Bleomycin administered by laser-assisted drug delivery or intradermal needle-injection results in distinct biodistribution patterns in skin: in vivo investigations with mass spectrometry imaging.

Bleomycin (BLM) is being repositioned in dermato-oncology for intralesional and intra-tumoural use. Although conventionally administered by local needle injections (NIs), ablative fractional lasers (AFLs) can facilitate topical BLM delivery. Adding local electroporation (EP) can augment intracellular uptake in the target tissue. Here, we characterize and compare BLM biodistribution patterns, cutaneous pharmacokinetic profiles, and tolerability in an in vivo pig model following fractional laser-assisted topical drug delivery and intradermal NI, with and without subsequent EP. In vivo pig skin was treated with AFL and topical BLM or NI with BLM, alone or with additional EP, and followed for 1, 2 and 4 h and eventually up to 9 d. BLM biodistribution was assessed by spatiotemporal mass spectrometry imaging. Cutaneous pharmacokinetics were assessed by mass spectrometry quantification and temporal imaging. Tolerability was evaluated by local skin reactions (LSRs) and skin integrity measurements. AFL and NI resulted in distinct BLM biodistributions: AFL resulted in a horizontal belt-shaped BLM distribution along the skin surface, and NI resulted in BLM radiating from the injection site. Cutaneous pharmacokinetic analyses and temporal imaging showed a substantial reduction in BLM concentration within the first few hours following administration. LSRs were tolerable overall, and all interventions permitted almost complete recovery of skin integrity within 9 d. In conclusion, AFL and NI result in distinct cutaneous biodistribution patterns and pharmacokinetic profiles for BLM applied to in vivo skin. Evaluation of LSRs showed that both methods were similarly tolerable, and each method has potential for individualized approaches in a clinical setting.

Maternal ABVD chemotherapy for Hodgkin lymphoma in a dichorionic diamniotic pregnancy: a case report.

BACKGROUND: Hodgkin lymphoma (HL) is the most common hematological malignancy during pregnancy. The first-line treatment for HL in pregnancy is the standard ABVD regimen without any drug and/or dose adjustment. However, data on chemotherapy during twin pregnancies are sparse, and a better understanding of the mechanisms involved in exposure to and the toxic effects of anticancer drugs in the fetuses is needed. CASE PRESENTATION: A 41-year-old dichorionic diamniotic pregnant patient was given ABVD treatment for HL at a gestational age of 28 weeks and 3 days. The patient received 2 cycles of chemotherapy with a 15-day therapeutic window including an actual 25 mg/m2 dose of doxorubicin per cycle. Unlike the female twin, the male twin presented four days after birth a left cardiac dysfunction. Doxorubicin cardiotoxicity in the male newborn was also supported by high blood levels of troponin. At one month of age, echocardiography findings were normal. We investigated literature data on physiological aspects of pregnancy that may influence doxorubicin pharmacokinetics, and pharmacodynamic and pharmacokinetic data on the use of doxorubicin in pregnancy. We detailed the role of the transporters in doxorubicin placenta distribution, and tried to understand why only one fetus was affected. CONCLUSIONS: Fetal safety depends at least on maternal doxorubicin pharmacokinetics.Because of drug interactions (i.e. drug metabolism and drug transport), care should always be taken to avoid maternal pharmacokinetic variability. The toxic effects were discrepant between the dizygotic twins, suggesting additional fetus-specific pharmacokinetic/pharmacodynamic factors in doxorubicin toxicity.

Converting bleomycin into a prodrug that undergoes spontaneous reactivation under physiological conditions.

