Selective Delivery Of Anticancer Drugs Research Articles

Delivery of Drugs into Cancer Cells Using Antibody-Drug Conjugates Based on Receptor-Mediated Endocytosis and the Enhanced Permeability and Retention Effect.

Innumerable people worldwide die of cancer every year, although pharmaceutical therapy has actualized many benefits in human health. For background, anti-cancer drug development is difficult due to the multifactorial pathogenesis and complicated pathology of cancers. Cancer cells excrete hydrophobic low-molecular anti-cancer drugs by overexpressed efflux transporters such as multiple drug resistance 1 (MDR1) at the apical membrane. Mutation-driven drug resistance is also developed in cancer. Moreover, the poor distribution of drug to cancer cells is a serious problem, because patients suffer from off-target side effects. Thus, highly selective and effective drug delivery into solid cancer cells across the membrane should be established. It is known that substances (10-100 nm in diameter) such as monoclonal antibodies (mAbs) (approximately 14.2 nm in diameter) or nanoparticles spontaneously gather in solid tumor stroma or parenchyma through the capillary endothelial fenestration, ranging from 200-2000 nm, in neovasculatures due to the enhanced permeability and retention (EPR) effect. Furthermore, cancer antigens, such as HER2, Nectin-4, or TROP2, highly selectively expressed on the surface of cancer cells act as a receptor for receptor-mediated endocytosis (RME) using mAbs against such antigens. Thus, antibody-drug conjugates (ADCs) are promising anti-cancer pharmaceutical agents that fulfill accurate distribution due to the EPR effect and due to antibody-antigen binding and membrane permeability owing to RME. In this review, I introduce the implementation and possibility of highly selective anti-cancer drug delivery into solid cancer cells based on the EPR effect and RME using anti-cancer antigens ADCs with payloads through suitable linkers.

Shell-Sheddable Micelles Based on Poly(ethylene glycol)-hydrazone-poly[R,S]-3-hydroxybutyrate Copolymer Loaded with 8-Hydroxyquinoline Glycoconjugates as a Dual Tumor-Targeting Drug Delivery System.

The development of selective delivery of anticancer drugs into tumor tissues to avoid systemic toxicity is a crucial challenge in cancer therapy. In this context, we evaluated the efficacy of a combination of nanocarrier pH-sensitivity and glycoconjugation of encapsulated drugs, since both vectors take advantage of the tumor-specific Warburg effect. Herein, we synthesized biodegradable diblock copolymer, a poly(ethylene glycol)-hydrazone linkage-poly[R,S]-3-hydroxybutyrate, which could further self-assemble into micelles with a diameter of ~55 nm. The hydrazone bond was incorporated between two copolymer blocks under an acidic pH, causing the shell-shedding of micelles which results in the drug’s release. The micelles were stable at pH 7.4, but decompose in acidic pH, as stated by DLS studies. The copolymer was used as a nanocarrier for 8-hydroxyquinoline glucose and galactose conjugates as well as doxorubicin, and exhibited pH-dependent drug release behavior. In vitro cytotoxicity, apoptosis, and life cycle assays studies of blank and drug-loaded micelles were performed on Normal Human Dermal Fibroblasts-Neonatal (NHDF-Neo), colon carcinoma (HCT-116), and breast cancer (MCF-7) for 24, 48, and 72 h. A lack of toxicity of blank micelles was demonstrated, whereas the glycoconjugates-loaded micelles revealed enhanced selectivity to inhibit the proliferation of cancer cells. The strategy of combining pH-responsive nanocarriers with glycoconjugation of the drug molecule provides an alternative to the modus operandi of designing multi-stimuli nanocarriers to increase the selectivity of anticancer therapy.

Cell-penetrating peptides in protein mimicry and cancer therapeutics.

