INNO-206, the (6-maleimidocaproyl hydrazone derivative of doxorubicin), shows superior antitumor efficacy compared to doxorubicin in different tumor xenograft models and in an orthotopic pancreas carcinoma model

The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (INNO-206) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that is being assessed clinically. The prodrug binds rapidly to circulating serum albumin and releases doxorubicin selectively at the tumor site. This novel mechanism may provide enhanced antitumor activity of doxorubicin while improving the overall toxicity profile. Preclinically, INNO-206 has shown superior activity over doxorubicin in a murine renal cell carcinoma model and in breast carcinoma xenograft models. In this work, we compared the antitumor activity of INNO-206 and doxorubicin at their respective maximum tolerated doses in three additional xenograft models (breast carcinoma 3366, ovarian carcinoma A2780, and small cell lung cancer H209) as well as in an orthotopic pancreas carcinoma model (AsPC-1). INNO-206 showed more potent antitumor efficacy than free doxorubicin in all tumor models and is thus a promising clinical candidate for treating a broad range of solid tumors.     

Experimental antitumor activity of BMY-28090, a new antitumor antibiotic

Summary BMY-28090 is a novel actinomycete fermentation derived antitumor agent. The cytotoxic effect of BMY-28090 was evaluated in two murine and eight human tumor cell lines in vitro. Following 72-hour exposures, BMY-28090 was cytotoxic for all of these cell lines with IC50 values of < 0.02 to 3.25 g/ml. BMY-28090 was evaluated for in vivo antitumor activity in a variety of experimental murine tumor and human tumor xenograft models. Initial testing against the murine tumor models was performed using BMY-28090 as the water insoluble free base whereas subsequent antitumor tests were performed using water soluble lactate or succinate salts. BMY-28090 administered ip demonstrated good, reproducible antitumor activity against ip implanted P388 leukemia, L1210 leukemia, B16 melanoma and M5076 sarcoma. The water soluble preparations of BMY-28090 were active iv against sc implanted B16 melanoma and M5076 sarcoma as well as subrenal capsule (src) M5076 sarcoma; activity against src implanted B16 was marginal. BMY-28090 lactate was also evaluated for activity against src implanted MX-1 human mammary tumor xenografts in nude mice and the HCT116 human colon tumor xenografts in immune-suppressed BDF mice. At maximum tolerated doses administered ip, BMY-28090 was active against the MX-1 xenograft in two of three tests, causing > 90% inhibition of tumor growth. BMY-28090 administered iv at maximally tolerated doses had marginal activity against the HCT116 xenografts, producing 61% and 68% inhibition of tumor growth in two tests. The results of these studies demonstrated that BMY-28090 has a broad spectrum of in vitro cytotoxicity against both murine and human tumor cell lines. Moreover, BMY-28090 had in vivo antitumor activity against murine leukemias, murine solid tumors and human tumor xenografts, including tumors located distal to the site of drug administration.A preliminary report of some of this research was presented at the Annual Meeting of the American Association for Cancer Research, Los Angeles, CA, May 1986 (1090).

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Comparison of the antitumor activity of gemcitabine and ara-C in a panel of human breast, colon, lung and pancreatic xenograft models

Summary Gemcitabine is a new deoxycytidine analog that exhibits significant cytotoxicity against a variety of cultured murine and human tumor cells. The cytotoxic action of gemcitabine appears to be due to the inhibition of DNA synthesis by inhibition of ribonucleotide reductase and by competition with dCTP for incorporation into DNA. We have previously shown that gemcitabine, but not cytosine arabinoside (ara-C), has a broad spectrum of antitumor activity against 7 different types of murine solid tumors. The activity of gemcitabine was schedule dependent. To further characterize its activity, gemcitabine was tested against 12 human carcinoma xenografts. When given on an every 3 day × 4 schedule, the following percent inhibitions (at maximally tolerated doses [MTD]; MTD/2) in tumor growth were seen: MX-1 mammary (93%; 80%), CX-1 colon (92%; 82%), HC-1 colon (96%; 92%), GC3 colon (98%; 94%), VRC5 colon (99%; 100%), LX-1 lung (76%; 61%), CALU-6 lung (75%; 38%), NCI-H460 lung (45%; 46%), HS766T pancreatic (73%; not tested), PaCa-2 pancreatic (69%; 40%), PANC-1 pancreatic (70%; 60%), and BxPC-3 pancreatic (9%; 19%). In contrast, only the LX-1 lung carcinoma xenograft was responsive to ara-C treatment, which inhibited tumor growth by a marginal 62 percent. Thus, like its activity against murine solid tumors, gemcitabine has excellent antitumor activity against a broad spectrum of human solid tumors.     

