甘草次酸修饰姜黄素阳离子脂质体对肿瘤Walker256细胞的影响

目的：研究姜黄素及甘草次酸修饰姜黄素阳离子脂质体对Walker256细胞的影响。方法：不同浓度姜黄素与甘草次酸修饰姜黄素阳离子脂质体处理Walker256细胞后,采用CCK-8法检测细胞增殖抑制率;用流式细胞仪检测细胞吸收、细胞周期变化情况;Annexin V/PI双染法检测细胞凋亡;Western blot检测Wnt及β-catenin表达水平。结果：姜黄素和甘草次酸修饰姜黄素阳离子脂质体对肿瘤细胞Walker256均具有明显的抑制作用。与游离姜黄素相比,甘草次酸修饰姜黄素阳离子脂质体明显增强细胞对姜黄素的吸收,显著增强对Walker256细胞的增殖抑制、凋亡、细胞周期G2期的阻滞作用,明显下调Wnt及β-catenin的表达。结论：甘草次酸修饰姜黄素阳离子脂质体比游离姜黄素具有更强的抗肿瘤Walker256细胞的作用。     

和厚朴酚脂质体的制备及其体内外抗乳腺癌作用研究

目的 制备和厚朴酚脂质体（HK-Lipsomes）,探讨其对小鼠乳腺癌细胞（4T1细胞）的体内外生长抑制作用。方法 将蛋黄卵磷脂、胆固醇、mPEG2000-DSPE2000、和厚朴酚按照质量比3：1：1：1,以注入法制备成和厚朴酚脂质体。通过Zetasizer nano ZS测定和厚朴酚脂质体的粒径,透射电镜观察和厚朴酚脂质体的形态。用噻唑蓝（MTT）比色法评价和厚朴酚脂质体对4T1细胞的细胞毒性。建立小鼠4T1乳腺癌肿瘤模型,以紫杉醇注射液为阳性对照,考察腹腔给药后和厚朴酚脂质体对肿瘤的抑制作用。结果 制备得到的和厚朴酚脂质体的平均粒径为（113.8±0.2）nm,多分散指数（0.209±0.005）,电位为（-30.7±2.4）mV,透射电镜观察和厚朴酚脂质体为球型。和厚朴酚溶液和脂质体对4T1细胞的IC₅₀值分别为（43.74±2.38）μg/mL和（12.52±2.24）μg/mL。和厚朴酚脂质体高（60 mg/kg）、中（40 mg/kg）、低（20 mg/kg）剂量组的抑瘤率分别为85.19%、60.95%和37.83%,呈剂量相关性。结论 实验使用较为简便的制备方法成功制备粒径较小、包封率高的和厚朴酚脂质体。荷瘤小鼠体内实验显示抑瘤效果良好。     

大豆糖苷修饰阳离子脂质体的体外肝细胞靶向性

目的研究肝靶向物质大豆糖苷(soybean-derived sterylglucoside,SG)的加入对阳离子脂质体肝细胞靶向性的影响。方法以荧光素钠(FS)为模型药物，采用HepG₂ 2.2.15细胞模型和SD雄性大鼠，检测SG，SG/Brij-35(卞泽-35)和SG/PEG-DSPE(polyethylene glycol-distearoylphosphatidylethanolamine)修饰的阳离子脂质体的物理化学性质，在细胞培养水平和离体肝脏水平考察阳离子脂质体的转染和肝细胞选择性。结果未修饰以及SG，SG/Brij-35和SG/PEG-DSPE修饰的FS阳离子脂质体在中性溶液中的包封率分别为91.74%，88.46%，89.70%和83.12%，粒径分别为124.4，113.7，110.8和93.0 nm，空白脂质体在溶液中表面电荷为正。细胞培养和肝脏灌流结果说明，阳离子脂质体的转染率显著高于中性脂质体，SG单独修饰后的阳离子脂质体的细胞转染率较未修饰有显著提高，SG/Brij-35修饰的阳离子脂质体则表现出肝实质细胞选择性。结论阳离子脂质体可以促进FS进入肝脏细胞，具有较高的肝细胞摄取率，而SG/Brij-35的修饰可以提高脂质体的肝细胞选择性。     