Extensive research has been undertaken in the pursuit of anticancer therapeutics. Many anticancer drugs require specificity of delivery to cancer cells, whilst sparing healthy tissue. Cell-penetrating peptides (CPPs), now well established as facilitators of intracellular delivery, have in recent years advanced to incorporate target specificity and thus possess great potential for the targeted delivery of anticancer cargoes. Though none have yet been approved for clinical use, this novel technology has already entered clinical trials. In this review we present CPPs, discuss their classification, mechanisms of cargo internalization and highlight strategies for conjugation to anticancer moieties including their incorporation into therapeutic proteins. As the mainstay of this review, strategies to build specificity into tumor targeting CPP constructs through exploitation of the tumor microenvironment and the use of tumor homing peptides are discussed, whilst acknowledging the extensive contribution made by CPP constructs to target specific protein-protein interactions integral to intracellular signaling pathways associated with tumor cell survival and progression. Finally, antibody/antigen CPP conjugates and their potential roles in cancer immunotherapy and diagnostics are considered. In summary, this review aims to harness the potential of CPP-aided drug delivery for future cancer therapies and diagnostics whilst highlighting some of the most recent achievements in selective delivery of anticancer drugs, including cytostatic drugs, to a range of tumor cells both in vitro and in vivo.

Molecularly Engineered Aptamers Targeting Tumor Tissue and Cancer Cells for Efficient in Vivo Recognition and Enrichment

Molecularly Engineered Aptamers Targeting Tumor Tissue and Cancer Cells for Efficient in Vivo Recognition and Enrichment

Synthesis and physicochemical evaluation of fluorinated lipopeptide precursors of ligands for microbubble targeting.

Ligand-targeted microbubbles are focusing interest for molecular imaging and delivery of chemotherapeutics. Lipid–peptide conjugates (lipopeptides) that feature alternating serine–glycine (SG)n segments rather than classical poly(oxyethylene) linkers between the lipid polar head and a targeting ligand were proposed for the liposome-mediated, selective delivery of anticancer drugs. Here, we report the synthesis of perfluoroalkylated lipopeptides (F-lipopeptides) bearing two hydrophobic chains (CnF2n+1, n = 6, 7, 8, 1–3) grafted through a lysine moiety on a hydrophilic chain composed of a lysine–serine–serine (KSS) sequence followed by 5 SG sequences. These F-lipopeptides are precursors of targeting lipopeptide conjugates. A hydrocarbon counterpart with a C10H21 chain (4) was synthesized for comparison. The capacity for the F-lipopeptides to spontaneously adsorb at the air/water interface and form monolayers when combined with dipalmitoylphosphatidylcholine (DPPC) was investigated. The F-lipopeptides 1–3 demonstrated a markedly enhanced tendency to form monolayers at the air/water interface, with equilibrium surface pressures reaching ≈7–10 mN m−1 versus less than 1 mN m−1 only for their hydrocarbon analog 4. The F-lipopeptides penetrate in the DPPC monolayers in both liquid expanded (LE) and liquid condensed (LC) phases without interfacial film destabilization. By contrast, 4 provokes delipidation of the interfacial film. The incorporation of the F-lipopeptides 1–3 in microbubbles with a shell of DPPC and dipalmitoylphosphatidylethanolamine-PEG2000 decreased their mean diameter and increased their stability, the best results being obtained for the C8F17-bearing lipopeptide 3. By contrast, the hydrocarbon lipopeptide led to microbubbles with a larger mean diameter and a significantly lower stability.

How to exploit different endocytosis pathways to allow selective delivery of anticancer drugs to cancer cells over healthy cells.

