomimetic nanoreactor for combinational chemo/chemodynamic therapy of choriocarcinoma through synergistic apoptosis and ferroptosis strategy

Choriocarcinoma is a malignant tumor caused by aberrant proliferation and excessive invasion of trophoblastic cells in the uterus. Treatment for choriocarcinoma is hampered by severe side effects and drug resistance caused by insufficient delivery of chemotherapeutics. This dilemma can be solved by a novel approach of nanoparticle-based antineoplastic drug delivery through homologous targeting. Therefore, we developed a cancer cell membrane-coated biomimetic nanoreactor (MMC) built on a ferric metal–organic framework (MIL-100) encapsulating methotrexate (MTX) to achieve maximum therapeutic effects with negligible side effects. MMC could specifically target tumor cells and accumulate within tumor sites. MMC showed significant anticancer effects on JEG-3 cells, including inhibiting cell proliferation by cell cycle arrest at G0/G1 stage, and reducing endocrine function and migration ability. Furthermore, OH overproduction by the Fenton reaction caused apoptosis and remarkable chemodynamic therapy (CDT) effects, glutathione scavenging led to intracellular redox dyshomeostasis and lipid peroxidation resulted in ferroptosis. In vivo studies demonstrated satisfactory tumor inhibition effects on tumor-bearing mice without appreciable toxicity. Further transcriptomics analysis revealed that MMC influences multiple pathways in cancer and cell death, including apoptosis and ferroptosis. This elaborately synthesized biomimetic nanoreactor offers a multifunctional reference for cancer therapy by presenting a new strategy for combining chemotherapy with CDT through synergistic apoptosis and ferroptosis.

Increased delivery and cytotoxicity of doxorubicin in HeLa cells using the synthetic cationic peptide pEM-2 functionalized liposomes

HypothesisDue to the inability of nano-carriers to passively cross the cell membrane, cell penetration enhancers are used to accelerate cytoplasmic delivery of antineoplastic drugs. In this regard, snake venom phospholipase A2 peptides are known for their ability to destabilize natural and artificial membranes. In this context, functionalized liposomes with peptide pEM-2 should favor the incorporation of doxorubicin and increase its cytotoxicity in HeLa cells compared to free doxorubicin, and doxorubicin encapsulated in non-functionalized liposomes. ExperimentsSeveral characteristics were monitored, including doxorubicin loading capacity of the liposomes, as well as the release and uptake before and after functionalization. Cell viability and half-maximal inhibition concentrations were determined in HeLa cells. FindingsIn vitro studies showed that functionalization of doxorubicin-loaded PC-NG liposomes with pEM-2 not only improved the amount of doxorubicin delivered compared to free doxorubicin or other doxorubicin-containing formulations, but also showed enhanced cytotoxicity against HeLa cells. The PC-NG liposomes loaded with doxorubicin improved treatment efficacy by reducing the IC50 value and incubation time. This increase in cell toxicity was directly related to the concentration of pEM-2 peptide bound to the liposomes. We conclude that the cytotoxicity observed in HeLa cells due to the action of doxorubicin was strongly favored when encapsulated in synthetic liposomes and functionalized with the pEM-2 peptide.

Microneedles: structure, classification, and application in oral cancer theranostics.

Oral cancer is a malignant tumor that threatens the health of individuals on a global scale. Currently available clinical treatment methods, including surgery, radiotherapy, and chemotherapy, significantly impact the quality of life of patients with systemic side effects. In the treatment of oral cancer, local and efficient delivery of antineoplastic drugs or other substances (like photosensitizers) to improve the therapy effect is a potential way to optimize oral cancer treatments. As an emerging drug delivery system in recent years, microneedles (MNs) can be used for local drug delivery, offering the advantages of high efficiency, convenience, and noninvasiveness. This review briefly introduces the structures and characteristics of various types of MNs and summarizes MN preparation methods. An overview of the current research application of MNs in different cancer treatments is provided. Overall, MNs, as a means of transporting substances, demonstrate great potential in oral cancer treatments, and their promising future applications and perspectives of MNs are outlined in this review.