乳腺癌血管生成拟态与MVD、MMP-2表达及预后的关系

目的:研究乳腺癌中是否存在血管生成拟态(VM),及其与基质金属蛋白酶(MMP-2)表达及预后的关系。方法:选取乳腺癌石蜡标本180例,进行PAS和CD34双重染色,观察是否存在VM;然后对存在VM者和对照组进行MMP-2染色、乳腺癌微血管密度(MVD)计数以及随访,并比较他们之间的相互关系。结果:9例标本中存在VM。VM组的生存率和MVD值明显低于无血管生成VM组。而VM组的MMP-2值明显高于无VM组。结论:乳腺癌中存在VM,可能是高度恶性生物学行为的基础之一。     

Development and characterization of octreotide-modified curcumin plus docetaxel micelles for potential treatment of non-small-cell lung cancer

We prepared octreotide (OCT)-modified curcumin plus docetaxel micelles to enhance active targeting and inhibit tumor metastasis by destroying vasculogenic mimicry (VM) channels. Soluplus was applied as an amphiphilic material to form micelles via film dispersion. The cytotoxic effects, active cellular targeting, and inhibitory effects on metastasis were systematically evaluated in vitro using A549 cells, and in vivo antitumor effects were evaluated using xenograft tumor-bearing mice. In vitro assays indicated that the OCT-modified curcumin plus docetaxel micelles showed robust cytotoxicity on A549 cells and effectively inhibited VM channels and tumor metastasis. Studying the mechanism of action indicated that OCT-modified curcumin plus docetaxel micelles downregulated MMP-2 and HIF-1α. In vivo assays indicated that OCT-modified curcumin plus docetaxel micelles increased drug accumulation at tumor sites and showed obvious antitumor efficacy. The developed OCT-modified curcumin plus docetaxel micelles may offer a promising treatment strategy for non-small-cell lung cancer.     

培美曲塞-磷脂偶联物修饰的靶向性舒尼替尼与长春瑞滨脂质体的研制及其在体外对耐药性乳腺癌的抑制效应

乳腺癌是女性最易罹患的疾病,而肿瘤多药耐药性通常是化疗失败的主要原因。本研究以培美曲塞（PMT）和DSPE-PEG2000-NH2为原料合成了新的靶向性偶联物DSPE—PEG2000．PMT,并将其修饰到脂质体表面,制备了同时包封有舒尼替尼与长春瑞滨的靶向性脂质体,以增强化疗药物对多药耐药性乳腺癌的治疗效果。经过质谱分析证实,合成的靶向性载体材料DSPE．PEG2000-PMT与目标产物相符。建立了可同时检测舒尼替尼和长春瑞滨含量的高效液相色谱分析方法,检测波长为215nm,柱温30℃,流动相为乙腈-0．05MKH2P04（pH3．5）-三乙胺（35：65：0．3,v／v／v）。舒尼替尼和长春瑞滨的最低检测浓度分别为25ng／mL和5ng／mL,最低定量浓度均为0．25μg／mL。两药在0．5-25．0μg／mL范围内线性良好。各脂质体包封率均大于90％,粒径均-（～90nm）,Zeta电位略显负电性。在体外耐药乳腺癌MCF-7／Adr细胞中评价了靶向性舒尼替尼与长春瑞滨脂质体的抗增殖效应。结果显示,同对照组相比,靶向性舒尼替尼与长春瑞滨脂质体对MCF-7／Adr细胞具有最强的抑制增殖效应。以靶向性香豆素脂质体为荧光探针,考察了靶向性脂质体在耐药乳腺癌MCF-7／Adr细胞中的靶向性,同非靶向性制剂相比,靶向脂质体在耐药性癌细胞中摄取最多。因此,制备的靶向性舒尼替尼与长春瑞滨脂质体是-种新的靶向制剂,能够被耐药乳腺癌细胞靶向性摄取,可在体外显著抑制耐药性乳腺癌生长,从而为耐药乳腺癌的化学治疗提供了-种新的策略。     

The efficacy of WGA modified daunorubicin anti-resistant liposomes in treatment of drug-resistant MCF-7 breast cancer

Background: Breast cancer is the most common malignancy and remains a leading cause of cancer-related deaths in female. Chemotherapy failure of breast cancer is mainly associated with multidrug resistance of cancer cells.

