[Show abstract][Hide abstract] ABSTRACT: To review the ocular pharmacology and antitumor activity of topotecan for the treatment of retinoblastoma by an evaluation of different routes of administration.
[Show abstract][Hide abstract] ABSTRACT: Nanotechnology has become a key tool to overcome the main (bio)pharmaceutical drawbacks of drugs and to enable their passive or active targeting to specific cells and tissues. Pediatric therapies usually rely on the previous clinical experience in adults. However, there exists scientific evidence that drug pharmacokinetics and pharmacodynamics in children differ from those in adults. For example, the interaction of specific drugs with their target receptors undergoes changes over the maturation of the different organs and systems. A similar phenomenon is observed for toxicity and adverse effects. Thus, it is clear that the treatment of disease in children cannot be simplified to the direct adjustment of the dose to the body weight/surface. In this context, the implementation of innovative technologies (e.g., nanotechnology) in the pediatric population becomes extremely challenging. The present article overviews the different attempts to use nanotechnology to treat diseases in the pediatric population. Due to the relevance, though limited available literature on the matter, we initially describe from preliminary in vitro studies to preclinical and clinical trials aiming to treat pediatric infectious diseases and pediatric solid tumors by means of nanotechnology. Then, the perspectives of pediatric nanomedicine are discussed.
Advanced drug delivery reviews 05/2014; · 11.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diffuse intrinsic pontine gliomas (DIPGs) are highly infiltrative malignant glial neoplasms of the ventral pons that, due to their location within the brain, are unsuitable for surgical resection and consequently have a universally dismal clinical outcome. The median survival time is 9–12 months, with neither chemotherapeutic nor targeted agents showing substantial survival benefit in clinical trials in children with these tumors1. We report the identification of recurrent activating mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, in 21% of DIPG samples. Strikingly, these somatic mutations (encoding p.Arg206His, p.Arg258Gly, p.Gly328Glu, p.Gly328Val, p.Gly328Trp and p.Gly356Asp substitutions) have not been reported previously in cancer but are identical to mutations found in the germ line of individuals with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP)2 and have been shown to constitutively activate the BMP–TGF-β signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.
[Show abstract][Hide abstract] ABSTRACT: Using a mouse model of ependymoma-a chemoresistant brain tumor-we combined multicell high-throughput screening (HTS), kinome-wide binding assays, and in vivo efficacy studies, to identify potential treatments with predicted toxicity against neural stem cells (NSC). We identified kinases within the insulin signaling pathway and centrosome cycle as regulators of ependymoma cell proliferation, and their corresponding inhibitors as potential therapies. FDA approved drugs not currently used to treat ependymoma were also identified that posses selective toxicity against ependymoma cells relative to normal NSCs both in vitro and in vivo, e.g., 5-fluorouracil. Our comprehensive approach advances understanding of the biology and treatment of ependymoma including the discovery of several treatment leads for immediate clinical translation.
Cancer cell 09/2011; 20(3):384-99. · 25.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The authors demonstrated previously that the combination of topotecan (TPT) and carboplatin (CBP) was more effective than current chemotherapeutic combinations used to treat retinoblastoma in an orthotopic xenograft model. However, systemic coadministration of these agents is not ideal, because both agents cause dose-limiting myelosuppression in children.
To overcome the toxicity associated with systemic TPT and CBP, the authors explored subconjunctival delivery of TPT or CBP in an orthotopic xenograft model and in a genetic mouse model of retinoblastoma (Chx10-Cre;Rb(lox/lox);p107(-/-);p53(lox/lox)). The effects of combined subconjunctival CBP (CBP(subcon)) and systemic TPT (TPT(syst)) were compared with the effects of combined TPT(subcon) and CBP(syst.) at clinically relevant dosages.
Pharmacokinetic and tumor-response studies, including analyses of ocular and hematopoietic toxicity, revealed that CBP(subcon)/TPT(syst) was more effective and had fewer side effects than TPT(subcon)/CBP(syst).
For the first time, retinoblastoma was ablated and long-term vision was preserved in a mouse model by using a clinically relevant chemotherapy regimen. These results eventually may be translated into a clinical trial for children with this debilitating cancer.
Cancer 01/2011; 117(2):421-34. · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To study the role of drug transporters in central nervous system (CNS) penetration and cellular accumulation of erlotinib and its metabolite, OSI-420.