Antitumor effect of kigamicin D on mouse tumor models

Kigamicin D is a novel anticancer agent that was identified using a new screening strategy that targets the tolerance of cancer cells to nutrient starvation [1, 2]. Oral administration of kigamicin D was previously described to show a strong antitumor effect in human tumor xenograft models of pancreatic tumors [2]. In this paper we describe that kigamicin D shows the same selective cytotoxicity against normal human cells such as lung fibroblast and prostate stromal cells under nutrient starved condition as against cancer cells. Kigamicin D inhibited tumor cell-induced angiogenesis in a dorsal air sac assay. On the basis of these results we tested other human tumor xenograft models and transplantable syngeneic tumor models in order to determine the spectrum of activity of kigamicin D against various cancers. Kigamicin D showed a weak antitumor effect against LX-1 and DMS-273 lung cancers, but had no effect on DLD-1 colon cancers. When tested against syngeneic tumors, kigamicin D showed a weak antitumor effect against colon26, but showed augmentation of tumor growth on IMC carcinoma at a broad dosage level. Kigamicin D does not show good antitumor activity against human xenograft tumors except pancreatic tumors and murine syngeneic tumors. We found that kigamicin D has excellent antitumor effect specific to pancreatic cancers. Surprisingly, high dosage of kigamicin D increased tumor growth of IMC carcinoma by than 200%. The phenomenon suggests that kigamicin D may cause some immunological response to the tumor.     

Discovery of a tetrahydroisoquinoline-based hydroxamic acid derivative (ZYJ-34c) as histone deacetylase inhibitor with potent oral antitumor activities

Histone deacetylase (HDAC) has emerged as an attractive target for the development of antitumor agents during the past decade. Previously tetrahydroisoquinoline-bearing hydroxamic acid analogue, ZYJ-25e (1), was identified and validated as a potent histone deacetylase inhibitor (HDACi) with marked in vitro and in vivo antitumor potency. In the present study, further modification of 1 led to another more potent, orally active HDACi, ZYJ-34c (4). Compared to FDA-approved drug suberoylanilide hydroxamic acid (SAHA), compound 4 exhibited higher in vivo antitumor potency in a human breast carcinoma (MDA-MB-231) xenograft model and in a mouse hepatoma-22 (H22) pulmonary metastasis model and similar in vivo antitumor potency in a human colon tumor (HCT116) xenograft model.     

Efficient growth inhibition of ErbB2-overexpressing tumor cells by anti-ErbB2 ScFv-Fc-IL-2 fusion protein in vitro and in vivo

Aim： To investigate the antitumor activities of an anti-ErbB2 scFv-Fc-interleukin 2 （IL-2） fusion protein （HFI） in vitro and in vivo. Methods： Fusion protein HFI was constructed. The efficacy of HFI in mediating tumor cell lysis was determined by colorimetric lactate dehydrogenase release assays. The antitumor activity of HFI was evaluated in tumor xenograft models. Results： The fusion protein was folded as a homodimer formed by covalently linking Fc portions and it retained ErbB2 specificity and IL-2 biological activity. HFI mediated antibody-dependent cell- mediated cytotoxicity （ADCC） at low effector-to-target ratios in vitro and improved the therapeutic efficacy of IL-2 in experiments in vivo. Conclusion： The genetically-engineered anti-ErbB2 scFv-Fc-IL-2 fusion protein exhibited high efficiency both in mediating ADCC in vitro and significant antitumor activity in tumor xenograft models.     

USP apparatus 4 method for in vitro release testing of protein loaded microspheres

In this study, we investigated whether the therapeutic efficacy of liposomal doxorubicin (DXR-SL) could be enhanced by angiotensin II (AT)-induced hypertension. AT-induced hypertension increased the volume of tumor blood flow in mice bearing a poorly vascularized Lewis lung carcinoma (LLC) tumor, but only slightly in mice bearing a well-vascularized colon carcinoma Colon 26 (C26) tumor. In therapeutic efficacy, AT-induced hypertension enhanced the antitumor activity of DXR-SL in mice bearing LLC and C26 tumors. Localization of DXR-SL after injection by AT-induced hypertension was observed outside tumor blood vessels in LLC and C26 tumors, but within them under the normotension. From these findings, AT-induced hypertension had potential to improve the delivery of DXR-SL to both well- and poorly vascularized solid tumors.     