Purpose: The WGA modified daunorubicin anti-resistant liposomes were developed for circumventing the multidrug resistance and eliminating cancer cells.

Methods: WGA was modified on liposomal surface for increasing the intracellular uptake. Tetrandrine was inserted into the phospholipid bilayer for reversing cancer drug-resistance, and daunorubicin was encapsulated in liposomal aqueous core as an anticancer agent. Evaluations were performed on MCF-7 cells, MCF-7/ADR cells and xenografts of MCF-7/ADR cells.

Results: In vitro results showed that WGA modified daunorubicin anti-resistant liposomes exhibited suitable physicochemical properties, significantly increased intracellular uptake in both MCF-7 cells and MCF-7/ADR cells, and circumvented the multidrug resistance via inhibiting P-gp. In vivo results demonstrated that the targeting liposomes showed a long-circulatory effect in blood system, and could remarkably accumulate at the tumor location. The involved action mechanisms for the enhanced anticancer efficacy were activation of pro-apoptotic proteins (Bax and Bok), apoptotic enzymes (caspase 8, caspase 9 and caspase 3).

Conclusion: The established WGA modified daunorubicin anti-resistant liposomes could provide a potential strategy for treating resistant MCF-7 breast cancer.     

Augmented efficacy and the mechanism of a combined use of daunorubicin with rofecoxib in treatment of triple-negative breast cancer

Triple-negative breast cancer is the tumor that lacks expressions of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). A regular chemotherapy cannot eradicate triple-negative breast cancer. In the present study, we aimed to develop a combined use of daunorubicin and rofecoxib to treat triple-negative breast cancer, and reveal the underlying mechanisms. A gradient elution HPLC-UV method was developed for quantification, and the evaluations were performed on the triple-negative breast cancer MDA-MB-231 cells using a high content screening system. The results demonstrated that daunorubicin alone was insensitive to the triple negative breast cancer cells, while the combined use of daunorubicinand rofecoxib was able to effectively kill these triple-negative cancer cells, exhibiting a rofecoxib concentration-dependent manner. The mechanism revealed that the augmented anticancer efficacy was associated with direct killing effect, inducing apoptosis and inducing autophagy by the combination treatment. Besides, the apoptosis signaling pathways were correlated to a cascade of reactions by activating apoptotic enzyme caspase family and by suppressing anti-apoptotic gene expressed protein Bcl-2 family. In conclusion, this study provided a fundamental evidence for further developing the combined use of daunorubicin and rofecoxib formulation, hence offering a promising strategy for eradicating the triple negative breast cancer.     

Hyaluronic acid modified chitosan nanoparticles for effective management of glaucoma: development,characterization, and evaluation

In clinical practices, solution of dorzolamide hydrochloride (DH) and timolol maléate (TM) is recommended for the treatment of glaucoma. However, low drug-contact time and poor ocular bioavailability of drugs due to drainage of solution, tear turnover and its dilution or lacrimation limits its uses. In addition, systemic absorption of TM may induce undesirable cardiovascular side effects. Chitosan (CS) is a polycationic biodegradable polymer which provides sustained and local delivery of drugs to the ocular sites. Hyaluronic acid (HA) also provides synergistic effect for mucoadhesion in association with chitosan. In the present study, hyaluronic acid modified chitosan nanoparticles (CS-HA-NPs) loaded with TM and DH were developed and characterized. The CS-HA-NPs were evaluated for size, shape, zeta potential, entrapment efficiency, and mucoadhesive strength. The in vitro release study was also performed in PBS pH 7.4. The ocular irritation potential of CS-HA-NPs was estimated using draize test on albino rabbits. A significant reduction in IOP level was obtained using CS-HA-NPs as compared to plain solution of drug and a comparable higher reduction in IOP level was observed as to CS-NPs. These results suggest that HA potentialy enhance the mucoadhesiveness and efficiency of CS-NPs and may be promising carrier for ocular drug delivery.     

