Folate receptor fr is a cellular marker selectively overexpressed in a significant fraction of. This study attempted to prepare polyethyleneglycol modified pegylated and folate pegylated liposomes containing paclitaxel ptx in order to reduce the toxicity and improve the bioavailability and biocompatibility by targeting drugs to the lymphatics using cancer cell specific ligand folate to prevent metastasis via the lymphatic system. The first description of direct folate cytotoxic drug conjugates was by ladino et al. Intracellular uptake and intracavitary targeting of folate. Submitted in fulfillment of the academic requirements for the degree of. The folate receptor fr is overexpressed in a broad spectrum of malignant tumors and represents an attractive target for selective delivery of anticancer agents to frexpressing tumors. Mycn amplification is highly associated with malignancy and correlates with poor prognosis in patients with neuroblastoma. Folate targeted liposomes have been well considered in folate receptor fr overexpressing cells including mcf7 and 4t1 cells in vitro and in vivo. Liposomes were prepared using hspc, cholesterol, and fapegsa.
Tumour celltargeted liposomal delivery has the potential to enhance the therapeutic efficacy and reduce the toxicity of anticancer agents. A small fraction of a folatepolyethyleneglycol pegdistearoyl. This study examined the effect of polyethylene glycol peg spacer length and folate ligand density on the targeting ability of folatemodified liposomes. These bimodal liposomes were composed of both a paramagnetic and a fluorescent lipid, and utilized a peglipid amphiphile for prolonged in vivo circulation. A folate receptortargeted lipoplex delivering interleukin. Preparation, characterization and pharmacokinetics of folate. Request pdf folate receptor targeted liposomes encapsulating anticancer drugs among all available lipid based nanoparticulate systems, the success of liposomal drug delivery system is evident. Codelivery of doxorubicin and bmi1 sirna by folate receptor. This selectivity was completely inhibited with an excess of folic acid present in the cell culture media. Silencing of the mycn gene by sirna delivered by folate. Tumor marker folate receptor frtargeted fluorescent paramagnetic bimodal liposomes were synthesized to codeliver paramagnetic and fluorescence agents for magnetic resonance mr and optical bimodal imaging contrast enhancement. Gadoliniumdtpa liposomes as a potential mri contrast agent.
Microfluidic synthesis of pegylated and folate receptortargeted liposomes for drug delivery renee r. As shown in table 2, the particle size and ee of both pegylated and folatepegylated liposomes in ph 7. Targeting liposomes to the fr has been proposed as a way to enhance the effects of liposomebased chemotherapy. Folate, as a targeting ligand, offers unique advantages over immunoliposomes, i. Strategy for the treatment of acute myelogenous leukemia. The development of new treatment options is needed and efforts have focused on targeted therapies which aim to improve patient outcome by increasing antitumor activity while minimizing toxicity. This study attempted to prepare polyethyleneglycol modified pegylated and folatepegylated liposomes containing paclitaxel ptx in order to reduce the toxicity and improve the bioavailability and biocompatibility by targeting drugs to the lymphatics using cancer cell specific ligand folate to prevent metastasis via the lymphatic system. To compare the in vivo tissue distribution of folatetargeted liposomes ftls injected i. Folate receptortargeted fluorescent paramagnetic bimodal liposomes for tumor imaging nan ding1,2, yao lu1, robert j lee3, chang yang1, lei huang1, jian liu1, guangya xiang1,41school of pharmacy, tongji medical college, huazhong university of science and technology, wuhan, peoples republic of china. Folate receptor targeted imaging using poly ethylene. This study examines folatelipid conjugates as a means of enhancing the tumor selectivity of liposomeencapsulated drugs in a mouse lymphoma model. Liposomes were modified with folate derivatized peg. Folate receptortargeted quantum dot liposomes as fluorescence probes liposomes as fluorescence probes article pdf available in journal of drug targeting 177.
Cholesterol as a bilayer anchor for pegylation and targeting. In this paper, we describe the newly designed liposomes modified with amphiphilic farred squaraine dye and folic acid for its application in folate receptor targeted bioimaging. This study examined the effect of polyethylene glycol peg spacer length and folate ligand density on the targeting ability of folate modified liposomes. To compare the in vivo tissue distribution of folate targeted liposomes ftls injected i.
Full text folate receptortargeted liposomes enhanced the. Folate receptortargeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular. Strong implication for enhanced potency and safety. Preparation and evaluation of pegylated and folatepegylated. Folate receptor targeted liposomes bentham science. Folate receptor targeted imaging using pegfolate 407 weeks after kb cell implantation and at a total of 5 weeks after initiation of the folatefree diet. Codelivery of doxorubicin and bmi1 sirna by folate receptor targeted liposomes exhibits enhanced antitumor effects in vitro and in vivo.