Bleomycin is an anticancer antibiotic effective against a range of human malignancies. Yet its usefulness is limited by serious side effects. In this study, we converted bleomycin into a prodrug by covalently linking 2-sulfo, 9 fluorenylmethoxycarbonyl (FMS) to the primary amino side chain of bleomycin. FMS-bleomycin lost its efficacy to bind transition metal ions and therefore was converted into an inactive derivative. Upon incubation in vitro under physiological conditions, the FMS-moiety undergoes spontaneous hydrolysis, generating native bleomycin possessing full anti-bacterial potency. FMS hydrolysis and reactivation takes place with a t1/2 value of 17 ±â€¯1 h. In silico simulation predicts a narrow therapeutic window in human patients of seven hours, starting 40 min after administration. In mice, close agreement was obtained between the experimental and the simulated pharmacokinetic profiles for FMS-bleomycin. FMS-bleomycin is thus shown to be a classical prodrug: it is inactive at the time of administration and the non-modified (active) bleomycin is released with a desirable pharmacokinetic profile following administration, suggesting it may have therapeutic value in the clinic.

Vascularization of the tumours affects the pharmacokinetics of bleomycin and the effectiveness of electrochemotherapy.

Pre-clinical and clinical data indicate differences in the responses of melanoma and carcinoma tumours to electrochemotherapy. The purpose of this study was to investigate the origin of this difference, whether it is due to the intrinsic difference in tumour cell susceptibility to the chemotherapeutic, or due to the tumour micro-environment. For this purpose, we performed a pre-clinical study in B16F1 melanoma and TS/A carcinoma tumours in mice, in which the antitumour effectiveness of electrochemotherapy with bleomycin, the intrinsic sensitivity of tumour cells in vitro, the pharmacokinetics of bleomycin in plasma and tumours, and the vascularization of tumours in vivo were evaluated. The results of the treatment show that carcinoma was significantly more responsive to electrochemotherapy than melanoma. This effect cannot be ascribed to the intrinsic sensitivity of these cells, as melanoma cells were more sensitive than carcinoma cells in vitro. The difference in responses could be ascribed to differences in the pharmacokinetics of bleomycin; at the time of electroporation in carcinomas, more bleomycin was accumulated. This effect could be due to differences in tumour vascularization, as carcinoma tumours had numerous well-distributed, small blood vessels, while melanomas were less vascularized, exhibiting predominantly larger vessels. In conclusion, this study provides evidence on the importance of the tumour micro-environment, particularly the tumour vasculature, in the responses of the tumours to bleomycin electrochemotherapy. Vasculature is important for the pharmacokinetics of bleomycin, influencing drug accumulation and drug distribution in tumours, and might be used as a predictive factor for the tumour response to electrochemotherapy.

Folic acid conjugated nanoliposomes as promising carriers for targeted delivery of bleomycin.

Targeted drug delivery has received considerable attention due to its key role in improving therapeutic efficacy and reducing the side effects of anticancer drugs. Bleomycin (BLM) is an anticancer antibiotic with short half-life, low therapeutic and high side effects that limit its clinical applications. This study aims to evaluate the anticancer potential of folate-targeted liposomal bleomycin (FL-BLM) and its free-folate form (L-BLM) on two different cancer cell lines including human cervix carcinoma HeLa, and human breast carcinoma MCF-7 cells. Furthermore, the effect of FL-BLM in induction of apoptosis and cell cycle arrest was studied by flow cytometry. FL-BLM was prepared by thin film hydration method and folic acid was conjugated to nanoliposomes by post insertion technique. Anticancer activity was evaluated by MTT assay. The cytotoxicity of FL-BLM against HeLa cells was significantly increased compared to L-BLM and conventional BLM. Flow cytometry and annexin-V analysis indicated that FL-BLM effectively induced apoptosis and cell-cycle arrest in HeLa cells especially at G2/M phase. In addition, the uptake of FL-BLM by Hela cells was significantly increased as compared to the MCF-7 cells. Overall, our findings indicated that FL-BLM may be promising formulation for targeted drug delivery to folate receptor-positive tumour cells.

Enhanced antitumor effect of targeted nanoliposomal bleomycin.