Synthesis and antitumor activities of conjugates of mitomycin C-polysaccharide from Tremella fuciformis]

The conjugates of mitomycin C (MMC) with glucuronoxylomannan (AC) from Tremella fuciformis were synthesized by the use of spacers (glycine, glycylglycine, glycylglycylglycine). In i.p.-i.p. system the antitumor activity of the conjugates (MMC-G-ACP, MMC-GG-ACP, MMC-GGG-ACP) against P388 leukemia in mice was slightly lower than that of MMC by the evaluation of life span, ILS (%). In s.c.-i.p. system the antitumor activity of the conjugates against sarcoma 180 solid tumor in mice was similar to that of MMC, except for MMC-G-ACP. The reduction of the number of leukocytes caused by MMC was suppressed by attaching MMC to AC. The conjugates did not lower the cytotoxicity of MMC against L1210 mouse leukemia cells in vitro. The release rate of MMC from the conjugates in vitro (half time of MMC release: MMC-G-ACP, 8.8 h; MMC-GG-ACP, 3.1 h; MMC-GGG-ACP, 2.9 h) was much faster than that of MMC-dextran, and differed in the length of the spacer. The results would give useful information on macromolecular carriers in drug-delivery system.     

Evaluation of the effect of SMA-pirarubicin micelles on colorectal cancer liver metastases and of hyperbaric oxygen in CBA mice

Tetrahydropyranyladriamycin (THP or pirarubicin) destroys tumors via several mechanisms; one of which involves the production of ROS that requires molecular oxygen for its generation. SMA forms stable self-assembled associated micelles with pirarubicin (SMA-pirarubicin), and confers macromolecular characteristics to pirarubicin. This micellar macromolecular drug is selectively delivered to solid tumors via the EPR effect and its preferential tumor accumulation suppresses the systemic toxicity whilst its prolonged high concentration at the site of tumor enhances its efficacy much higher compared to free pirarubicin. Administration of SMA-pirarubicin micelle under HBO can further enhance the delivery of molecular oxygen that facilitates tumor selective generation of ROS, thus augmenting its antitumor potency. In this study, we evaluated the efficacy of SMA-pirarubicin micelles either as single drug or in combination with HBO in a mouse metastatic colorectal cancer model. At or below the maximum tolerated dose, SMA-pirarubicin remarkably reduced metastatic tumor nodules and it was far more effective than free pirarubicin. The data also suggests a potential benefit of combined therapy of HBO with micellar anthracyclins.     

Antitumor activity of RT2 peptide derived from crocodile leukocyte peptide on human colon cancer xenografts in nude mice

RT2, derived from the leukocyte peptide of Crocodylus siamensis, can kill human cervical cancer cells via apoptosis induction, but no evidence has shown in vivo. In this study, we investigated the antitumor effect of RT2 on human colon cancer xenografts in nude mice. Twenty‐four mice were injected subcutaneously with human colon cancer HCT 116 cells. Eleven days after cancer cell implantation, the mice were treated with intratumoral injections of phosphate buffered saline (PBS) or RT2 (0.01, 0.1, and 1 mg/mouse) once every 2 days for a total of 5 times. The effect of a 10‐day intratumoral injection of RT2 on body weight, biochemical, and hematological parameters in BALB/c mice showed no significant difference between the groups. Tumor volume showed a significant decrease only in the treatment group with RT2 (1 mg/mouse) at day 6 (P < .05), day 8 (P < .01), and day 10 (P < .01) after the first treatment. The protein expression levels of cleaved poly (ADP‐ribose) polymerase (PARP), apoptosis‐inducing factor (AIF), and the p53 tumor suppressor protein (p53) in xenograft tumors increased after treatment with RT2 (1 mg/mouse) compared to those in the PBS‐injected group. Moreover, RT2 increased the expression of Endo G and Bcl‐2 family proteins. Therefore, the peptide RT2 can inhibit tumor growth via the induction of apoptosis in an in vivo xenograft model.     