Folatetargeted liposomes have been well considered in folate receptor fr overexpressing cells including mcf7 and 4t1 cells in vitro and in vivo. Pdf codelivery of doxorubicin and bmi1 sirna by folate. International journal of nanomedicine 20111111 folate receptor targeted fluorescent paramagnetic bimodal liposomes for tumor imaging. Tumor cell targeting is a promising drug delivery strategy. The average particle size of liposomes used in this study was approximately nm, and the folate modi.
A folate receptortargeted liposomal formulation for paclitaxel. Nan ding, yao lu, robert j lee, chang yang, lei huang, jian liu, guangya xiang. Preparation, characterization and pharmacokinetics of folate receptortargeted liposomes for docetaxel delivery guangxi zhai, 1, 2, jun wu, 1, guangya xiang, 1, 3 wenxue mao, 4 bo yu, 5, 6 hong li, 1 longzhu piao, 1 l. Folate receptor targeted bimodal liposomes for tumor. Targeting the folate receptor for the treatment of ovarian cancer. Devoe1 1university of maryland, college park, usa, 2university of maryland, baltimore, usa, 3national institute of standards and technology, usa. In this study, we prepared and characterized different targeted. Targeting the folate receptor for the treatment of ovarian. In this paper, we describe the newly designed liposomes modified with amphiphilic farred squaraine dye and folic acid for its application in folate receptortargeted bioimaging. A small fraction of a folate polyethyleneglycol pegdistearoyl.
Multimodality imaging offers unique advantages over traditional single modality imaging. Enhanced intracellular uptake of the engineered liposomes has been demonstrated on skov3 ovarian cancer cells. Farred fluorescent liposomes for folate receptortargeted. Aug 25, 2010 mycn amplification is highly associated with malignancy and correlates with poor prognosis in patients with neuroblastoma. Microfluidic synthesis of peg and folateconjugated. The liposomes were specifically targeted to breast cancer cells overexpressed folate receptor.
Each liposome preparation was assessed at concentrations ranging between 6 and 100 nmolml of phospholipid and the cellassociated. Cholesterol as a bilayer anchor for pegylation and. Based on the natural high affinity of folate for the. Improved therapeutic activity of folatetargeted liposomal. The zeta potential values of the blank liposomes figure figure1a, 1a, both plp and fplp, were higher than that of the pdnaliposome complexes fplppil15, fplppc3. To overcome these barriers, we developed a folate receptor targeted codelivery system folate doxorubicinbmi1 sirna. Folate receptortargeted fluorescent paramagnetic bimodal. Jul 15, 2002 this result also implies that the circulating folate in serum is not high enough to cause significant inhibition of the binding of folatecoated liposomes to the target cells. Apr 01, 2011 as a result, the photocytotoxicity induced by folate targeted liposomes was improved. Calf thymus dna ctdna has been shown to stimulate macrophages to produce cytokines both in vitro and in vivo when complexed with cationic liposomes. We considered that this result was due to the release of ptx which was attached to the surface of the liposomes. Folate receptor targeted imaging using peg folate 407 weeks after kb cell implantation and at a total of 5 weeks after initiation of the folate free diet. Folate receptortargeted liposomes loaded with a diacid metabolite of norcantharidin enhance antitumor potency for h22 hepatocellular carcinoma both in vitro and in vivo minchen liu, 1 lin liu, 1 xiarong wang, 1 wuping shuai, 2 ying hu, 3 min han, 1 and jianqing gao 1. This formulation was designed to overcome vehicle toxicity associated with the traditional cremophor elbased formulation and to provide the added advantages of prolonged systemic circulation time and selective targeting of the fr, which is frequently overexpressed on.
Folate receptor targeted liposomes encapsulating anticancer. Folatereceptortargeted delivery of doxorubicin nanoaggregates stabilized by doxorubicinpegfolate conjugate. Imaging of the radiolabeled conjugate after sedating the mice with ketamine mixed with xylazine, 99mtc pegfolate. Request pdf folate receptortargeted liposomes as vectors for therapeutic agents the folate receptor is a cell surface protein that has recently been identified as a tumor marker, due to its. Pdf folate receptortargeted liposomes loaded with a. Folate receptor targeted liposomes encapsulating anti. Effects of polyethylene glycol spacer length and ligand. B clinical effects of liposomes encapsulating methotrexate on arthritis. This result also implies that the circulating folate in serum is not high enough to cause significant inhibition of the binding of folatecoated liposomes to the target cells. The folate receptor is an attractive target for selective tumor delivery of liposomal doxorubicin dxr because it is abundantly expressed in a large percentage of tumors. A folate receptortargeted liposomal formulation for. Folate receptor targeted liposomes loaded with a diacid metabolite of norcantharidin enhance antitumor potency for h22 hepatocellular carcinoma both in vitro and in vivo minchen liu,1 lin liu,1 xiarong wang,1 wuping shuai,2 ying hu,3 min han,1 jianqing gao1 1institute of pharmaceutics, college of pharmaceutical sciences, 2first affiliated hospital, college of medicine, zhejiang university. To overcome these barriers, we developed a folate receptor targeted codelivery system folatedoxorubicinbmi1 sirna. Devoe1 1university of maryland, college park, usa, 2university of maryland, baltimore, usa, 3national institute of.