It was recently shown that it is possible to exploit the nanoparticle shape to selectively target endocytosis pathways found in cancer and not healthy cells. It is important to understand and compare the endocytosis pathways of nanoparticles in both cancer and healthy cells to restrict the healthy cells from taking up anticancer drugs to help reduce the side effects for patients. Here, the clathrin-mediated endocytosis inhibitor, hydroxychloroquine, and the anticancer drug, doxorubicin, are loaded into the same mesoporous silica nanorods. The use of nanorods was found to restrict the uptake by healthy cells but allowed cancer cells to take up the nanorods via the macropinocytosis pathway. Furthermore, it is shown that the nanorods can selectively deliver doxorubicin to the nucleus of breast cancer cells and to the cytoplasm of pancreatic cancer cells. The dual-drug-loaded nanorods were able to selectively kill the breast cancer cells in the presence of healthy breast cells. This study opens exciting possibilities of targeting cancer cells based on the material shape rather than targeting antibodies.

Recent Trends in Nanocarrier-Based Targeted Chemotherapy: Selective Delivery of Anticancer Drugs for Effective Lung, Colon, Cervical, and Breast Cancer Treatment

Chemotherapy drugs are cytotoxic to tumor cells, but their lack of specificity leads to a range of side effects. The off-target effects of such drugs can be improved through the use of nanoparticles (NPs). Administered NPs show enhanced accumulation in tumor tissue near the blood vessels, enhancing both anticancer drug permeability and tumor retention. Several nanocarriers are now approved for clinical use in a range of cancer therapies, and many novel formulations are in the later stages of clinical trials. Here, we describe the advances in this area through the review of novel NP drug formulations developed over the last year. We focus specifically on lung, colon, cervical, and breast cancers and discuss the future of NPs as potential treatment options in these areas.

Colloidal Nanocarriers as Versatile Targeted Delivery Systems for Cervical Cancer.

The second most common malignant cancer of the uterus is cervical cancer, which is present worldwide, has a rising death rate and is predominant in developing countries. Different classes of anticancer agents are used to treat cervical carcinoma. The use of these agents results in severe untoward side-effects, toxicity, and multidrug resistance (MDR) with higher chances of recurrence and spread beyond the pelvic region. Moreover, the resulting clinical outcome remains very poor even after surgical procedures and treatment with conventional chemotherapy. Because of the nonspecificity of their use, the agents wipe out both cancerous and normal tissues. Colloidal nano dispersions have now been focusing on site-specific delivery for cervical cancer, and there has been much advancement. This review aims to highlight the problems in the current treatment of cervical cancer and explore the potential of colloidal nanocarriers for selective delivery of anticancer drugs using available literature. In this study, we surveyed the role and potential of different colloidal nanocarriers in cervical cancer, such as nanoemulsion, nanodispersions, polymeric nanoparticles, and metallic nanoparticles and photothermal and photodynamic therapy. We found significant advancement in colloidal nanocarrier-based cervical cancer treatment. Cervical cancer-targeted treatment with colloidal nanocarriers would hopefully result in minimal toxic side effects, reduced dosage frequency, and lower MDR incidence and enhance the patient survival rates. The future direction of the study should be focused more on the regulatory barrier of nanocarriers based on clinical outcomes for cervical cancer targeting with cost-effective analysis.

Strategies for Precise Engineering and Conjugation of Antibody Targeted-nanoparticles for Cancer Therapy.

Improvements in the diagnosis and treatment of cancer are urgently needed for use in nanotechnology. Nanoparticles (NPs) can reduce the side effects of traditional chemotherapy by sustained release of loaded drugs and increase therapeutic efficiency. NPs can also enhance endothelial permeation retention by size effect and its accumulation in tumor cells through passive targeting. Furthermore, it is critical to treat cancer with a controlled targeted drug which can be specifically delivered into tumor cells and released there, resulting in a targeted therapy to eradicate tumor cells while sparing normal cells. To this end, antibody-mediated targeting therapy has been developed, but imperfections in antibodies (Abs) limit this therapy. Therefore, the combination of NPs and Abs has been highly valued in recent years, because conjugating special Abs on the surface of NPs can increase targeting efficiency, enabling selective delivery of anti-cancer drugs to tumor cells. In this mini-review, we would like to enumerate the strategies for the conjugation of Abs to the surface of the NPs as well as the precise engineering of targeted NPs. The application of targeting antibody fragments in this drug delivery system will also be discussed.