Folate receptor (FR)-mediated drug delivery is a promising approach for active targeting of drugs to the FR-positive tumor cells. Bleomycin (BLM) is an antitumor antibiotic with poor therapeutic activity as a result of its limited diffusion into tumor cells. The aim of this study was to investigate whether FR-targeted PEGylated nanoliposomes (FPNL) can effectively deliver BLM to tumor cells and enhance its in vitro and in vivo efficacy. FPNL and PNL (non-targeted) were prepared by thin film hydration method, and their physiochemical properties, cellular uptake, tissue distribution and tumor inhibitory effects were investigated. In Lewis lung cancer (LLC1) cells, FPNL containing BLM showed 2.38-fold and 3.26-fold higher cytotoxicity compared to PNL-BLM and free BLM, respectively. Moreover, the uptake of FPNL by these cells was increased as compared to the PNL. Furthermore, FPNL showed significantly higher tumor distribution of BLM in the LLC1 cells and more tumor inhibition efficacy compared to free BLM and PNL. Both formulations of nanoliposomes had longer plasma half-life than that of free BLM. Therefore, FPNL may be suitable carriers for targeted drug delivery to FR-positive tumor cells.

Identification and quantification of bleomycin in serum and tumor tissue by liquid chromatography coupled to high resolution mass spectrometry.

Bleomycin is a cytotoxic antibiotic available as a compost of structurally strongly related glycopeptides, which is in vivo found chelated with several metals. Its pharmacotherapy has merely been based on experimental dose - response data, whereas its biodistribution and pharmacokinetics remain fundamentally unknown. This is reasoned by an absence of a specific and sensitive mass spectrometry-based analytical method for its determination in biological tissues. We herein reveal the results of our study on the mass spectrometric behavior of two main bleomycin fractions A2 and B2, including their metal complexes, particularly the predominant copper chelates. In the electrospray ion source bleomycin forms double charged species, where for the metal-free fraction A2 and its copper complex m/z 707.76 and m/z 707.21 are seen, respectively. Hence, the second isotopic ion of the chelate (m/z 707.71) nearly coincides with the first isotopic ion of the metal-free fraction. This phenomenon can only be followed by high-resolution mass spectrometry, and is considered the plausible reason, why the attempts to determine bleomycin with mass spectrometry have been so scarce. The presented paper further describes a sensitive and selective liquid chromatography - mass spectrometry analytical method for determination of bleomycin in serum and tumor tissues. This newly developed method was employed for bleomycin pharmacokinetic studies in serum and tumors of laboratory animals. Additionally, the method was employed for determination of bleomycin pharmacokinetic parameters in elderly patients in order to determine the effective therapeutic window of electrochemotherapy with bleomycin.

Bleomycin pharmacokinetics of bolus bleomycin dose in elderly cancer patients treated with electrochemotherapy.

PURPOSE: With the aim to determine effective therapeutic window of electrochemotherapy, we analyzed bleomycin pharmacokinetic parameters in elderly patients. METHODS: In prospective clinical study in the treatment of tumors with electrochemotherapy, blood samples of patients older than 65 years were collected after the bolus intravenous injection of bleomycin (15,000 IU/m(2)). In serum samples, quantitative analysis was performed with liquid chromatography coupled to high-resolution mass spectrometry. Based on the data, the pharmacokinetic parameters of bleomycin elimination were determined. RESULTS: Pharmacokinetic analysis of the data revealed a monophasic serum clearance curve, which demonstrates slow elimination of bleomycin, being less than 500 ml/min and a half-time of 30 min. CONCLUSIONS: Slow monophasic elimination of bleomycin from serum in elderly patients implies on the longer therapeutic window, from 8 to up to 40 min or even longer post-bleomycin injection for electrochemotherapy. However, prolonged therapeutic bleomycin serum concentrations may also affect the possible adverse effects, such as lung fibrosis and extensive necrosis of tumors due to the uptake of toxic bleomycin concentrations into the tumors. This may imply on lowering of bleomycin dosage, in particular in the elderly patients.

Bleomycin A6-loaded anionic liposomes with in situ gel as a new antitumoral drug delivery system.