Folate receptortargeted liposomes loaded with a diacid metabolite of norcantharidin enhance antitumor potency for. As a result, the photocytotoxicity induced by folatetargeted liposomes was improved. Triggered drug release was obtained with nir laser irradiation. Folate receptortargeted liposomes as vectors for therapeutic. Bmi1 gene overexpression is found in various human tumors and has been shown as a potential target for gene treatment. Pdf delivery of calf thymus dna to tumor by folate. On page 2425, right column, line 7, the sentence however, cholesterol. On the basis of the epr effect, liposomes further modified by tumoractivetargeted ligands such as antibodies, peptides, and small compounds like folate have been widely investigated. Folate receptor targeted gene delivery using cationic. This article is from international journal of nanomedicine, volume 9. Folate receptor targeted bimodal liposomes for tumor magnetic resonance imaging. Novel folate receptortargeted lipsomes encapsulated with small size gold nanorods and doxorubicin were developed.
Preparation, characterization and pharmacokinetics of. Antitumor activity of folate receptortargeted liposomal. Folate receptor targeted liposomes encapsulating anticancer drugs volume. A in vivo uptake specificity of fluorescently labeled liposomes 30 min.
The objective of this study is to design an optimum folate targeted liposomal formulations which show the best liposome cell uptake to tumor cells. Based on the natural high affinity of folate for the folate receptor protein fr, which is commonly expressed on the. Folate receptortargeted liposomes loaded with a diacid. Preparation and evaluation of pegylated and folate. Targeted delivery via selective cellular markers can potentially increase the efficacy and reduce the toxicity of therapeutic agents. In addition, direct cytotoxicity of ctdna has been found in tissue culture and in mice. Doctor of philosophy in the discipline of biochemistry, school of life sciences. Liposomes were modified with folatederivatized peg. Folate targeting is a method utilized in biotechnology for drug delivery purposes. Receptorbased tumorselective delivery of therapeutic agents. Pdf folate receptor targeted bimodal liposomes for tumor.
Tumourselective drug delivery via folate receptortargeted liposomes. In addition to evaluating the microfluidic technology as a suitable method for online formation of functionalized liposomes, this work presents several ancillary advancements over previous. Imatinib inhibits plateletderived growth factor receptor pdgfr, and. This increase in liposome uptake could be blocked by 1 mm free folate.
New folate receptor targeted nano liposomes for delivery. Pdf folate receptortargeted liposomes loaded with a diacid. Effectsofpolyethyleneglycolspacerlengthandliganddensity. Oc1 folatetargeted liposomes for rheumatoid arthritis. Preparation and characterization of liposomes and lipoplexes. Prospects in folate receptortargeted radionuclide therapy. Discipline of biochemistry, school of life sciences, westville campus, university of kwazulu natal, durban 4000, south africa. Pdf folate receptortargeted quantum dot liposomes as. Plp and fplp were produced using a film hydration method as previously described 17, 19, 38. Folate receptor targeted liposomes loaded with a diacid metabolite of norcantharidin enhance antitumor potency for h22 hepatocellular carcinoma both in vitro and in vivo minchen liu, 1 lin liu, 1 xiarong wang, 1 wuping shuai, 2 ying hu, 3 min han, 1 and jianqing gao 1. But ee had tendency to be slightly decreased as time went by. Fluorescence microscopy demonstrated differing intracellular fluorescence distributions for targeted phsensitive and nonphsensitive liposomes. The folate receptor is overexpressed in a broad spectrum of malignant tumors and represents an attractive target for selective delivery of anticancer agents to folate receptorexpressing tumors.
