Carrier For Anticancer Agents Research Articles

Quaternary Ammonium Palmitoyl Glycol Chitosan (GCPQ) Loaded with Platinum-Based Anticancer Agents-A Novel Polymer Formulation for Anticancer Therapy.

Quaternary ammonium palmitoyl glycol chitosan (GCPQ) has already shown beneficial drug delivery properties and has been studied as a carrier for anticancer agents. Consequently, we synthesised cytotoxic platinum(IV) conjugates of cisplatin, carboplatin and oxaliplatin by coupling via amide bonds to five GCPQ polymers differing in their degree of palmitoylation and quaternisation. The conjugates were characterised by 1H and 195Pt NMR spectroscopy as well as inductively coupled plasma mass spectrometry (ICP-MS), the latter to determine the amount of platinum(IV) units per GCPQ polymer. Cytotoxicity was evaluated by the MTT assay in three human cancer cell lines (A549, non-small-cell lung carcinoma; CH1/PA-1, ovarian teratocarcinoma; SW480, colon adenocarcinoma). All conjugates displayed a high increase in their cytotoxic activity by factors of up to 286 times compared to their corresponding platinum(IV) complexes and mostly outperformed the respective platinum(II) counterparts by factors of up to 20 times, also taking into account the respective loading of platinum(IV) units per GCPQ polymer. Finally, a biodistribution experiment was performed with an oxaliplatin-based GCPQ conjugate in non-tumour-bearing BALB/c mice revealing an increased accumulation in lung tissue. These findings open promising opportunities for further tumouricidal activity studies especially focusing on lung tissue.

Polymer-dendrimer Hybrids as Carriers of Anticancer Agents.

In recent years, polymeric materials with the ability to self-assemble into micelles have been increasingly investigated for application in various fields, mainly in biomedicine. Micellar morphology is important and interesting in the field of drug transport and delivery since micelles can encapsulate hydrophobic molecules in their nucleus, improve the solubility of drugs, have active molecules in their outer layer, and, due to their nanometric size, they can take advantage of the EPR effect, prolong circulation time and avoid renal clearance. Furthermore, bioactive molecules (could be joined covalently or by host-host interaction), such as drugs, bioimaging molecules, proteins, targeting ligands, "cross-linkable" molecules, or linkages sensitive to internal or external stimuli, can be incorporated into them. The confined multivalent cooperativity and the ability to modify the dendritic structure provide versatility to create and improve the amphiphiles used in the micellar supramolecular field. As discussed in this review, the most studied structures are hybrid copolymers, which are formed by the combination of linear polymers and dendrons. Amphiphilic dendrimer micelles have achieved efficient and promising results in both in vitro and in vivo tests, and this encourages research for their future application in nanotherapies.

Harnessing albumin as a carrier for cancer therapies.

Serum albumin, a natural ligand carrier that is highly concentrated and long-circulating in the blood, has shown remarkable promise as a carrier for anti-cancer agents. Albumin is able to prolong the circulation half-life of otherwise rapidly cleared drugs and, importantly, promote their accumulation within tumors. The applications for using albumin as a cancer drug carrier are broad and include both traditional cancer chemotherapeutics and new classes of biologics. Strategies for leveraging albumin for drug delivery can be classified broadly into exogenous and in situ binding formulations that utilize covalent attachment, non-covalent association, or encapsulation in albumin-based nanoparticles. These methods have shown remarkable preclinical and clinical successes that are examined in this review.

Tailored mesoporous silica nanosystem with enhanced permeability of the blood-brain barrier to antagonize glioblastoma.

Cancer-targeted drug delivery systems with permeability of the blood-brain barrier (BBB) have become of great interest for the rational design of high-efficiency anticancer agents. Herein, a tailored mesoporous silica nanoparticles (MSNs) nanosystem modified by RGD (arginine-glycine-aspartate) peptide was designed and tested for use as a carrier of anticancer agents, by using a novel organic selenium compound BSeC as a model molecule. As expected, the nanosystem (BSeC@MSNs-RGD) could effectively enhance the BBB permeability and the cellular uptake of BSeC in tumor cells. The internalized BSeC@MSNs-RGD triggered mitochondrial dysfunction and intracellular ROS overproduction, which subsequently activated the p53 and MAPKs pathways. Moreover, the nanosystem could inhibit the U87 tumor spheroids growth, significantly prolong the blood circulation time of the loaded drug in vivo and effectively reduce its in vivo toxicity. Taken together, this study provides a strategy for the rational design of a tailored nanomedicine with enhanced BBB permeability to treat human brain glioma.