The goal is to develop an in situ gel system comprising anionic liposomes (AL) containing bleomycin A6 (BLM A6) dispersed within the thermosensitive in situ gel for sustained release. The results indicated that the gelation temperature decreased due to AL within gel. Similarly, viscosity and mechanical parameters, such as gel strength for gel, could be enhanced by inducing lipid material with negative charge (phosphatidylglycerol) at 37 °C, which provided against corrosion at physiological condition. The in vitro release experiments performed with a dialysis method revealed that in situ gel with AL exhibited the longer drug-release period compared to that with or without nonionic liposomes. An in vivo fluorescence imaging study suggested that the gel with AL loading FITC-BLM A6 stayed in administration site at least for five days. A thermosensitive in situ gel with anionic liposome was a promising carrier for hydrophilic BLM A6, to be used in parenteral delivery system for anti-tumor treatment.

Pharmacokinetic evaluation of anticancer drugs in Hodgkin's lymphoma patients after their simultaneous administration.

A pharmacokinetic study of anticancer drugs was carried out in 18 Hodgkin's lymphoma male patients. The anticancer drugs were administered to the patient by a standard procedure and a validated HPLC method was used for plasma concentration determination. Maximum plasma concentration (Cmax) of Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) were 7.71, 4.32, 7.95 and 6.51µg/ml respectively. Adriamycin and Dacarbazine exhibited longer Tmax compared to Bleomycin and Vinblastine. Area under the curve values of ABVD were 118.30, 82.11, 245.54 and 86.62µg/ml*h. The elimination rate constant of Dacarbazine was highest. Vinblastine exhibited highest half-life and mean residence time. Clearances of ABVD were 346.69, 2499.44, 45.90 and 5800.05ml/h. The apparent volume of distribution was highest for Dacarbazine and lowest for Vinblastine. The pharmacokinetic parameters can be utilized for monitoring of plasma concentrations, therapeutic drug monitoring and dosage adjustments to optimize anticancer efficacy in patients of Hodgkin's lymphoma.

The treatment of keloids and hypertrophic scars with intralesional bleomycin in skin of color.

Intralesional injection with corticosteroid remains the mainstay of therapy for hypertrophic scars and keloids, however some lesions are unresponsive or may result in skin atrophy. Intralesional bleomycin injection is an alternative therapy that has been widely reported. In order to compare the effectiveness and safety of bleomycin for the treatment of keloids and hypertrophic scars in skin of color population, Fitzpatrick skin type III to V patients with keloids or hypertrophic scars were randomized into two groups. Group A was treated monthly with intralesional triamcinolone acetonide (10 mg/mL), while group B with intralesional bleomycin (1 mg/mL) for three consecutive months. Evaluation of the treatment was performed using "Patient and Observer Scar Assessment Scale" (POSAS), self-rated patient satisfaction score, photography, and ultrasonography. Two patients had their bleomycin blood levels monitored. Twenty-six patients with keloids or hypertrophic scars were recruited. The clinical improvement as assessed by the POSAS was not statistically significant. In terms of patients satisfaction score, one half of both groups reported a very good improvement. Photographic as well as ultrasonographic evaluation showed no difference between the two groups. Bleomycin was found to enter the blood circulation in a very small amount. The major side effect was hyperpigmentation. There was no skin atrophy detected in this study. Intralesional bleomycin is a safe and effective treatment for keloids and hypertrophic scars. The treatment is comparable to intralesional triamcinolone. Unfortunately, hyperpigmentation was the major side effect in darker skin type.

Injectable chitosan thermogels for sustained and localized delivery of pingyangmycin in vascular malformations.