Hypoxic-Sensitive Nano-Carriers for Anti-Neoplastic Drug Delivery: New Perspectives

Since the inception of Anti-neoplastic drug delivery in the 1950s oncologists and researchers have revolutionized the field of diagnostics and treatment with novel therapeutic modalities. Tumor hypoxia remains the first and foremost factor contributing to a resistance in anti-neoplastic drugs, ionized radiation and chemotherapy by solid tumors. The laps in vasculature in solid tumors promulgates tumor resistance by inhibiting the hypoxia inducible factor (HIF) within the tumor. It is on this basis that the selectivity of hypoxic cells are datelined. Based on clinical studies it was revealed that hypoxia does not occur in healthy human tissue; thus, paving the way for the exploitation of hypoxia as an advantage in creating novel therapeutic methods of detection and treatment for solid tumors with an added advantage of nano-science. The biological application of nano-carriers is a fast developing area of nano-science that is expected to realize new and innovative possibilities in the diagnosis and treatment of human cancers. Cancer diagnostics using nano-carriers entails the use of fluorescent nanoparticles for a multiplex of simultaneous profiling of tumor bio-markers. These fluorescent probes are also used for detection of multiple RNA matrices and genes within in-situ hybridization. It is expected that in the very near future, the application of conjugated nanoparticles in anti-neoplastic tumor detection and drug delivery will enable oncologists and scientists to pinpoint and identify cancer-related proteins on tumor surfaces, providing a new method of analysis; thus, creating personalized treatment methods for individual tumors. Nano-carriers possess an extraordinary possibility as contrast agents for cancer cell detection in vivo, and for monitoring the response to treatment of select cancers. Keywords: Nano-Medicine, Hypoxia, Solid Tumors, HIF factor. DOI: 10.7176/JHMN/102-04 Publication date: October 31 st 2022

Formulation of Self-micro Emulsifying Drug Delivery Systems (SMEDDS) of Paclitaxel utilizing factorial design

Background: The antineoplastic drugs possess poor aqueous solubility along with low bioavailability. This limits delivery of antineoplastic drugs through oral route. SMEDDS is a well-accepted means for addressing the lower aqueous solubility and bioavailability issues of a lipophilic drugs. Paclitaxel (PTX) is an antineoplastic drug. PTX is found to be very useful in the treatment of ovarian and breast cancers. PTX have very low aqueous solubility (0.3 µg/ml). 
 Objective: This study aims to formulate SMEDDS incorporating PTX to enhance its aqueous solubility. 
 Methodology: Isopropyl myristate (IM), tween 80 (T80) and transcutol (TC) were used to formulate SMEDDS. IM was considered as oil, T80 as surfactant and TC as co surfactant. 32 factorial design analysis helps in studying the effect of an independent factor on a dependent factor on statistical principles. Independent factors, first – concentrations of oil, second – mixture of surfactant and co-surfactant (Smix), and two dependent factors, first – emulsification time and second – in vitro drug release were chosen. All the nine formulated B1-B9 were subjected to various physicochemical tests. 
 Result and discussion: The globule size was found to be 136.38 – 223.14 nm, zeta potential ranges between -31.54 to -7.58, drug content ranges between 65.34 – 83.56%. Statistical analysis shows that an increasing amount of surfactant decreases emulsification time. This may also decrease the average droplet size of resultant SMEDDS. When the concentration of tween 80 was increased, it was observed that the release of PTX also increased. Rapid and more extent of PTX released from formulated SMEDDS indicates that the aqueous solubility of PTX has increased. B9 formulation releases 99.46% PTX at end of 60 minutes whereas 35.23% of pure PTX powder was solubilized in dissolution medium. 
 Conclusion: This study states that the prepared SMEDDS possess acceptable properties to be considered as immediate release dosage forms. This conclusion was drawn based on in vitro release study.

Synergistic Effect of Toceranib and Nanohydroxyapatite as a Drug Delivery Platform-Physicochemical Properties and In Vitro Studies on Mastocytoma Cells.