Zirconium Phosphate Nanoplatelet Potential for Anticancer Drug Delivery Applications.

Zirconium phosphate (ZrP) nanoplatelets can intercalate anticancer agents via an ion exchange reaction creating an inorganic delivery system with potential for cancer treatment. ZrP delivery of anticancer agents inside tumor cells was explored in vitro. Internalization and cytotoxicity of ZrP nanoplatelets were studied in MCF-7 and MCF-10A cells. DOX-loaded ZrP nanoplatelets (DOX@ZrP) uptake was assessed by confocal (CLSM) and transmission electron microscopy (TEM). Cytotoxicity to MCF-7 and MCF-10A cells was determined by the MTT assay. Reactive Oxy- gen Species (ROS) production was analyzed by fluorometric assay, and cell cycle alterations and induction of apoptosis were analyzed by flow cytometry. ZrP nanoplatelets were localized in the endosomes of MCF-7 cells. DOX and ZrP nanoplatelets were co-internalized into MCF-7 cells as detected by CLSM. While ZrP showed limited toxicity to MCF-7 cells, DOX@ZrP was cytotoxic at an IC₅₀ similar to that of free DOX. Meanwhile, DOX lC₅₀ was significantly lower than the equivalent concentration of DOX@ZrP in MCF-10A cells. ZrP did not induce apoptosis in both cell lines. DOX and DOX@ZrP induced significant oxidative stress in both cell models. Results suggest that ZrP nanoplatelets are promising as carriers of anticancer agents into cancer cells.

Nanomedicines for Cancer Therapy: An Update of FDA Approved and Those under Various Stages of Development

Gopalakrishna pillai, Maria LC Coronel. Scienece and technology of the emerging nanomedicines in cancer therapy: A primer for physicians and pharmacists. SAGE Open Medicine2013;1.

Science and technology of the emerging nanomedicines in cancer therapy: A primer for physicians and pharmacists

Nanomedicine, the medical applications of devices based on nanotechnology, promises an endless range of applications from biomedical imaging to drug and gene delivery. The size range of the nanomaterials is strictly defined as 1–100 nm, although many marketed nanomedicines are in the submicron range of 100–1000 nm. The major advantages of using nanomaterials as a carrier for anticancer agents are the possibility of targeted delivery to the tumor; their physical properties such as optical and magnetic properties, which can be exploited for developing contrast agents for tumor imaging; their ability to hold thousands of molecules of a drug and deliver at the required site and also the ability to overcome solubility and stability issues. Currently, there are several nanotechnology-enabled diagnostic and therapeutic agents undergoing clinical trials and a few already approved by Food and Drug Administration. Targeted delivery of anticancer agents is achieved by exploiting a unique characteristic of the rapidly dividing tumor cells called “the enhanced permeability and retention effect.” Nanoparticles with mean diameter between 100 and 200 nm or even above 200 nm have also been reported to be taken up by tumor cells via the enhanced permeability and retention effect. In addition to this passive targeting based on size, the nanoparticle surface may be modified with a variety of carefully chosen ligands that would interact with specific receptors on the surface of the tumor cells, thus imparting additional specificity for active targeting. Regional release of a drug contained in a nanoparticulate system by the application of external stimuli such as hyperthermia to a thermosensitive device is another innovative strategy for targeted delivery. Nanoparticles protect the enclosed drug from rapid elimination from the body, keep them in circulation for prolonged periods and often evade expulsion by the efflux pump mechanisms, which also leads to avoidance of development of resistance. This review focuses on the science and technology of Food and Drug Administration–approved cancer nanomedicines such as Abraxane, Doxil, DaunoXome and those drug-delivery systems that have reached an advanced stage of clinical development utilizing liposomes, albumin nanospheres, thermosensitive devices and gold nanoshells.