Pingyangmycin (PYM) is an effective drug to treat vascular malformations (VM), but can easily diffuse from the injection site, which will reduce its therapeutic effect and increase side effect. Our study was to evaluate PYM-loaded chitosan thermogels for sustained and localized embolization therapy. It was shown that in vitro release of PYM thermogels could be delayed up to 12 days. The results measured by MTT assay showed that PYM thermogels could inhibit proliferation and induce apoptosis of EA.hy926 cells in a concentration and time dependent manner. In vivo pharmacokinetics study demonstrated that compared with PYM injections, PYM thermogels had a better sustained delivery of PYM. Macroscopic observation and histological examination of rabbit ear veins displayed that after administration with PYM thermogels for 18 days, obvious venous embolization and inflammatory response could be found. These results indicate that PYM thermogels is likely to achieve excellent prospects for VM treatment.

Bleomycin sulphate loaded nanostructured lipid particles augment oral bioavailability, cytotoxicity and apoptosis in cervical cancer cells.

In present investigation, bleomycin sulphate loaded nanostructured lipid particles (BLM-NLPs) were constructed to enhance the oral bioavailability by overwhelming the first pass hepatic metabolism. The particles size and nanoencapsulation efficiency of BLM-NLPs were measured to be 17.4±5.4nm and 45.3±3.4%, respectively. Our studies indicated that the drug was molecularly dispersed in the lipid nanocoacervates, with amorphous geometry, without altering the chemical structure, as ascertained by spectral studies. The nanoformulation, BLM-NLPs was analyzed for dissolution testing, cytotoxicity, apoptosis and cellular uptake in human cervical cancer cell line, HeLa cells. BLM-NLPs released the drug with first order kinetic in simulated intestinal fluid (pH∼6.8±0.1), characterized by initial burst and followed by slow release. Further, an enhanced cytotoxicity (∼5.6 fold lower IC50), improved intracellular concentration (∼4.38 fold) and greater degree of apoptosis was induced by BLM-NLPs in HeLa cells, as compared to BLM alone. Moreover, BLM-NLPs also showed dose-dependent internalization, as evinced by cellular uptake study. The in vivo study indicated a significantly (P<0.0001) smaller elimination rate constant (KE), volume of distribution (Vd) and clearance rate (CLTotal) for BLM-NLPs, as compared to BLM solution in post-oral administrations. This clearly depicts the retention and stability of tailored nanoformulation in intestinal absorption pathway. In addition, our nanoformulation, BLM-NLPs documented significantly (P<0.0001)∼3.4 fold (66.20±2.57%) higher bioavailability than BLM solution (19.56±0.79%). In conclusion, our in vitro and in vivo results warrant the safety, efficacy and potency of tailored nanoformulation in clinical settings.

Cationic lipid:DNA complexes allow bleomycin uptake by melanoma cells.

Bleomycin is a chemotherapeutic agent barely diffusible through the plasmatic membrane. We evaluated DNA/cationic lipids complexes (lipoplexes) as mediators of its uptake in four spontaneous canine melanoma derived cell lines (Ak, Bk, Br and Rkb). Cell survival after lipofection plus or minus bleomycin was determined by the acid phosphatase method and the cellular uptake of lipoplexes, carrying the E. coli ß-galactosidase gene, was evidenced by SYBR Green I staining. The four cell lines resulted sensitive to the bleomycin/lipoplexes system in both spatial configurations. Survival rates values were lower than 20% in monolayers of the four tested lines and lower than 30% in three lines (Ak, Bk and Rkb) when grown as spheroids. The sensitization to bleomycin depended on lipoplexes in Ak and Rkb while Bk (in both spatial configurations) and Br (as monolayers) were sensitive to bleomycin alone. Although some degree of sensitivity to bleomycin was induced by cationic lipids alone in Ak and Rkb monolayers, the maximal bleomycin effects appeared in the presence of lipoplexes. The sensitization was independent of transcriptional activity. The co-administration of lipoplexes diminished bleomycin IC50: 10-fold in Ak and Rkb monolayers; and sensitized the Ak and Rkb resistant spheroids. The bleomycin cytotoxic effects depended on lipoplexes concentration and diminished when cells were incubated at 8°C. Our results suggest that lipoplexes sensitize cells to bleomycin, increasing its uptake by an active transport mechanism, such as endocytosis. The bleomycin/lipoplexes system appears as a promising combination of chemotherapy and non-viral cancer gene therapy.

