Up-regulation of folate receptor (FR) type-␤ in acute myelogenous leukemia (AML) by all-trans retinoic acid (ATRA) and its restricted normal tissue distribution makes it a potential target for therapeutic intervention. The FR-␤ in peripheral blood granulocytes was unable to bind folate and appeared to have a variant GPI membrane anchor, evident from its insensitivity to phosphatidylinositol-specific phospholipase C but not nitrous acid. Granulocyte FR-␤ lacked mutations, and neither deglycosylation nor detergent solubilization restored folate binding. The posttranslational modification causing its nonfunctionality was evi- IntroductionAcute myelogenous leukemia (AML) is the most common type of acute leukemia in adults. Standard chemotherapy results in a 70% complete remission rate in AML patients. 1 Treatment with drugs such as anthracyclines, however, is associated with severe side effects such as myelosuppression and dose-limiting cardiotoxicity and a high incidence of relapse. 2 Relapsed disease is frequently refractory to chemotherapy and exhibits multidrug resistance (MDR). 3 A potential means of treating AML is by targeted drug delivery through liposomes. Liposomal delivery of drugs has been shown to extend their systemic circulation time, reduce dose-limiting toxicity, and overcome MDR. [4][5][6][7] Liposomal anthracyclines have reached clinical use for the treatment of Kaposi sarcoma 5 and are in clinical trial for solid tumors and leukemias. [8][9][10][11][12][13][14] Liposomal delivery has also been shown to increase anthracycline cytotoxicity in tumor cells exhibiting MDR. 6,7,[15][16][17] The efficacy of liposomal drugs can potentially be further enhanced by selective targeting to tumor cells through a cell surface molecule that is differentially expressed on tumor cells. 18,19 The folate receptor (FR) is a promising target because of its narrow tissue specificity, its overexpression in malignant tissues, and its ability to bind and internalize folic acid conjugates. Of the 3 human folate receptor isoforms, 20-22 2 (FR-␣ and FR-␤) are attached to the cell surface through a glycosyl-phosphatidylinositol (GPI) membrane anchor, 20,23 whereas the third (FR-␥) is constitutively secreted. 24 The expression of FR-␣ in normal tissues is restricted to certain epithelial cells, where it is inaccessible by the circulation. 25,26 FR-␣ is found to be amplified in many epitheliallineage human tumors, including approximately 90% of ovarian carcinomas. [26][27][28][29] A wide variety of experimental therapies, 30 including drug-loaded liposomes, 31-34 have successfully targeted FR-␣ selectively in gynecologic and other tumors. The expression of FR-␤ in normal tissues is restricted to placenta and hematopoietic cells, where it is expressed in the myelomonocytic lineage and is particularly elevated during neutrophil maturation or during monocyte or macrophage activation. 29,35,36 FR-␤ is also known to be expressed in chronic myelogenous leukemia (CML) and in AML. 22,37,38 FR-␤ from membrane preparations from CML and ...

Boron neutron capture therapy (BNCT) depends on the selective delivery of a sufficient number of (10)B atoms to tumor cells to sustain a lethal (10)B(n,alpha)(7)Li reaction. Expression of FR frequently is amplified among human tumors. The goal of the present study was to investigate folate receptor (FR)-targeted liposomes as potential carriers for a series of boron-containing agents. Two highly ionized boron compounds, Na(2)[B(12)H(11)SH] and Na(3) (B(20)H(17)NH(3)), were incorporated into liposomes by passive loading with encapsulation efficiencies of 6% and 15%, respectively. In addition, five weakly basic boronated polyamines were investigated. Two were the spermidine derivatives: N(5)-(4-carboranylbutyl)spermidine.3HCl (SPD-5), N(5)-[4-(2-aminoethyl-o-carboranyl)butyl]spermidine.4HCl (ASPD-5). Three were the spermine derivatives: N(5)-(4-carboranylbutyl)spermine.4HCl (SPM-5), N(5)-[4-(2-aminoethyl-o-carboranyl)butyl]spermine.5HCl (ASPM-5), and N(5),N(10)-bis(4-carboranylbutyl)spermine.4 HCl (SPM-5,10). These were incorporated into liposomes by a pH-gradient-driven remote-loading method with varying loading efficiencies, which were influenced by the specific trapping agent and the structure of the boron compound. Greater loading efficiencies were obtained with lower molecular weight boron derivatives, using ammonium sulfate as the trapping agent, compared to those obtained with sodium citrate. The in vitro uptake of folate-derivatized, boronated liposomes was investigated using human KB squamous epithelial cancer cells, which have amplified FR expression. Higher cellular boron uptake (up to 1584 microg per 10(9) cells) was observed with FR-targeted liposomes than with nontargeted control liposomes (up to 154 microg per 10(9) cells), irrespective of the chemical form of the boron and the method used for liposomal preparation. KB cell binding of the FR-targeted liposomes was saturable and could be blocked by 1 mM free folic acid. Our findings suggest that further evaluation of FR-targeted liposomes is warranted to assess their potential as boron carriers for neutron capture therapy.