A new combination of Toceranib (Toc; 5-[(5Z)-(5-Fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrrole-3-carboxamide) with nanohydroxyapatite (nHAp) was proposed as an antineoplastic drug delivery system. Its physicochemical properties were determined as crystallinity, grain size, morphology, zeta potential and hydrodynamic diameter as well as Toceranib release. The crystalline nanorods of nHAp were synthesised by the co-precipitation method, while the amorphous Toceranib was obtained by its conversion from the crystalline form during nHAp–Toc preparation. The surface interaction between both compounds was confirmed using Fourier-transform infrared spectroscopy (FT-IR), ultraviolet-visible spectroscopy (UV–Vis) and scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDS). The nHAp–Toc showed a slower and prolonged release of Toceranib. The release behaviour was affected by hydrodynamic size, surface interaction and the medium used (pH). The effectiveness of the proposed platform was tested by comparing the cytotoxicity of the drug combined with nHAp against the drug itself. The compounds were tested on NI-1 mastocytoma cells using the Alamar blue colorimetric technique. The obtained results suggest that the proposed platform shows high efficiency (the calculated IC50 is 4.29 nM), while maintaining the specificity of the drug alone. Performed analyses confirmed that nanohydroxyapatite is a prospective drug carrier and, when Toceranib-loaded, may be an idea worth developing with further research into therapeutic application in the treatment of canine mast cell tumour.

Enhancing the anticancer effect of paclitaxel by using polymeric nanoparticles decorated with colorectal cancer targeting CPKSNNGVC-peptide

The major disadvantage of cancer chemotherapy is its lack of specificity. In recent years, selective delivery of chemotherapeutic agents to tumor sites has evolved rapidly in the form of both diagnostic and therapeutic tools in combating cancer. Herein, we develop a new polymeric nanoparticle delivery system that targets both monocarboxylate transporter 1 (MCT1) receptor-positive cancer cells and angiogenic endothelial cells using a tumor homing peptide (CPKSNNGVC, CPK in short) as a nanoparticle surface-bound targeting ligand. By using an emulsion-solvent evaporation method, multipotent drug paclitaxel (PTX)-encapsulated poly (dl-lactide-co-glycolide) (PLGA) nanoparticles (diameter of 215 ± 4 nm; zeta potential of −12 ± 3 mV; 16–17.5% w/w PTX) were synthesized. CPK peptide was thereafter conjugated to the surface of nanoparticles via maleimide-thiol chemistry (CPK-PTX-NPs). Importantly, the highly stable CPK-PTX-NPs exhibited MCT1 receptor-mediated cellular uptake and apoptosis-mediated cell death in MCT1 receptor-overexpressing colorectal cancer (CRC) cells, while the other nontargeting nanoparticles failed to show MCT1 receptor-mediated cellular uptake. Remarkably, the targeted CPK-PTX-NPs selectively inhibited the formation of new blood vessels from pre-existing blood vessels (angiogenesis) in a chick embryo angiogenesis assay. In conclusion, our findings show that MCT1 receptor-selective, PTX-encapsulated and CPK peptide-decorated polymeric nanoparticles act as effective carriers for CRC-specific delivery of antineoplastic drugs to ensure significantly enhanced therapeutic efficacy.

Fabrication of poly(t-butyl betaine carboxylate)-based nanoparticles and study on their in vivo biosecurity

The purpose of this article was to fabricate the novel poly(t-butyl betaine carboxylate)-S-S-poly (1, 3-dioxan-2-one) nanoparticles (PCB-tBU-S-S-PDI NPs) and study their in vivo biosecurity. The poly(t-butyl betaine carboxylate) (PCB-tBU) segment was conjugated to the poly(1, 3-dioxan-2-one)(PDI) moity with a disulfide bond to obtain the copolymer PCB-tBU-S-S-PDI. Hydrogen nuclear magnetic resonance (1H NMR) and Fourier transform infrared spectroscopy (FTIR) spectra were applied to study the structure of PCB-tBU-S-S-PDI. The cargo-free NPs were administrated to Sprague-Dawley (SD) rats by intraperitoneal injection every 3 days for 30 days. Then, the blood routine examination, blood biochemistry, and histologic slides of rat’s organs were carried out to monitor the in vivo biosecurity of cargo-free PCB-tBU-S-S-PDI NPs. 1H NMR and FTIR spectra confirmed the successfully synthesis of PCB-tBU-S-S-PDI. The cargo-free NPs showed spherical morphology with an average of 139.8 ± 0.26 nm. The results of blood biochemistry and blood routine examination suggested that the cargo-free PCB-tBU-S-S-PDI NPs did not show any influence on the liver and renal functions of treated rats. Significantly, the physiological slides of treated rat’s organs did not show any physiological and pathological changes. These phenomena suggested that the PCB-tBU-S-S-PDI NPs had good biosecurity, and it could be used as a vehicle for antineoplastic drug delivery.