Estrogen-functionalized liposomes grafted with glutathione-responsive sheddable chotooligosaccharides for the therapy of osteosarcoma

An estrogen (ES)-functionalized cationic liposomal system was developed and exploited for targeted delivery to osteosarcoma. Natural biocompatible chotooligosaccharides (COS, MW2-5?KDa) were covalently tethered to the liposomal surface through a disulfate bond (-SS-) to confer reduction-responsive COS detachment, whereas estrogen was grafted via polyethylene glycol (PEG 2?K) chain to achieve estrogen receptor-targeting. The liposomal carriers were prepared by the ethanol injection method and fluorescent anticancer drug doxorubicin (DOX) was loaded with ammonium sulfate gradient. The physicochemical properties, reduction-sensitivity, and the roles of estrogen on cellular uptake and tumor-targeting were studied. The Chol-SS-COS/ES/DOX liposomes were spherical with an average size about 110?nm, and high encapsulation efficiency. The liposomes were stable in physiological condition but rapidly release the payload in response to tumoral intracellular glutathione (20?mM). MTT cytotoxicity assay confirmed that Chol-SS-COS/ES/DOX liposomes exhibited higher cytotoxicity to MG63 osteosarcoma cells than to liver cells (LO2). Flow cytometry (FCM) and confocal laser scanning microscopy revealed that cellular uptake of Chol-SS-COS/ES/DOX liposomes by MG63, than the free DOX or Chol-SS-COS/DOX. Ex vivo fluorescence distribution study showed that the multifunctional liposomes selectively accumulated in the MG63 xenografts versus the organs. Chol-SS-COS/ES/DOX liposomes strongly inhibited the tumor growth and enhanced the animal survival rate. Overall, the COS grafted estrogen-functionalized cationic liposomes, fortified with glutathione-responsiveness, showed great potential for specific intracellular drug delivery to estrogen receptor-expressing tumors such as osteosarcoma.     

Transferrin and octaarginine modified dual-functional liposomes with improved cancer cell targeting and enhanced intracellular delivery for the treatment of ovarian cancer

Off-target effects of drugs severely limit cancer therapy. Targeted nanocarriers are promising to enhance the delivery of therapeutics to tumors. Among many approaches for active tumor-targeting, arginine-rich cell penetrating peptides (AR-CPP) and ligands specific to target over-expressed receptors on cancer-cell surfaces, are popular. Earlier, we showed that the attachment of an AR-CPP octaarginine (R8) to the surface of DOXIL^® (Doxorubicin encapsulated PEGylated liposomes) improved cytoplasmic and nuclear DOX delivery that enhanced the cytotoxic effect in vitro and improved therapeutic efficacy in vivo. Here, we report on DOX-loaded liposomes, surface-modified with, R8 and transferrin (Tf) (Dual DOX-L), to improve targeting of A2780 ovarian carcinoma cells via the over-expressed transferrin receptors (TfRs) with R8-mediated intracellular DOX delivery. Flow cytometry analysis with fluorescently labeled DualL (without DOX) showed two-fold higher cancer-cell association than other treatments after 4?h treatment. Blocking entry pathways of R8 (macropinocytosis) and Tf (receptor-mediated endocytosis, RME) resulted in a decreased cancer-cell association of DualL. Confocal microscopy confirmed involvement of both entry pathways and cytoplasmic liposome accumulation with nuclear DOX delivery for Dual DOX-L. Dual DOX-L exhibited enhanced cytotoxicity in vitro and was most effective in controlling tumor growth in vivo in an A2780 ovarian xenograft model compared to other treatments. A pilot biodistribution study showed improved DOX accumulation in tumors after Dual DOX-L treatment. All results collectively presented a clear advantage of the R8 and Tf combination to elevate the therapeutic potential of DOX-L by exploiting TfR over-expression imparting specificity followed by endosomal escape and intracellular delivery via R8.     