Investigation of therapeutic efficiency of bleomycin and bleomycin-glucuronide labeled with (131)I on the cancer cell lines.

The aim of this study is to determine the incorporations of radiolabeled bleomycin ((131)I-BLM) and bleomycin-glucuronide ((131)I-BLMGLU) on PC-3 (human prostate carcinoma cell line), Caco-2 (human colon adenocarcinoma cell line), Hutu-80 (Human Duodenum adenocarcinoma cell line), and A549 (Human lung adenocarcinoma epithelial cell line) cancerous cell lines. For this purpose, BLM and BLMGLU enyzmatically synthesized were labeled with (131)I, quality control studies were done and the incorporation yields of (131)I-BLM and (131)I-BLMGLU on these cell lines were measured. Quality-control studies showed that the radiolabeling yields were obtained as 95% and 90% for (131)I-BLM and (131)I-BLMGLU, respectively. Also, as a result of the cell culture studies, it was found that (131)I-BLM and (131)I-BLMGLU had higher incorporation on PC-3 cells than that of other cell lines. In addition to this, it was reported that the incorporation yield of (131)I-BLMGLU was higher than that (131)I-BLM. At the end of the study, cytotoxicities of BLM and BLMGLU on PC-3 cancerous cell line were inspected and fluorescent images of BLM and BLMGLU were taken on PC-3 cells by using fluorescein isothiocyanate. In conclusion, cell culture studies demonstrated that the incorporation values of (131)I-BLMGLU on the four cell lines were about five to six times higher than (131)I-BLM. Radiolabeled glucuronide derivatives can be used in cancer therapy and tumor imaging, depending on the properties of radioiodine for the ß-glucuronidase-rich tissues because glucuronidation leads to rapid and higher incorporation on adenocarcinoma cells.

Selective induction of glutathione S-transferases in round spermatids from the Brown-Norway rat by the chemotherapeutic regimen for testicular cancer.

Chemotherapeutic drugs can affect DNA in male germ cells, thereby impacting on the integrity of the genome transmitted to offspring. Drug metabolizing enzymes can protect cells from xenobiotic insult. We analyzed the expression pattern of such enzymes in isolated round spermatids from rats exposed to drugs used to treat testicular cancer: bleomycin, etoposide, and cisplatin (BEP). The number of isozymes expressed and the overall relative expression values were highest for the glutathione S-transferases (GSTs). Moreover, BEP treatment significantly increased the expression of 8 GSTs and 3 aldehyde dehydrogenases. Increased expression of GST isozymes was confirmed by qRT-PCR and Western blot analysis. Although Gst genes can be targets for epigenetic modifications, promoter DNA methylation was not affected by BEP treatment. As GSTs are involved in drug resistance mechanisms, we hypothesize that BEP induction of GST expression may lead to the survival of damaged germ cells and the production of abnormal sperm.

[In vivo distribution of FITC-labeled boanmycin hydrochloride in situ gel].

This study is to evaluate the sustained-release effect of the thermosensitive in situ gel for injection of boanmycin hydrochloride (BAM) by bioluminescence imaging in nude mice. BAM was labeled with fluorescein isothiocyanate (FITC). The FITC-labeled BAM (FITC-BAM) was purified by dialysis and Sephadex G25 gel column, and then was identified by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF). The model of experimental hepatoma HepG-2 nude mice was established, and the optical imaging system was applied to evaluate the distribution of FITC-BAM in vivo. Results of MALDI-TOF proved that the major molecular ratio of BAM : FITC was 1 : 1 or 1 : 2. Bioluminescence imaging showed that the diffusion of FITC-BAM in situ gel group was significantly delayed compared with the negative control group. This study demonstrated that the thermosensitive in situ gel can effectively delay the release of boanmycin hydrochloride, and extend the retention time in vivo.