Efficacy of MGI 114 (HMAF) against the MRP+ metastatic MV522 lung carcinoma xenograft

This study is part of an effort to evaluate efficacy of the novel agent MGI 114 (HMAF) against tumors resistant to conventional chemotherapeutic agents. MGI 114 is a novel semisynthetic anticancer agent currently in chemotherapeutic phase II trials to evaluate activity against various solid tumors. Previous studies indicate MGI 114 was active against human MDR1/gp170+ solid tumor xenografts. Recent evidence suggests overexpression of the MRP protein may also be clinically relevant to development of drug resistance in solid tumors. We evaluated the efficacy of MGI 114 against a human MRP+ lung carcinoma xenograft. Parent MV522 lung carcinoma cells were transfected with a MRP cDNA expression vector and resistant cells selected by exposure to vinblastine (30-fold resistance). Analysis of resistant clones indicated 20- to 40-fold increases in expression of both MRP mRNA and MRP protein. Administration of MGI 114 at the maximum tolerated dose (7 mg/kg, 5 x/week for 3 weeks) to MRP tumor-bearing mice demonstrated this novel agent was active against MRP+ tumors and significantly extended their lifespan (p<0.001). In contrast, other cytotoxic agents had minimal activity against this MRP+ xenograft. These results indicate MGI 114 should retain activity in vivo against MRP+ tumor types. The development of this MRP+ xenograft model, in conjunction with the parent MV522 and MDR1/gp170+ xenograft models, will be useful for screening new classes of agents for activity against multidrug-resistant tumors.     

CD44-targeting for antitumor drug delivery: a new SN-38-hyaluronan bioconjugate for locoregional treatment of peritoneal carcinomatosis

An innovative approach for cancer therapy implies the use of drugs covalently conjugated to macromolecular carriers that specifically target molecules over-expressed on tumor cells. This drug delivery strategy may allow a controlled release of the drug and a high targeting selectivity on tumor cells, increasing drug cytotoxicity and decreasing its undesirable side effects. We provide in vitro and in vivo preclinical data on the antitumor efficacy of ONCOFID?-S, a new bioconjugate of hyaluronic acid (HA) with SN-38 (the CPT11 active metabolite), that support the validity of the drug delivery strategy implying the use of HA as macromolecular carrier of antineoplastic drugs, an approach based on the over-expression of its target CD44 (the receptor for HA-mediated motility) in a wide variety of cancers. We show that ONCOFID?-S exerts a strong in vitro anti-proliferative activity on CD44 over-expressing rat DHD/K12/trb colon adenocarcinoma cells, as well as on gastric, breast, oesophageal, ovarian and lung human cancer cells, higher than that exerted by unconjugated SN-38. We also demonstrated the in vivo anti-tumor efficacy of locoregional treatment with ONCOFID?-S on two pre-clinical models of colorectal cancer (CRC) in BDIX rats: a) syngeneic model of subcutaneous tumor; b) syngeneic model of metastatic tumor induced by injection of cells into the peritoneal cavity, mimicking the clinical situation of peritoneal carcinomatosis. Specifically, in the latter model ONCOFID?-S is able to dramatically reduce all parameters indicative of a poor prognosis in peritoneal metastatization of CRC without any myelotoxicity or mesothelial inflammation. We propose this CD44-targeted therapeutic strategy for locoregional treatment of peritoneal carcinomatosis from CRC, against which systemic chemotherapy results almost inefficient.     

Design and development of ligand-appended polysaccharidic nanoparticles for the delivery of oxaliplatin in colorectal cancer

Hyaluronic acid–coupled chitosan nanoparticles bearing oxaliplatin (L-OHP) encapsulated in Eudragit S100–coated pellets were developed for effective delivery to colon tumors. The in vitro drug release was investigated using a USP dissolution rate test paddle-type apparatus in different simulated gastrointestinal tract fluids. In therapeutic experiments the pellets of free drug, and hyaluronic acid–coupled and uncoupled chitosan nanoparticles bearing L-OHP were administered orally at the dose of 10 mg L-OHP/kg body weight to tumor-bearing Balb/c mice. In vivo data showed that hyaluronic acid–coupled chitosan nanoparticles delivered 1.99 ± 0.82 and 9.36 ± 1.10 μg of L-OHP/g of tissue in the colon and tumor, respectively after 12 hours, reflecting its targeting potential to the colon and tumor. These drug delivery systems show relatively high local drug concentration in the colonic milieu and colonic tumors with prolonged exposure time, which provides a potential to enhance antitumor efficacy with low systemic toxicity for the treatment of colon cancer.From the Clinical EditorIn this study, a nanoparticle system was developed to deliver oxaliplatin to colorectal tumors. In murine models, the drug delivery system showed relatively high local drug concentration in colonic tumors with prolonged exposure time, which provides a potential for enhanced antitumor efficacy with low systematic toxicity.     