Abstract 2909: Doxorubicin-loaded zirconium phosphate nanoparticles for intracellular anticancer drug delivery to breast cancer cells

Abstract Purpose: Doxorubicin (DOX), is an anthracycline antibiotic widely used for the treatment of several solid tumors but its usage is limited by serious side effects to healthy tissues. The purpose of this study was to explore the effectiveness of zirconium phosphate nanoparticles (ZrP) as carrier of anticancer agents (ie. DOX) to tumor cells and potentially reduce side effects to healthy tissue. Methods: Confocal Microscopy (CM) was used to assess internalization and localization of doxorubicin-loaded ZrP nanoparticles (DOX:ZrP) in MCF-7 breast cancer cell line. The cytotoxicity of ZrP and DOX:ZrP in MCF-7 and MCF-10A cells was studied using MTT assay. Results: Co-internalization of DOX and ZrP nanoparticles into the cytoplasm and nucleus of MCF-7 cells was detected using CM. A high fluorescence in cell nucleus demonstrated DOX release from ZrP nanoparticles. ZrP alone is non-toxic to MCF-7 and MCF-10A cells. After a 48-hour treatment of MCF-7 cells with DOX:ZrP or DOX alone the IC50 obtained was 23µM and 24 µM, respectively. DOX cytotoxicity to MCF-7 cells after 72-hour treatment was three times higher than DOX:ZrP with IC50 of 0.74 µM and 3.15 µM, respectively. Conclusion: ZrP nanoparticles are internalized and can effectively deliver DOX to the interior of cancer cells. ZrP nanoparticles might provide a versatile platform for transportation of anticancer agents resulting in improved cancer therapy by reducing the side effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2909. doi:1538-7445.AM2012-2909

Feasibility evaluation of neutron capture therapy for hepatocellular carcinoma using selective enhancement of boron accumulation in tumour with intra-arterial administration of boron-entrapped water-in-oil-in-water emulsion

Hepatocellular carcinoma (HCC) is one of the most difficult to cure with surgery, chemotherapy, or other combinational therapies. In the treatment of HCC, only 30% patients can be operated due to complication of liver cirrhosis or multiple intrahepatic tumours. Tumour cell destruction in boron neutron-capture therapy (BNCT) is due to the nuclear reaction between (10)B atoms and thermal neutrons, so it is necessary to accumulate a sufficient quantity of (10)B atoms in tumour cells for effective tumour cell destruction by BNCT. Water-in-oil-in-water (WOW) emulsion has been used as the carrier of anti-cancer agents on intra-arterial injections in clinical. In this study, we prepared (10)BSH entrapped WOW emulsion by double emulsifying technique using iodized poppy-seed oil (IPSO), (10)BSH and surfactant, for selective intra-arterial infusion to HCC, and performed simulations of the irradiation in order to calculate the dose delivered to the patients. WOW emulsion was administrated with intra-arterial injections via proper hepatic artery on VX-2 rabbit hepatic tumour models. We simulated the irradiation of epithermal neutron and calculated the dose delivered to the tissues with JAEA computational dosimetry system (JCDS) at JRR4 reactor of Japan Atomic Research Institute, using the CT scans of a HCC patient. The (10)B concentrations in VX-2 tumour obtained by delivery with WOW emulsion were superior to those by conventional IPSO mix emulsion. According to the rabbit model, the boron concentrations (ppm) in tumour, normal liver tissue, and blood are 61.7, 4.3, and 0.1, respectively. The results of the simulations show that normal liver biologically weighted dose is restricted to 4.9 Gy-Eq (CBE; liver tumour: 2.5, normal liver: 0.94); the maximum, minimum, and mean tumour weighted dose are 43.1, 7.3, and 21.8 Gy-Eq, respectively, in 40 min irradiation. In this study, we show that (10)B entrapped WOW emulsion could be applied to novel intra-arterial boron delivery carrier for BNCT, and we show the possibility to apply BNCT to HCC. We can irradiate tumours as selectively and safety as possible, reducing the effects on neighbouring healthy tissues.

Synthesis, characterization, and drug-release behavior of novel PEGylated bovine serum albumin as a carrier for anticancer agents