Cancer-derived EVs show tropism for tissues at early stage of neoplastic transformation.

From the past decade, extracellular vesicles (EVs) have attracted considerable attention as tools for the selective delivery of anti-neoplastic drugs to cancer tissues. Compared to other nanoparticles, EVs display interesting unique features including immune compatibility, low toxicity and the ability to encapsulate a large variety of small- and macro-molecules. However, in virtually all studies, investigations on EVs have been focused on fully transformed cancers: the possibility to apply EV technology also to early-stage tumors has never been explored.Methods: Herein, we studied the ability of cancer-derived EVs to recognize and deliver their cargo also to incipient cancers. To this purpose, EV biodistribution was studied in MMTV-NeuT genetically modified mice during early mammary transformation, in fully developed breast tumors and in the normal gland of wild type syngeneic mice. EVs were loaded with indocyanine green (ICG), a near-infrared (NIR) dye together with oncolytic viruses and i.v. injected in mice. The nanoparticle biodistribution was assayed by in vivo and ex vivo optical imaging (detecting the ICG) and semiquantitative real-time PCR (measuring the adenoviral genome) in different tissues.Results: Our results demonstrate the ability of cancer-derived EVs to recognize early-stage neoplastic tissues opening the possibility to selectively deliver theranostics also for tumor prevention.Conclusions: Taken together our study demonstrates the ability of EVs to recognize and deliver diagnostic and therapeutic agents not only to fully transformed tissues but also to early stage tumors. These findings pave the way for the synthesis of “universal” EVs-based formulation for targeted cancer therapy.

Simultaneous targeting of primary tumor, draining lymph node, and distant metastases through high endothelial venule-targeted delivery

Cancer patients with malignant involvement of tumor-draining lymph nodes (TDLNs) and distant metastases have the poorest prognosis. A drug delivery platform that targets the primary tumor, TDLNs, and metastatic niches simultaneously, remains to be developed. Here, we generated a novel monoclonal antibody (MHA112) against peripheral node addressin (PNAd), a family of glycoproteins expressed on high endothelial venules (HEVs), which are present constitutively in the lymph nodes (LNs) and formed ectopically in the tumor stroma. MHA112 was endocytosed by PNAd-expressing cells, where it passed through the lysosomes. MHA112 conjugated antineoplastic drug Paclitaxel (Taxol) (MHA112-Taxol) delivered Taxol effectively to the HEV-containing tumors, TDLNs, and metastatic lesions. MHA112-Taxol treatment significantly reduced primary tumor size as well as metastatic lesions in a number of mouse and human tumor xenografts tested. These data indicate that human metastatic lesions contain HEVs and provide a platform that permits simultaneous targeted delivery of antineoplastic drugs to the three key sites of primary tumor, TDLNs, and metastases.

Amino Acid-functionalized hollow mesoporous silica nanospheres as efficient biocompatible drug carriers for anticancer applications.

Herein, a series of new amino acid-functionalized hollow mesoporous silica nanospheres (HMSNs) by post-grafting methods were prepared. These new materials were characterized by different techniques and were studied as matrices for the antineoplastic drug (cisplatin) transport and delivery. The results demonstrate that the surface functionalization of the carriers has a remarkable positive influence on the loading efficiency and release rate of cisplatin. The highest drug entrapment efficiency and the most optimal release properties were observed when the (2-(butylamino) ethyl) glycine groups are grafted on the HMSNs surface (AFS-2-HMSNs sample). Moreover, the in vitro cytotoxic effect of both empty and cisplatin-loaded AFS-2-HMSNs sample (CDDP@AFS-2-HMSNs) on MCF-7 cells (human breast adenocarcinoma cell line) and HepG2 cells (human liver carcinoma cell line) were evaluated by MTT assay. The most important outcome is that the empty carrier revealed no cytotoxicity to cancer cells. However, CDDP@AFS-2-HMSNs caused a notable inhibition of cell viability which was affected from the dose and time. Our results demonstrate that the synthesized materials could be used as carriers for drug delivery with controlled release applications.