Mitochondria-localized in situ generation of rhodamine photocage with fluorescence turn-on enabling cancer cell-specific drug delivery triggered by green light.

In this work, we have developed a rhodamine dye based water-soluble, mitochondria-indicating photocage, which gets activated in the mitochondria producing a fluorescent signal and on-demand releases the caged anticancer drug, chlorambucil, in the cancer cells selectively upon irradiation of green light.

Design of a new pH‐activatable cell‐penetrating peptide for drug delivery into tumor cells

Cell-penetrating peptides (CPPs) have been considered as potential drug delivery vectors due to their remarkable membrane translocation capacity. However, lack of specificity and extreme systemic toxicity hamper their successful application for drug delivery. Here, we designed a new pH-activatable CPP, LHHLLHHLHHLLHH-NH2 (LH), by substitution of all lysines and two leucines of LKKLLKLLKKLLKL-NH2 (LK) with histidines. As expected, histidine-rich LH could be activated and penetrate into cells at pH 6.0, whereas its membrane transduction activity could be shielded at pH 7.4. In contrast, LK showed no obviously different cellular uptake at both pH conditions. Importantly, LH was significantly less cytotoxicity compared with LK at both pH values, suggesting a better safety for further application. In addition, after conjugation of camptothecin (CPT) with LH, this conjugate displayed remarkably pH-dependent antitumor activity than free CPT and LK-CPT. This study provides a new tumor pH-responsive CPP with low toxicity for selective anticancer drug delivery.

Targeted delivery of doxorubicin for the treatment of bone metastasis from breast cancer using alendronate-functionalized graphene oxide nanosheets

Selective delivery of anti-cancer drugs to bone tumors remains an on-going developmental issue due to problems of drug availability and the physiological nature of bone. This study was undertaken to enhance accumulation of doxorubicin (DOX) in bone metastasis microenvironments using alendronate-functionalized graphene oxide nanosheets (NGO-ALs). In vivo biodistribution study showed NGO-ALs were retained for longer and at higher concentrations in bone tumor areas than non-functionalized NGOs. Our findings suggest that NGO-ALs could be used as a promising carrier to enhance antitumor effects and diminish the off-target effects of DOX for the treatment of bone metastasis.

Circulating Lipoproteins: A Trojan Horse Guiding Squalenoylated Drugs to LDL-Accumulating Cancer Cells

Selective delivery of anticancer drugs to rapidly growing cancer cells can be achieved by taking advantage of their high receptor-mediated uptake of low-density lipoproteins (LDLs). Indeed, we have recently discovered that nanoparticles made of the squalene derivative of the anticancer agent gemcitabine (SQGem) strongly interacted with the LDLs in the human blood. In the present study, we showed both invitro and invivo that such interaction led to the preferential accumulation of SQGem in cancer cells (MDA-MB-231) with high LDL receptor expression. As a result, an improved pharmacological activity has been observed in MDA-MB-231 tumor-bearing mice, an experimental model with a low sensitivity to gemcitabine. Accordingly, we proved that the use of squalene moieties not only induced the gemcitabine insertion into lipoproteins, but that it could also be exploited to indirectly target cancer cells invivo.

Chitosan-Acrylic Polymeric Nanoparticles with Dynamic Covalent Bonds. Synthesis and Stimuli Behavior.