Construction of folate-conjugated epirubicin liposomes for enhancing the cellular uptake and the co-localization with nuclei of invasive breast cancer cells

Drug resistance of anthracycline in the invasive cancer is associated with the lowered cellular drug uptake and diminished co-localization of drug with nuclei. In the present study, we aimed to construct the folate-conjugated epirubicin liposomes by incorporating a synthesized folate-lipid derivative; and to assess the effects on cellular drug uptake, co-localization of drug with nuclei and efficacy in treatment of invasive breast cancer cells. The studies were performed on invasive human breast cancer cells. The folate-PEG₂₀₀₀-DSPE conjugate was synthesized, and the constructed folate-conjugated epirubicin liposomes were approximately 100 nm in size. The in vitro studies demonstrated that the folate-conjugated epirubicin liposomes had the strongest cellular drug uptake and co-localization with nuclei of the invasive breast cancer cells. Besides, the liposomes displayed the most significant efficacy in killing the invasive cancer cells, in preventing their invasive potential, and in penetrating ability into breast cancer spheroid as well. In conclusion, the constructed folate-conjugated epirubicin liposomes were able to enhance the efficacy in treatment of invasive breast cancer by improving the cellular drug uptake and increasing the co-localization with nuclei, hence offering a new strategy for potentially eradicating the invasive breast cancer cells.     

Dasatinib self-assembled nanoparticles decorated with hyaluronic acid for targeted treatment of tumors to overcome multidrug resistance

Multidrug resistance (MDR) and lack of targeting specificity are the main reasons why traditional drug therapies fail and produce toxic side effects in cancer chemotherapy. In order to increase targeting specificity and maximize therapeutic efficacy, new intelligent drug delivery systems are needed. In this study, we prepared the hyaluronic acid (HA) conjugated dasatinib (DAS) and D-α-tocopherol acid polyethylene glycolsuccinate (TPGS) copolymer nanoparticles (THD-NPs). The water solubility of the hydrophobic drug DAS was improved by chemically linking with HA. HA can bind to the over-expressed CD44 protein of tumor cells to increase targeting specificity, TPGS can inhibit the activity of P-glycoprotein (P-gp), and increase the intracellular accumulation of drugs. The prepared drug-loaded nanoparticle has a particle size of 82.23 ± 1.07 nm with good in vitro stability. Our in vitro studies showed that THD-NPs can be released more rapidly in a weakly acidic environment (pH = 5.5) than in a normal physiological environment (pH = 7.4), which can realize the selective release of nanoparticles in tumor cells. Compared to free drugs, THD-NPs showed more efficient cellular uptake, effectively increased the cytotoxic effect of DAS on nasopharyngeal carcinoma HNE1 cells drug resistance HNE1/DDP cells and increased the accumulation of drugs in HNE1/DDP cells, which may be due to the inhibitory effect of TPGS on the efflux function of P-gp. In vivo experiments showed that THD-NPs can effectively inhibit tumor growth without obvious side effects. In conclusion, the targeted and pH-sensitive nanosystem, we designed has great potential to overcome drug resistance and increase therapeutic effects in cancer treatment.     

吉西他滨联合顺铂治疗多药耐药的晚期乳腺癌的临床观察

目的观察吉西他滨联合顺铂方案治疗蒽环类及紫杉类耐药晚期乳腺癌的疗效与安全性。方法2007年1月～2008年4月以吉西他滨联合顺铂方案治疗蒽环类及紫杉类耐药晚期乳腺癌15例,吉西他滨1000 mg.m-2静滴,第1、8天,顺铂25 mg.m-2,静脉滴注,第1～3天;每21 d为一周期,至少治疗2周期。结果全组患者均可评价疗效,其中完全缓解（CR）1例（6.7%）,部分缓解（PR）6例（40.0%）,稳定（SD）5例（33.3%）,进展（PD）3例（20.0%）,总有效率（ORR）46.7%,TTP6.4月,MST13.2月;Ⅲ～Ⅳ度毒性反应分别为血小板减少20.0%,白细胞减少26.7%,恶心或呕吐13.3%。结论吉西他滨和顺铂联合方案治疗蒽环类及紫杉类耐药晚期乳腺癌的疗效较好,使用方便,毒性反应较轻,是蒽环类及紫杉类耐药晚期乳腺癌的有效解救治疗方案。     

Combination immunotherapy of chlorogenic acid liposomes modified with sialic acid and PD-1 blockers effectively enhances the anti-tumor immune response and therapeutic effects