Low, involves the attachment of the vitamin, folate, to a moleculedrug to form a folate conjugate. Targeting liposomes to the fr has been proposed as a way to enhance the effects of. Liposomes incorporating a lipophilic folate derivative, such as folate pegdspe or folate pegchol, have been shown to efficiently deliver antitumor agents into frbearing tumor cells via receptor mediated endocytosis. Moreover, a549 cells folate receptor deficient cells have. Incorporation of folate constructs onto the surface of drugloaded liposomes was shown to dramatically improve the potency and specificity of the liposomes against frpositive tumor cells 28,29. While conventional therapies have improved the outcome for patients with ovarian cancer, the disease still accounts for the most gynecological cancerrelated deaths. The median serum folate level in humans has shown an increase since the fda recommended dietary folate supplementation in the late 1990s from 12. Receptortargeted delivery of liposomes via folate pegchol article in journal of liposome research 1023. This trojan horse process, which was created by drs. Pdf formulation strategies for folatetargeted liposomes and. Strong implication for enhanced potency and safety author links open overlay panel somayeh handali a eskandar moghimipour a b maryam kouchak a zahra ramezani a mohsen amini c kambiz ahmadi angali d sadegh saremy b farid abedin dorkoosh e f mohsen rezaei g. Pdf the folate receptor fr is a tumorassociated antigen that can bind with folic acid fa and its conjugates with high affinity and ingests. In vivo fate of folatetargeted polyethyleneglycol liposomes.
The folate receptor fr has two glycosyl phosphatidylinositol gpianchored isoforms. Folate receptor targeted gene delivery using cationic liposomes as nonviral vectors s. Efficient intracellular drug and gene delivery using folate. Folate receptortargeted liposomes loaded with a diacid metabolite of norcantharidin enhance antitumor potency for h22 hepatocellular carcinoma both in vitro and in vivo minchen liu,1 lin liu,1 xiarong wang,1 wuping shuai,2 ying hu,3 min han,1 jianqing gao1 1institute of pharmaceutics, college of pharmaceutical sciences, 2first affiliated hospital, college of medicine, zhejiang university. A novel micellar drug delivery approach shiladitya bhattacharya, xiaoling li, janakiram nyshadham and bhaskara jasti department of pharmaceutics and medicinal chemistry, thomas j. Anticancer drugs, drug encapsulation, folate receptor targeting, liposomes, ovarian cancer. However, sirnabased treatments targeting bmi1 gene have been restricted to limited delivery, low bioavailability and hence relatively reduced efficacy. Folate receptor targeting liposomes reduce intratumoral accumulation. New folate receptor targeted nano liposomes for delivery of 5fluorouracil to cancer cells. More than 80% of folate ligand was inserted in liposomes at each ratio, which was. Therefore, combining phsensitive formulations with fr targeting could potentially improve drug or gene delivery to. Receptortargeted delivery of liposomes via folatepeg.
The fr is overexpressed on several cancer cell types including breast, ovarian, endometrial, brain, and bladder cancer. Folate targeted bimodal paramagnetic and fluorescent liposomes were developed and showed enhanced accumulation in a folate receptor expressing tumor model. Uptake of folatetargeted radiolabeled liposomes into j6456fr lymphoma cells. Folate receptortargeted liposomes enhanced the antitumor. Folate receptor targeting of radiolabeled liposomes reduces. Imaging of the radiolabeled conjugate after sedating the mice with ketamine mixed with xylazine, 99mtc peg folate was administered intravenously via a tail vein to the animals. Formulation strategies for folatetargeted liposomes and. Long school of pharmacy, 751 brookside road, university of the pacific, stockton, ca, usa for correspondence bjasti. Codelivery of doxorubicin and bmi1 sirna by folate. Folatetargeted bimodal paramagnetic and fluorescent liposomes were developed and showed enhanced accumulation in a folate receptor expressing tumor model. Folate receptor targeted imaging using poly ethylene glycol. In vivo specific targeting and prophylactic efficiency of folate receptortargeted liposomes in arthritic mice. Folate receptor targeted bimodal liposomes for tumor magnetic. These bimodal liposomes were composed of both a paramagnetic and a fluorescent lipid, and utilized a peg.
Efficient intracellular drug and gene delivery using. Moreover, a549 cells folate receptor deficient cells have not shown variations in the liposomal incorporation. A novel liposomal formulation of paclitaxel targeting the folate receptor fr was synthesized and characterized. We developed a novel liposomemycn sirnafolic acid complex, and the transfection efficacy was measured in lan5 cells by cy3 fluorescence density in each microgram of protein from the transfected cell lysate.
The folate receptor fr is a tumorassociated antigen that can bind with folic acid fa and its conjugates with high affinity and ingests. Codelivery of doxorubicin and bmi1 sirna by folate receptor targeted liposomes exhibits enhanced antitumor effects in vitro and in vivo tan yang1, 1bin li 1, 1shibo qi, yong liu, yongkang gai1, peng ye1, guang yang, wendian zhang1, peng zhang2, xingxing he3, weijie li4, zhiping zhang1, guangya xiang1, chuanrui xu1 1. Low, involves the attachment of the vitamin, folate folic acid, to a moleculedrug to form a folate conjugate. These studies suggest that cholesterol is a viable bilayer anchor for synthesis of pegylated and. New folate receptor targeted nano liposomes for delivery of 5.