To develop a novel pH-sensitive PEGylated carrier for protein-based anticancer agents, we modified bovine serum albumin (BSA) with poly(ethylene glycol) citrate ester (PEG–CA) through amidation with its amino groups. Increasing the mixing ratio of albumin from 3 to 6 with respect to PEG–CA resulted in a 2-fold increase in the degree of albumin modification. Adriamycin (ADR)-loaded PEG–CA–BSA hydrogels and microparticles were prepared, and the cumulative amounts of ADR released from the PEG–CA–BSA hydrogels (phosphate-buffered saline, pH 7.4) showed that all the PEG-CA-BSA(x) (x represents degree of substitution of PEG to amino group of albumin, i.e. 26%, 28%, 31% and 49%) hydrogels had lower ADR release rates with a slight initial burst release. During the first 24 h, the cumulative releases were 15.5% for PEG–CA–BSA(49), 24% for PEG–CA–BSA(31), 31% for PEG–CA–BSA(28), and 38% for PEG–CA–BSA(26). Afterward, all the release rates slowed, and they were almost in the following order: PEG–CA–BSA(26) > PEG–CA–BSA(28) > PEG–CA–BSA(31) > PEG–CA–BSA(49). The release rates of ADR from the microparticles were dependent on the amount of glutaraldehyde. According to our findings, a higher PEG–CA/BSA molar ratio led to a reduced cumulative amount of ADR released from the hydrogels, whereas higher release rates were observed for microparticles with a lower amount of BSA in the conjugates in a pH-dependent manner. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011

1106 Cognitive study of reactivity to IPH1101 of peripheral gamma delta T lymphocytes from solid tumour patients

Hepatocellular carcinoma (HCC) is one of the most difficult to cure with surgery, chemotherapy, or other combinational therapies. In the treatment of HCC, only 30% patients can be operated due to complication of liver cirrhosis or multiple intrahepatic tumours. Tumour cell destruction in boron neutron-capture therapy (BNCT) is due to the nuclear reaction between 10B atoms and thermal neutrons, so it is necessary to accumulate a sufficient quantity of 10B atoms in tumour cells for effective tumour cell destruction by BNCT. Water-in-oil-in-water (WOW) emulsion has been used as the carrier of anti-cancer agents on intra-arterial injections in clinical. In this study, we prepared 10BSH entrapped WOW emulsion by double emulsifying technique using iodized poppy-seed oil (IPSO), 10BSH and surfactant, for selective intra-arterial infusion to HCC, and performed simulations of the irradiation in order to calculate the dose delivered to the patients.WOW emulsion was administrated with intra-arterial injections via proper hepatic artery on VX-2 rabbit hepatic tumour models. We simulated the irradiation of epithermal neutron and calculated the dose delivered to the tissues with JAEA computational dosimetry system (JCDS) at JRR4 reactor of Japan Atomic Research Institute, using the CT scans of a HCC patient.The 10B concentrations in VX-2 tumour obtained by delivery with WOW emulsion were superior to those by conventional IPSO mix emulsion. According to the rabbit model, the boron concentrations (ppm) in tumour, normal liver tissue, and blood are 61.7, 4.3, and 0.1, respectively. The results of the simulations show that normal liver biologically weighted dose is restricted to 4.9 Gy-Eq (CBE; liver tumour: 2.5, normal liver: 0.94); the maximum, minimum, and mean tumour weighted dose are 43.1, 7.3, and 21.8 Gy-Eq, respectively, in 40 min irradiation. In this study, we show that 10B entrapped WOW emulsion could be applied to novel intra-arterial boron delivery carrier for BNCT, and we show the possibility to apply BNCT to HCC. We can irradiate tumours as selectively and safety as possible, reducing the effects on neighbouring healthy tissues.

Control of polymer particle size using porous glass membrane emulsification: A review

Much attention has in recent years been paid to fine applications of polymer particles, e.g., carrier for enzyme, separation media for protein, DNA and cell, and carrier for drug in Drug Delivery System (DDS). Control of polymer particle size is especially important in such fine applications. For instance, when the particles are used as a carrier of anti-cancer agents, the locations of particles containing anti-cancer agents also depend on the size of the particles. In this paper, various techniques of controlling polymer particle size are described, with emphasis on Shirasu Porous Glass (SPG) membrane emulsification, as carried out in our research group.

Evaluation of methods for complexing prednimustine to low density lipoprotein

Many cancer cells express a higher receptor-mediated uptake of low-density lipoprotein (LDL) than normal cells. LDL has been proposed as a carrier for anticancer agents in order to improve the selectivity of cancer chemotherapeutics. In this study two reassembly and one transfer method for preparation of prednimustine-LDL complex were evaluated. All three methods gave stable complexes between drug and lipoprotein, but only the reassembly methods gave satisfactory incorporation of drug. The binding, uptake, and metabolism of the drug-LDL conjugates by T-47D breast cancer cells and GM 2000 LDL-receptor negative fibroblasts showed similar values for all three types of complexes and native LDL. Native LDL was able to compete for the cellular uptake of 125I-labelled drug-LDL complexes as well as for the 125I-labelled native LDL, strongly suggesting a LDL-receptor mediated uptake. The cytotoxicity of the complexes prepared by the reassembly methods was tested on cultured T-47D cells. The preparations showed high and similar activities with ID50 values near 2 μg/ml while the free drug gave a value of 5.1 μg/ml under the same incubation conditions. The results are discussed in terms of important factors for the successful conjugation of drugs with LDL.