Melanoma is one of the most common malignant tumors. The anti-PD-1 antibody is used for the treatment of metastatic melanoma. Treatment success is only 35–40% and a range of immune-related adverse reactions can occur. Combination of anti-PD1 antibody therapy with other oncology therapies has been attempted. Herein, we assessed whether chlorogenic acid liposomes modified with sialic acid (CA-SAL) combined with anti-PD1 antibody treatment was efficacious as immunotherapy for melanoma. CA-SAL liposomes were prepared and characterized. In a mouse model of B16F10 tumor, mice were treated with an anti-PD1 antibody, CA-SAL, or combination of CA-SAL + anti-PD1 antibody, and compared with no treatment controls. The tumor inhibition rate, tumor-associated macrophages (TAMs) phenotype, T-cell activity, and safety were investigated. We observed a significant decrease in the proportion of M2-TAMs and CD4⁺Fop3⁺ T cells, while there was a significant increase in the proportion of M1-TAMs and CD8⁺ T cells, and in the activity of T cells, and thus in the tumor inhibition rate. No significant toxicity was observed in major organs. CA-SAL and anti-PD1 Ab combination therapy presented synergistic anti-tumor activity, which enhanced the efficacy of the PD-1 checkpoint blocker in a mouse model of melanoma. In summary, combination immunotherapy of CA-SAL and anti-PD1 Ab has broad prospects in improving the therapeutic effect of melanoma, and may provide a new strategy for clinical treatment.     

A novel type of functional epirubicin liposomes modified with DSPE-PEG2000-cyclopamine conjugate for eliminating heterogeneous breast cancer cells

Common chemotherapy is unable to eliminate the heterogeneous side population of cancer cells (such as cancer stem-likecells), resulting in poor prognosis. The heterogeneity of cancer cells causes an extensive multidrug resistance through the aberrantly active Hedgehog (Hh) signaling pathway. Cyclopamine is a chemical compound that can block Hh signaling pathway, and a combination use of cyclopamine with anticancer drug would be beneficial for killing heterogeneous cancer cells. In the present study, we aimed to develop a kind type of functional drug liposomes for eliminating heterogeneous cancer. The study was performed on human breast cancer cells. A distearoylphosphoethanolamine polyethylene glycol (DSPE-PEG₂₀₀₀)-cyclopamine conjugate was newly synthesized by a nucleophilic substitution reaction, and confirmed by MALDI-TOF mass. An HPLC method was established and validated for qualification of epirubicin. Functional epirubicin liposomes were successful constructed by modifyingwith DSPE-PEG₂₀₀₀-cyclopamine, displaying a particle size in nano-scale (approximately 98 nm) and a high epirubicin encapsulation (>97%). The CD44+/CD24-side population was characterized in defining heterogeneous breast cancer cells. As compared with regular epirubicin liposomes, functional epirubicin liposomes exhibited an evidently enhanced cellular drug uptake and a significant killing effect in overall breast cancer cells. In conclusion, the functional epirubicin liposomes could be a useful drug delivery carrier for eliminating heterogeneous breast cancer cells.     

Zoledronic acid for the treatment of prostate cancer

Introduction: Prostate cancer remains the most common solid tumor afflicting men in the developed world. Metastatic prostate cancer is a source of great morbidity and mortality especially due to osseous involvement that gives rise to significant symptoms of pain or pathologic fractures or cord compression. Bisphosphonates had been widely used in the treatment of metastatic prostate bone metastases given their demonstrated benefit with a delay of skeletal-related events (SREs) but without prostate-specific antigen (PSA) response or overall survival benefit.

Areas covered: In this review, the authors summarize the available literature on the clinical studies that led to the development and regulatory approval of zoledronic acid in men with metastatic prostate cancer. The authors also provide their expert opinion and future perspectives on this therapeutic.

Expert opinion: Zoledronic acid is an established adjunctive treatment and bone-targeted therapy for the supportive care of men with metastatic castration-resistant prostate cancer. Efforts to study its utility in earlier phases of metastatic hormone-sensitive prostate cancer has not shown superior outcomes compared with standard androgen deprivation therapy (ADT) or docetaxel alone.     