Enhanced therapeutic efficacy of a novel liposome-based formulation of SN-38 against human tumor models in SCID mice

SN-38 is an active metabolite of CPT-11. The poor solubility of SN-38 in any pharmaceutically acceptable solvent and pH-dependent activity has limited its clinical use. Our objective was to evaluate an easy-to-use liposome-based formulation of SN-38 (LE-SN38) and compare the antitumor activity with its pro-drug CPT-11 against cancer cell lines and human xenograft tumor models. The cytotoxicity of LE-SN38 and CPT-11 was determined in four human cancer cell lines using the sulforhodamine B assay. The therapeutic efficacy was tested against human colon (HT-29) and breast (MX-1) xenograft tumor models in SCID mice. LE-SN38 with greater than 95% drug entrapment was found to be highly cytotoxic against four different cell lines with GI50 values of less than 0.1 microM. In the HT-29 tumor model, LE-SN38 (q x d5) at 2, 4 or 8 mg/kg resulted in 33, 81 and 91% tumor growth inhibition, respectively, compared to the drug-free liposome group. In contrast, similar dose levels of CPT-11 treatment led to only 2, 36 and 46% growth inhibition. For the MX-1 model, LE-SN38 (q x d5) regressed tumor growth by 44 and 88% at 4 and 8 mg/kg dose, respectively, whereas no regression was observed in the CPT-11-treated group. We conclude that LE-SN38 is a novel liposome-based formulation with enhanced therapeutic efficacy against human tumor models.     

Antitumor Effect of Paclitaxel-Loaded PEGylated Immunoliposomes Against Human Breast Cancer Cells

Purpose The antitumor effect of paclitaxel-loaded PEGylated immunoliposome (PILs) was investigated in breast cancer cell lines and the xenograft model. Methods Herceptin was conjugated to paclitaxel-loaded PEGylated liposomes (PLs). In vitro cellular uptake and cytotoxicity of PILs were determined in breast cancer cell lines while in vivo antitumor efficacy was evaluated in the xenograft nude mouse model. Results The PILs formulation was able to significantly increase the HER2 mediated cellular uptake of paclitaxel compared to the PLs in cell lines overexpressing HER2 (BT-474 and SK-BR-3 cells). However, in the MDA-MB-231 cells, which express low levels of HER2, the difference between the PILs and PLs formulation was not significant. The biological activity of Herceptin was maintained throughout the conjugation process as exhibited by the antitumor dose–response curves determined for Herceptin itself, for the thiolated Herceptin alone and subsequently for the immunoliposome-coupled Herceptin. In BT-474 and SK-BR-3 cells, the cytotoxicity of the PILs was more potent than that of Taxol. Moreover, in in vivo studies, PILs showed significantly higher tumor tissue distribution of paclitaxel in the BT-474 xenograft model and more superior antitumor efficacy compared to Taxol and PLs. However, in the MDA-MB-231 xenograft model, PILs and PLs showed similar tumor tissue distribution as well as antitumor activity. Conclusions These results suggest that HER2-mediated endocytosis is involved in the PILs formulation. The ability of the PILs formulation to efficiently and specifically deliver paclitaxel to the HER2-overexpressing cancer cells implies that it is a promising strategy for tumor-specific therapy for HER2-overexpressing breast cancers.     

Synthesis of a macromolecular camptothecin conjugate with dual phase drug release

A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t(1/2) = 2.2 +/- 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t(1/2) = 2.1 +/- 0.2 h, while the conjugate half-life was 14.2 +/- 1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics.     