PEGylated polylysine derived copolymers with reduction‐responsive side chains for anticancer drug delivery

AbstractReduction‐responsive drug delivery systems have recently gained intense attention in intracellular delivery of anticancer drugs. In this study, we developed a PEGylated polypeptide, poly(ethylene glycol)‐block‐poly(ϵ‐propargyloxycarbonyl‐l‐lysine) (PEG113‐b‐PPAL), as a novel clickable substrate for conjugation of reduction‐responsive side chains for antineoplastic drug delivery. PEG113‐b‐PPAL was synthesized through ring‐opening polymerization of alkyne‐containing N‐carboxyanhydride monomers. A designed disulfide‐containing side chain was introduced onto the PEGylated polypeptide by click reaction. The obtained copolymer PEG113‐b‐P(Lys‐DSA) formed micelles by self‐assembly, which exhibited reduction‐responsive behavior under the stimulus of 10 mmol L–1 glutathione (GSH) in water. A small molecule intermediate, compound 2, was used as a model to investigate the thiol reduction mechanism of PEG113‐b‐P(Lys‐DSA) copolymers. The anticancer drug doxorubicin (DOX) was then loaded into the micelles with a drug loading content of 6.73 wt% and a loading efficiency of 40.3%. Both the blank and the drug‐loaded micelles (DOX‐loaded polylysine derived polymeric micelles (LMs/DOX)) adopted a spherical morphology, with average diameters of 48.0 ± 13.1 and 63.8 ± 20.0 nm, respectively. The in vitro drug release results indicated that DOX could be released faster from the micelles by the trigger of GSH in phosphate buffered saline. Confocal laser scanning microscopy and flow cytometer analysis further proved the intracellular delivery of DOX by LMs/DOX and their GSH‐sensitive release behavior. A 3‐(4,5‐dimethyl‐thiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay showed that the polymers exhibited negligible cytotoxicity towards normal L929 cells or cancer MCF‐7 cells with a treated concentration up to 1.0 mg mL–1. In conclusion, our synthesized biocompatible and biodegradable PEGylated polypeptides hold great promise for intracellular antineoplastic drug delivery. © 2019 Society of Chemical Industry

Exosomes: Diagnostic Biomarkers and Therapeutic Delivery Vehicles for Cancer.

Exosomes are described as nanoscale extracellular vesicles (EVs) secreted by multiple cell types and extensively distributed in various biological fluids. They contain multifarious bioactive molecules and transfer them to adjoining or distal cells through systemic circulation, participating in intracellular and intercellular communication, and modulating host-tumor cell interactions. Recent research has indicated that exosomes obtained from different biological fluids and their contents (proteins, nucleic acids, glycoconjugates, and lipids) can serve as biomarkers for cancer diagnosis, prognosis, and therapeutic response. Furthermore, the discovery of exosomes as therapeutic delivery vehicles has drawn much attention in antineoplastic drug delivery. They can be utilized for therapeutic delivery of proteins, genetic drugs, and chemotherapeutic drugs. Herein, this review summarizes the biogenesis, structure, and components of exosomes, focusing primarily on their two possible applications as diagnostic biomarkers and therapeutic delivery vehicles for cancers.

Surgery with curative intent for stage IV gastric cancer: Is it a reality of illusion?

Gastric cancer with metastases outside of the regional lymph nodes is deemed oncologically unresectable. Nevertheless, some metastatic lesions are technically resectable by applying established surgical techniques such as para‐aortic lymphadenectomy and hepatectomy. At the time of compilation of the Japanese gastric cancer treatment guidelines version 4, systematic reviews were conducted to see whether it is feasible to make any recommendation to dissect both the primary and metastatic lesions with intent to cure, possibly as part of multimodality treatment. Long‐term survivors were found among carefully selected groups of patients both in prospective and retrospective studies. In addition, there is a growing list of publications reporting encouraging outcomes of gastrectomy conducted after exceptionally good response to chemotherapy, usually among patients who underwent R0 resection. This type of surgery is often referred to as conversion surgery. It is sometimes difficult to define a clear borderline between curative surgery scheduled after neoadjuvant chemotherapy and the conversion surgery. This review summarizes what we knew after the literature reviews conducted at the time of compiling the Japanese guidelines and in addition reflects some new findings obtained thereafter through clinical trials and retrospective studies. Metastases were divided into three categories based on the major metastatic pathways: lymphatic, hematogenous, and peritoneal. In each of these categories, there were findings that could provide hope for patients with metastatic disease. These findings implied that the surgical technique that we already use could become more useful upon further developments in antineoplastic agents and drug delivery.