Drug delivery represents one of the most important research fields within the pharmaceutical industry. Different strategies are reported every day in a dynamic search for carriers with the ability to transport drugs across the body, avoiding or decreasing toxic issues and improving therapeutic activity. One of the most interesting strategies currently under research is the development of drug delivery systems sensitive to different stimuli, due to the high potential attributed to the selective delivery of the payload. In this work, a stimuli-sensitive nanocarrier was built with a bifunctional acrylic polymer, linked by imine and disulfide bonds to thiolate chitosan, the latter being a biopolymer widely known in the field of tissue engineering and drug delivery by its biodegradability and biocompatibility. These polymer nanoparticles were exposed to different changes in pH and redox potential, which are environments commonly found inside cancer cells. The results proof the ability of the nanoparticles to keep the original structure when either changes in pH or redox potential were applied individually. However, when both stimuli were applied simultaneously, a disassembly of the nanoparticles was evident. These special characteristics make these nanoparticles suitable nanocarriers with potential for the selective delivery of anticancer drugs.

Synthetic low-density lipoprotein (sLDL) selectively delivers paclitaxel to tumor with low systemic toxicity.

Low density lipoprotein (LDL), which is a principal carrier for the delivery of cholesterol, has been used as a great candidate for the delivery of drugs to tumor based on the great requirements for cholesterol of many cancer cells. Mimicking the structure and composition of LDL, we designed a synthetic low-density lipoprotein (sLDL) to encapsulate paclitaxel-alpha linolenic acid (PALA) for tumor therapy. The PALA loaded sLDL (PALA-sLDL) and PALA-loaded microemulsion (PALA-ME, without the binding domain for LDLR) displayed uniform sizes with high drug loading efficiency (> 90%). In vitro studies demonstrated PALA-sLDL exhibited enhanced cellular uptake capacity and better cytotoxicity to LDLR over-expressed U87 MG cells as compared to PALA-ME. The uptake mechanisms of PALA-sLDL were involved in a receptor mediated endocytosis and macropinocytosis. Furthermore, the in vivo biodistribution and tumor growth inhibition studies of PALA-sLDL were investigated in xenograft U87 MG tumor-bearing mice. The results showed that PALA-sLDL exhibited higher tumor accumulation than PALA-ME and superior tumor inhibition efficiency (72.1%) compared to Taxol® (51.2%) and PALA-ME (58.8%) but with lower toxicity. These studies suggested that sLDL is potential to be used as a valuable carrier for the selective delivery of anticancer drugs to tumor with low systemic toxicity.

Controllable Construction of Biocompatible Supramolecular Micelles and Vesicles by Water-Soluble Phosphate Pillar[5,6]arenes for Selective Anti-Cancer Drug Delivery

The controllable construction of biocompatible supramolecular nanocarriers with different morphologies based on dynamic noncovalent interactions to achieve selective delivery of drugs with different properties remains highly challenging. We herein report controllable construction of two types of supramolecular nanocarriers based on biocompatible water-soluble phosphate-based pillar[5]arene (WP5P) or pillar[6]arene (WP6P) with pyridinium bromide guest G for the selective anticancer drug delivery. Solid supramolecular micelles could be obtained by the amphiphilic host–guest inclusion complex formed from WP5P and G, whereas hollow supramolecular vesicles were acquired from WP6P and G. Both of them showed pH- and Zn2+-responsiveness. Furthermore, the resulting solid micelles were able to encapsulate hydrophobic anticancer drug doxorubicin (DOX) to achieve DOX-loaded micelles, while hydrophilic anticancer drug mitoxantrone (MTZ) could be successfully loaded into the hollow vesicles. Additionally, the encapsula...

Enhancing Tumor Cell Response to Chemotherapy through the Targeted Delivery of Platinum Drugs Mediated by Highly Stable, Multifunctional Carboxymethylcellulose-Coated Magnetic Nanoparticles.