モノクローナル抗体を担体としたミサイル療法とその問題点

Drug delivery system using monoclonal antibody as a carrier of anticancer agents were reviewed. The conjugates composed of antibody and anticancer agents were classified into chemoimmunoconjugate, radioimmunocojugate and immunotoxin, Experimental studies of these three types of immunoconjugates were overviewed. Selected clinical studies using immunoconjugates were introduced. And side effects, immune responses and limited clinical effects were presented. Human antimouse antibody and nonspecific uptake of immunoconjugates by normal tissues such as liver are the most important problem to resolve. Chimeric antibody and more refined immunoconjugates were doveloped for further clinical trials. Our clinical trial was carried out against colorectal carcinoma using immunoconjugate(A7-NCS) composed of anti-colorectal carcinoma monoclonal antibody A7 and anticancer drug neocarcinostatin. Objective responses were observed in 4 of 15 metastatic liver tumor, although the long time survival could not be obtained. Finally we emphasized that many problems, most of them had been evident during clinical trials, should be evercome by the cooperations of scientists in the field of immunology, biotechnology, pharmacology and clinicians.

Low density lipoprotein for delivery of a water-insoluble alkylating agent to malignant cells. In vitro and in vivo studies of a drug-lipoprotein complex

Previous studies have shown that human leukaemic cells and certain tumour tissues have a higher receptor-mediated uptake of low density lipoprotein (LDL) than the corresponding normal cells or tissues. LDL has therefore been proposed as a carrier for anti-cancer agents. In the current study, a water-insoluble mitoclomine derivative (WB 4291) was incorporated into LDL. The WB 4291-LDL complex contained about 1,500 drug molecules per LDL particle and showed receptor-mediated toxicity in vitro as judged from the difference in growth inhibitory effect on normal and mutant (LDL-receptor-negative) cultured Chinese hamster ovary cells. However, cellular drug uptake did not exclusively occur by the receptor pathway since mutant cells were also affected to some extent. The LDL part of the complex had the same plasma clearance and organ distribution as native LDL after i.v. injection in mice and rabbits. Therapeutic effects were observed when Balb-C mice with experimental leukaemia were treated with the complex. After i.p. administration to mice with i.p. leukaemia median survival time was prolonged 2.5-fold and 40% became long time survivors. The effect was weaker (42% increase in life span) after i.v. injections of the complex to mice with i.v. leukaemia.

胆汁酸をキャリアとした新規制癌剤ＣＡ１０２

Exogeneous cholic acid is known to be absorbed from the small intestine and then maintained within the enterohepatic circulation. A noble compound, CA 102(a conjugate of cholic acid which could be a carrier of anticancer agents with an alkylating agent, bis-(chloroethyl)glycine was synthesized. The antitumor activity of CA 102 was characterized in vitro and in vivo using intraportal, s. c. and i. p. implanted colon 26 and other experimental ascitic tumors including S 180, Ehrlich, P 388, M 5076. It was shown that CA 102 itself had alkylating and cytocidal activity by reaction with 4-(4-nitrobenzyl) pyridine and by growth inhibition of cultured L 1210 cells, respectively. Intraperitoneal administration of CA 102 showed strong antitumor activity in experimental ascitic tumors. And CA 102 had strong antitumor activity by p. o. administration in intraportal implanted colon 26 but had no activity in s. c. and i. p. implanted colon 26. Acute toxicity of CA 102 was examined in mice. The high value of LD50 (more than 2, 000 mg/kg(p. o.))comparing with other antitumor drugs with direct alkylating and cytocidal activities such as nitrogen mustard (1.1 mg/kg (p. o., rat)) or carboquone (5, 43 mg/kg (i. p., mouse)) was observed. These studies strongly suggest that the localized distribution of CA 102 within the enterohepatic circulation reduced the systemic toxicity and increased the selective cytotoxicity against tumor cells in the liver.