The role of zoledronic acid in the adjuvant treatment of breast cancer: current perspectives

Importance of the field: Breast cancer is one of the leading causes of cancer-related deaths in the world. Despite the significant improvements in the adjuvant treatment strategies of early-stage breast cancer, many patients experience relapse. Bisphosphonates are widely used in the treatment of bone metastasis of solid tumors and multiple myeloma, as well as in osteoporosis. The results of clinical studies of adjuvant treatment on early-stage hormone-receptor-positive breast-cancer patients under hormonal treatment – especially with the bisphosphonate zoledronic acid – caused excitement because they demonstrated an additive effect on decreasing disease relapses at bone or other sites. A number of clinical and in vitro and in vivo preclinical studies, which are either ongoing or have just ended, are investigating the mechanisms and antitumoral activity of bisphosphonates.

Areas covered in this review: The current literature on the preclinical and clinical studies into antitumoral effect and adjuvant treatment of bisphosphonates, especially zoledronic acid, are summarized. Data in the literature over the last two decades were also reviewed.

What the reader will gain: The reader will find a summary of preclinical and clinical studies of antitumoral effect and adjuvant treatment with bisphosphonates, in particular zoledronic acid, as well as ongoing trials about adjuvant treatment of breast cancer with zoledronic acid and ibandronate.

Take home message: Current evidence supports zoledronic acid as an effective treatment in adjuvant breast-cancer therapy for hormone-receptor-positive breast-cancer patients when added to hormonotherapy. Uncertainty about effects of zoledronic acid and other bisphosphonates will be clarified after completion of ongoing trials.     

Co-delivery of gambogic acid and TRAIL plasmid by hyaluronic acid grafted PEI-PLGA nanoparticles for the treatment of triple negative breast cancer

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based combination therapy and gene therapy are new strategies to potentially overcome the limitations of TRAIL, however, the lack of efficient and low toxic vectors remains the major obstacle. In this study, we developed a hyaluronic acid (HA)-decorated polyethylenimine-poly(d,l-lactide-co-glycolide) (PEI-PLGA) nanoparticle (NP) system for targeted co-delivery of TRAIL plasmid (pTRAIL) and gambogic acid (GA) in triple-negative breast cancer (TNBC) therapy. GA was encapsulated into the core of the PEI-PLGA NPs while pTRAIL was adsorbed onto the positive NP surface via charge adsorption. The coating of HA on PEI-PLGA NPs functions as a targeting ligand by binding to CD44 receptor of TNBC cells and a shell to neutralize the excess positive charge of inner NPs. The resultant pTRAIL and GA co-loaded HA-coated PEI-PLGA NPs exhibited spherical shape (121.5?nm) and could promote the internalization of loaded cargoes into TNBC cells through the CD44-dependent endocytic pathway. The dual drug-loaded NPs significantly augmented apoptotic cell death in vitro and inhibited TNBC tumor growth in vivo. This multifunctional NP system efficiently co-delivered GA and pTRAIL, thus representing a promising strategy to treat TNBC and bringing forth a platform strategy for co-delivery of therapeutic DNA and chemotherapeutic agents in combinatorial TNBC therapy.     

Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment

Abstract

Engineered nanoparticles are widely used for delivery of drugs but frequently lack proof of safety for cancer patient’s treatment. All-in-one covalent nanodrugs of the third generation have been synthesized based on a poly(β-l-malic acid) (PMLA) platform, targeting human triple-negative breast cancer (TNBC). They significantly inhibited tumor growth in nude mice by blocking synthesis of epidermal growth factor receptor, and α4 and β1 chains of laminin-411, the tumor vascular wall protein and angiogenesis marker. PMLA and nanodrug biocompatibility and toxicity at low and high dosages were evaluated in vitro and in vivo. The dual-action nanodrug and single-action precursor nanoconjugates were assessed under in vitro conditions and in vivo with multiple treatment regimens (6 and 12 treatments). The monitoring of TNBC treatment in vivo with different drugs included blood hematologic and immunologic analysis after multiple intravenous administrations. The present study demonstrates that the dual-action nanoconjugate is highly effective in preclinical TNBC treatment without side effects, supported by hematologic and immunologic assays data. PMLA-based nanodrugs of the Polycefin? family passed multiple toxicity and efficacy tests in vitro and in vivo on preclinical level and may prove to be optimized and efficacious for the treatment of cancer patients in the future.