The fabrication of nanoparticles using different formulations, and which can be used for the delivery of chemotherapeutics, has recently attracted considerable attention. We describe herein an innovative approach that may ultimately allow for the selective delivery of anticancer drugs to tumor cells by using an external magnet. A conventional antitumor drug, cisplatin, has been incorporated into new carboxymethylcellulose-stabilized magnetite nanoparticles conjugated with the fluorescent marker Alexa Fluor 488 or folic acid as targeting agent. The magnetic nanocarriers possess exceptionally high biocompatibility and colloidal stability. These cisplatin-loaded nanoparticles overcome the resistance mechanisms typical of free cisplatin. Moreover, experiments aimed at the localization of the nanoparticles driven by an external magnet in a medium that mimics physiological conditions confirmed that this localization can inhibit tumor cell growth site-specifically.

Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER2-positive breast cancer.

Approximately 20% of breast cancer cases are human epidermal growth factor receptor 2 (HER2)-positive. This type of breast cancer is more aggressive and tends to reoccur more often than HER2-negative breast cancer. In this study, we synthesized trastuzumab (TZ)-grafted dendrimers to improve delivery of docetaxel (DTX) to HER2-positive breast cancer cells. Bioconjugation of TZ on the surface of dendrimers was performed using a heterocrosslinker, MAL-PEG-NHS. For imaging of cancer cells, dendrimers were also conjugated to fluorescein isothiocyanate. Comparative in vitro studies revealed that these targeted dendrimers were more selective, and had higher antiproliferation activity, towards HER2-positive MDA-MB-453 human breast cancer cells than HER2-negative MDA-MB-231 human breast cancer cells. When compared with unconjugated dendrimers, TZ-conjugated dendrimers also displayed higher cellular internalization and induction of apoptosis against MDA-MB-453 cells. Binding of TZ to the dendrimer surface could help site-specific delivery of DTX and reduce systemic toxicity resulting from its lack of specificity. In addition, in vivo studies revealed that the pharmacokinetic profile of DTX was significantly improved by the conjugated nanosystem.

Enzyme-activated intracellular drug delivery with tubule clay nanoformulation.

Fabrication of stimuli-triggered drug delivery vehicle s is an important milestone in treating cancer. Here we demonstrate the selective anticancer drug delivery into human cells with biocompatible 50-nm diameter halloysite nanotube carriers. Physically-adsorbed dextrin end stoppers secure the intercellular release of brilliant green. Drug-loaded nanotubes penetrate through the cellular membranes and their uptake efficiency depends on the cells growth rate. Intercellular glycosyl hydrolases-mediated decomposition of the dextrin tube-end stoppers triggers the release of the lumen-loaded brilliant green, which allowed for preferable elimination of human lung carcinoma cells (А549) as compared with hepatoma cells (Hep3b). The enzyme-activated intracellular delivery of brilliant green using dextrin-coated halloysite nanotubes is a promising platform for anticancer treatment.

Synthesis and Properties of Star HPMA Copolymer Nanocarriers Synthesised by RAFT Polymerisation Designed for Selective Anticancer Drug Delivery and Imaging.

High-molecular-weight star polymer drug nanocarriers intended for the treatment and/or visualisation of solid tumours were synthesised, and their physico-chemical and preliminary in vitro biological properties were determined. The water-soluble star polymer carriers were prepared by the grafting of poly(amido amine) (PAMAM) dendrimers by hetero-telechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers, synthesised by the controlled radical Reversible Addition Fragmentation chain Transfer (RAFT) polymerisation. The well-defined star copolymers with Mw values ranging from 2 · 10(5) to 6 · 10(5) showing a low dispersity (approximately 1.2) were prepared in a high yield. A model anticancer drug, doxorubicin, was bound to the star polymer through a hydrazone bond, enabling the pH-controlled drug release in the target tumour tissue. The activated polymer arm ends of the star copolymer carrier enable a one-point attachment for the targeting ligands and/or a labelling moiety. In this study, the model TAMRA fluorescent dye was used to prove the feasibility of the polymer carrier visualisation by optical imaging in vitro. The tailor-made structure of the star polymer carriers should facilitate the synthesis of targeted polymer-drug conjugates, even polymer theranostics, for simultaneous tumour drug delivery and imaging.