Mitochondrial Delivery of Phenol Substructure Triggers Mitochondrial Depolarization and Apoptosis of Cancer Cells.

Antitumor chemotherapy remains one of the most important challenge of the medicinal chemistry. Emerging research in chemotherapy is focused on exploiting the biochemical differences between cancer cell and normal cell metabolism in order to reduce the side effects and increase antitumor therapy efficacy. The higher mitochondrial transmembrane potential of cancer cells compared to not-transformed cells favors the intra-mitochondrial accumulation of cationic drugs in the former. This feature could be exploited to allow selective delivery of antineoplastic drugs to the cancer cells. In this work we designed and synthetized phenol derivatives joined to the triphenylphosphonium (TPP) cation, a well-known vector for mitochondrial targeting. Two designed phenol TPP-derivatives 1 and 2 show remarkable cytotoxic activity against different cancer cell lines, but were less toxic against normal cells. The differential cytotoxicity relied on the higher mitochondrial biogenesis and oxidative-phosphorylation metabolism of the former. By reducing mitochondrial mass and energetic metabolism, and increasing at the same time the levels of intra-mitochondrial reactive oxygen species, phenol TPP-derivatives 1 and 2 induced mitochondria depolarization and triggered a caspase 9/3-mediated apoptosis, limited to cancer cells. This work provides the rationale to further develop phenol TPP-derivatives targeting mitochondria as new and selective anticancer tools.

Application of mesenchymal stem cells in antineoplastic drugs delivery for tumor-targeted therapy

In recent years, a large number of studies have achieved tumor targeting by mesenchymal stem cells (MSC)-based delivery system attributed to the tumor tropism of MSCs. Biomacromolecules and antineoplastic drugs loaded on MSC via internalization or cell membrane anchoring can be released or expressed at tumor site to perform their antitumor effects. The genetically modified MSC are extensively studied, however, the applications of MSCs in targeted delivery of antineoplastic drug with small molecules are not well summarized. In this review, MSCs homing mechanism and the distribution of injected MSCs in vivo is introduced; the examples of antitumor drug-primed MSCs and drug loaded MSCs are presented; the drug loading and releasing process from MSCs is also illustrated; finally, challenges and future perspectives of MSCs-based drug delivery system on realizing its full potential are prospected.

Mesenchymal Stromal Cells for Antineoplastic Drug Loading and Delivery.

Mesenchymal stromal cells are a population of undifferentiated multipotent adult cells possessing extensive self-renewal properties and the potential to differentiate into a variety of mesenchymal lineage cells. They express broad anti-inflammatory and immunomodulatory activity on the immune system and after transplantation can interact with the surrounding microenvironment, promoting tissue healing and regeneration. For this reason, mesenchymal stromal cells have been widely used in regenerative medicine, both in preclinical and clinical settings. Another clinical application of mesenchymal stromal cells is the targeted delivery of chemotherapeutic agents to neoplastic cells, maximizing the cytotoxic activity against cancer cells and minimizing collateral damage to non-neoplastic tissues. Mesenchymal stem cells are home to the stroma of several primary and metastatic neoplasms and hence can be used as vectors for targeted delivery of antineoplastic drugs to the tumour microenvironment, thereby reducing systemic toxicity and maximizing antitumour effects. Paclitaxel and gemcitabine are the chemotherapeutic drugs best loaded by mesenchymal stromal cells and delivered to neoplastic cells, whereas other agents, like pemetrexed, are not internalized by mesenchymal stromal cells and therefore are not suitable for advanced antineoplastic therapy. This review focuses on the state of the art of advanced antineoplastic cell therapy and its future perspectives, emphasizing in vitro and in vivo preclinical results and future clinical applications.