Preclinical models in electrochemotherapy: the role of veterinary patients.

Electrochemotherapy is a tumor treatment that adapts the systemic or local delivery of anticancer drugs by the application of permeabilizing electric pulses with appropriate amplitude and waveforms. This allows the use of lipophobic drugs, which frequently have a narrow therapeutic index, with a decreased morbidity for the patient, while maintaining appropriate anticancer efficacy. Electrochemotherapy is used in humans for the treatment of cutaneous neoplasms or the palliation of skin tumor metastases, and a standard operating procedure has been devised. In veterinary oncology, the electrochemotherapy approach is gaining popularity, becoming a first-line treatment in consideration of its high efficacy and low toxicity. This review summarizes the state of the art in veterinary oncology as a preclinical model.

Radiolabeling of bleomycin-glucuronide with (131)I and biodistribution studies using xenograft model of human colon tumor in Balb/C mice.

Bleomycin-glucuronide (BLMG) is the glucuronide conjugate of BLM. In the present study, BLMG was primarily enzymatically synthesized by using a microsome preparate separated from rat liver, labeled with (131)I by iodogen method with the aim of generating a radionuclide-labeled prodrug, and investigated its bioaffinities with tumor-bearing Balb/C mice. Quality control procedures were carried out using thin-layer radiochromatography and high-performance liquid chromatography. Tumor growing was carried out by following Caco-2 cell inoculation into mice. Radiolabeling yield was found to be about 65%. Results indicated that (131)I-labeled BLMG ((131)I-BLMG) was highly stable for 24 hours in human serum. Biodistribution studies were carried out with male Albino Wistar rats and colorectal adenocarcinoma tumor-bearing female Balb/C mice. The biodistribution results in rats showed high uptake in the prostate, the large intestine, and the spinal cord. In addition to this, scintigraphic results agreed with those of biodistributional studies. Xenography studies with tumor-bearing mice demonstrated that tumor uptakes of (131)I-BLM and (131)I-BLMG were high in the first 30 minutes postinjection. Tumor-bearing animal studies demonstrated that (131)I-BLMG was specially retained in colorectal adenocarcinoma with high tumor uptake. Therefore, (131)I-BLMG can be proven to be a promising imaging and therapeutic agent, especially for colon cancer in nuclear medical applications.

Photochemical internalization of bleomycin for glioma treatment.

We study the use of photochemical internalization (PCI) for enhancing chemotherapeutic response to malignant glioma cells in vitro. Two models are studied: monolayers consisting of F98 rat glioma cells and human glioma spheroids established from biopsy-derived glioma cells. In both cases, the cytotoxicity of aluminum phthalocyanine disulfonate (AlPcS2a)-based PCI of bleomycin was compared to AlPcS(2a)-photodynamic therapy (PDT) and chemotherapy alone. Monolayers and spheroids were incubated with AlPcS(2a) (PDT effect), bleomycin (chemotherapy effect), or AlPcS(2a)+bleomycin (PCI effect) and were illuminated (670 nm). Toxicity was evaluated using colony formation assays or spheroid growth kinetics. F98 cells in monolayer/spheroids were not particularly sensitive to the effects of low radiant exposure (1.5 J/cm(2) @ 5 mW/cm(2)) AlPcS(2a)-PDT. Bleomycin was moderately toxic to F98 cells in monolayer at relatively low concentrations-incubation of F98 cells in 0.1 µg/ml for 4 h resulted in 80% survival, but less toxic in human glioma spheroids respectively. In both in vitro systems investigated, a significant PCI effect is seen. PCI using 1.5 J/cm(2) together with 0.25 µg/ml bleomycin resulted in approximately 20% and 18% survival of F98 rat glioma cells and human glioma spheroids, respectively. These results show that AlPcS(2a)-mediated PCI can be used to enhance the efficacy of chemotherapeutic agents such as bleomycin in malignant gliomas.