Evaluation of the effect of SMA–pirarubicin micelles on colorectal cancer liver metastases and of hyperbaric oxygen in CBA mice

Tetrahydropyranyladriamycin (THP or pirarubicin) destroys tumors via several mechanisms; one of which involves the production of ROS that requires molecular oxygen for its generation. SMA forms stable self-assembled associated micelles with pirarubicin (SMA–pirarubicin), and confers macromolecular characteristics to pirarubicin. This micellar macromolecular drug is selectively delivered to solid tumors via the EPR effect and its preferential tumor accumulation suppresses the systemic toxicity whilst its prolonged high concentration at the site of tumor enhances its efficacy much higher compared to free pirarubicin. Administration of SMA–pirarubicin micelle under HBO can further enhance the delivery of molecular oxygen that facilitates tumor selective generation of ROS, thus augmenting its antitumor potency. In this study, we evaluated the efficacy of SMA–pirarubicin micelles either as single drug or in combination with HBO in a mouse metastatic colorectal cancer model. At or below the maximum tolerated dose, SMA–pirarubicin remarkably reduced metastatic tumor nodules and it was far more effective than free pirarubicin. The data also suggests a potential benefit of combined therapy of HBO with micellar anthracyclins.     

Preclinical activity of an i.v. formulation of rubitecan in IDD-P against human solid tumor xenografts

An i.v. formulation of rubitecan (9-nitrocamptothecin) was evaluated in five human solid tumor xenograft models. Rubitecan in IDD-P, a particulate suspension of the insoluble analog, produced significant tumor growth delay in athymic nude mice bearing A375 melanoma, and MX-1 breast, SKMES non-small-cell lung, Panc-1 pancreatic and HT29 colon carcinomas. The activity of i.v. rubitecan was similar or somewhat superior to those of i.p. regimens with the reference drugs, irinotecan and topotecan. Tumor sensitivity to rubitecan in IDD-P was MX-1>A375>SKMES >Panc-1>HT29. Some complete regression responses were seen with MX-1, A375 and SKMES tumors treated with 2.5 mg/kg on a schedule of two 5-day dosing cycles separated by 2 drug-free days. In nude mice, the MTD of rubitecan in IDD-P lies between 2 and 2.5 mg/kg on this schedule; antitumor efficacy was achieved with doses between 2.5 and 1.25 mg/kg. Dosing with 6.6 mg/kg rubitecan in IDD-P on intermittent schedules (4- or 7-day intervals) was tolerated, but less efficacious, when tested in the A375 model. The good responses obtained with rubitecan in IDD-P suggest it could be used clinically in circumstances where an i.v. formulation offers advantages to oral or aerosol formulations.     

Antitumor diarylsulfonylureas: novel agents with unfulfilled promise

Summary Diarylsulfonylureas represent a class of antitumor agent with significant therapeutic efficacy against rodent and human models of cancer. Despite the exciting preclinical activity of sulofenur, the prototypic agent, clinical activity was poor. Here we review the activity of sulofenur and a second generation diarylsulfonylurea, LY295501 N-[5-(2,3-dihydrobenzofuryl) sulfonyl]-N′-(3,4-dichlorophenyl)urea, against colon tumor xenografts, and some of the cellular pharmacology of this class of antitumor agents.     

Transferrin coupled vesicular system for intracellular drug delivery for the treatment of cancer: Development and characterization

Objectives: In the present study attempt has been made to enhance the selective tumor cell killing in mouse xenograft model using DQAsomes as a mitochondriotropic carrier and transferrin (Tf) as a ligand to target tumor cells.

Methods: Tf modified DQAsomes (Tf-DQAsomes) were prepared by incubating preformed paclitaxel loaded DQAsomes with Tf in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride. Developed systems were characterized for size and size distribution, entrapment efficiency, and in vitro drug release. Fluorescence microscopy and flow cytometry were performed to evaluate cellular uptake of the carriers. Antitumor activity was determined using HeLa cells. In vivo therapeutic efficacy was determined in xenograft mouse model.

Key findings: Uptake studies demonstrated that Tf-DQAsomes result in higher flurescence intensity to the cancer cells as compared to plain DQAsomes. Tf-DQAsomes exhibited better antitumor activity in vitro as compared to plain DQAsomes and paclitaxel solution. In vivo biodistribution study revealed that paclitaxel concentration in the tumor was much higher in the case of Tf-DQAsomes as compared to plain DQAsomes and paclitaxel solution; however in other organs it was much lower than the latter two formulations. Tf-DQAsomes exhibited significant antitumor activity in the mouse xenograft model.

Conclusions: The finding demonstrated that Tf conjugated DQAsomes can effectively be delivered to the tumor in vivo and exhibit significant antitumor activity.