A two-step reaction sequence between artemisinin and methanolic ammonia followed by treatment with Amberlyst 15 yielded 11-azaartemisinin in 65% yield. Substituting a variety of primary alkyl- and heteroaromatic amines for ammonia in the reaction sequence yields N-substituted 11-azaartemisinins in similar or greater yield. When Amberlyst 15 is replaced by a mixture of sulfuric acid/silica gel, both 11-azaartemisinin and the expected metabolite, 10-azadesoxyartemisinin, are formed in 45% and 15% yields, respectively. In vitro and in vivo test data for a number of novel N-substituted 11-azaartemisinins, against drug-resistant strains of Plasmodium falciparum, show they possess antimalarial activities equal to or greater than that of artemisinin. The most active derivative, N-(2'-acetaldehydo)-11-azaartemisinin, 17, was 26 times more active in vitro and 4 times more active in vivo than artemisinin.

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FR-targeted liposomes are a highly efficacious vehicle for in vivo delivery of anticancer agents and have potential application in the treatment of FR(+) solid tumors.

Strategic modalities of drug delivery have the potential to greatly improve the therapeutic efficacy of available drugs in acute myelogenous leukaemia (AML). Folate receptor (FR) type beta is selectively expressed on the surface of approximately 70% of AMLs. Increased FR-beta expression in these cells can be induced by all-trans retinoic acid (ATRA) and other retinoid compounds in the absence of terminal differentiation or cell growth inhibition. An apparent post-transcriptional modification prevents FR-beta in normal haematopoietic cells from binding folate, in contrast to AML cells. FR-beta may, therefore, be used as a target for the selective delivery of chemotherapeutic drugs to AML cells; this treatment modality appears to be particularly efficacious when administered in conjunction with retinoid-induction of FR-beta. FR-targeted liposomal drug delivery can also bypass the P-glycoprotein (P-gp)-mediated drug efflux pump commonly associated with multiple drug resistance in AML. The rationale and merits of this novel experimental treatment for AML and the current status of this research are provided.

Objective. To explore the clinical effect of different delivery methods and the safety of vaginal delivery of second pregnancy after cesarean section and analyze the related factors. Methods. A total of 738 eligible pregnant women who underwent cesarean section from September 2018 to August 2020 were randomly selected from our hospital. Among them, 527 pregnant women successfully delivered vaginally were selected as the observation group, and 211 pregnant women who failed vaginal delivery were selected as the control group. To analyze the factors that influence the success of vaginal delivery of second pregnancy after cesarean section and compare the outcomes of mother and infant in two groups. Results. There was no significant difference in age, prenatal body mass index (BMI), and thickness of lower uterine segment between the two groups ( P > 0.05 ). There were significant differences in fetal head orientation, fetal abdominal circumference, fetal biparietal diameter, uterine height, premature rupture of membranes, Bishop score, and epidural anesthesia during labor between the two groups ( P < 0.05 ). Multivariate logistic regression analysis showed that fetal abdominal circumference, fetal head orientation, Bishop score, and epidural anesthesia during labor were independent factors affecting the success of VBAC ( P < 0.05 ). There was no significant difference in the incidence of uterine rupture between the two groups ( P > 0.05 ). The amount of postpartum hemorrhage in the observation group was significantly lower than that in the control group ( P < 0.05 ). There was no significant difference in Apgar score, asphyxia rate, and hospitalization rate between the two groups ( P > 0.05 ). There was no significant difference in the incidence of complications between the two groups ( P > 0.05 ). Conclusion. There are many factors that influence the success of vaginal delivery after cesarean section. Through prenatal comprehensive evaluation of vaginal delivery conditions, we can guide the parturient to choose a reasonable mode of delivery, reduce the incidence of complications, and improve the outcome of mother and baby.

Background: For enhancement of drug effectiveness and reduction of drug toxicity, liposomal drugs have been studied in laboratories and clinics for decades. Although the results obtained from in vitro are encouraging, but the results from in vivo tests were not satisfactory. The main reasons for this situation were that we do not have enough information about the way how liposomal particles penetrating into solid tumor tissue, and what happening to the liposome particles after they got into the tumor tissue. In this paper, we are going to report the results from our observations on the way folic acid targeted and non-targeted PEGyl-DSPC liposomal doxorubicin particles penetrate into solid tumor tissue.