After oral erlotinib administration to wild-type and ATP-binding cassette (ABC) transporter-knockout mice (Mdr1a/b(-/-), Abcg2(-/-), Mdr1a/b(-/-)Abcg2(-/-), and Abcc4(-/-)), plasma was collected and brain extracellular fluid (ECF) was sampled using intracerebral microdialysis. A pharmacokinetic model was fit to erlotinib and OSI-420 concentration-time data, and brain penetration (P(Brain)) was estimated by the ratio of ECF-to-unbound plasma area under concentration-time curves. Intracellular accumulation of erlotinib was assessed in cells overexpressing human ABC transporters or SLC22A solute carriers.
P(Brain) in wild-type mice was 0.27 ± 0.11 and 0.07 ± 0.02 (mean ± SD) for erlotinib and OSI-420, respectively. Erlotinib and OSI-420 P(Brain) in Abcg2(-/-) and Mdr1a/b(-/-)Abcg2(-/-) mice were significantly higher than in wild-type mice. Mdr1a/b(-/-) mice showed similar brain ECF penetration as wild-type mice (0.49 ± 0.37 and 0.04 ± 0.02 for erlotinib and OSI-420, respectively). In vitro, erlotinib and OSI-420 accumulation was significantly lower in cells overexpressing breast cancer resistance protein (BCRP) than in control cells. Only OSI-420, not erlotinib, showed lower accumulation in cells overexpressing P-glycoprotein (P-gp) than in control cells. The P-gp/BCRP inhibitor elacridar increased erlotinib and OSI-420 accumulation in BCRP-overexpressing cells. Erlotinib uptake was higher in OAT3- and OCT2-transfected cells than in empty vector control cells.
Abcg2 is the main efflux transporter preventing erlotinib and OSI-420 penetration in mouse brain. Erlotinib and OSI-420 are substrates for SLC22A family members OAT3 and OCT2. Our findings provide a mechanistic basis for erlotinib CNS penetration, cellular uptake, and efflux mechanisms.
Clinical Cancer Research 11/2010; 17(1):89-99. · 7.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, increases brain parenchymal extracellular fluid (ECF) accumulation of topotecan, a substrate of the ATP-binding cassette (ABC) transporters P-glycoprotein (Pgp/MDR-1) and breast cancer resistance protein (BCRP/ABCG2). The effect of modulating these transporters on topotecan penetration in gliomas has not been thoroughly studied. Thus, we performed intracerebral microdialysis on mice bearing orthotopic human gliomas (U87 and MT330) and assessed topotecan tumor ECF (tECF) penetration and the effect of gefitinib on topotecan tECF penetration and intratumor topotecan distribution. We found that topotecan penetration (P(tumor)) of U87 was 0.96 +/- 0.25 (n = 7) compared with that of contralateral brain (P(contralateral), 0.42 +/- 0.11, n = 5; P = 0.001). In MT330 tumors, P(tumor) (0.78 +/- 0.26, n = 6) and P(contralateral) (0.42 +/- 0.11, n = 5) also differed significantly (P = 0.013). Because both tumor models had disrupted blood-brain barriers and similar P(tumor) values, we used U87 and a steady-state drug administration approach to characterize the effect of gefitinib on topotecan P(tumor). At equivalent plasma topotecan exposures, we found that P(tumor) after gefitinib administration was lower. In a separate cohort of animals, we determined the volume of distribution of unbound topotecan in tumor (V(u,tumor)) and found that it was significantly higher in groups receiving gefitinib, implying that gefitinib administration leads to a greater proportion of intracellular topotecan. Our results provide crucial insights into the role that transporters play in central nervous system drug penetration and provide a better understanding of the effect of coadministration of transporter modulators on anticancer drug distribution within a tumor.
Cancer Research 06/2010; 70(11):4499-508. · 9.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We previously reported that administration of a single dose of gabapentin (GBP) immediately after training improves memory of mice in an inhibitory avoidance task (IA), whereas GBP administered repeatedly for 7 days impairs memory. This is in accordance with the observation that long-term clinical treatment with GBP may be associated with adverse cognitive side effects. In the present work we used a GBP-loaded poly(epsilon-caprolactone) implant, allowing controlled release of the drug and maintenance of constant plasma levels over 1 week. When GBP-loaded implants were inserted subcutaneously into mice, immediately after training in the IA task, memory consolidation was enhanced. Moreover, GBP released from implants had an anticonvulsant action against pentylenetetrazole-induced seizures. These results suggest that maintenance of stable GBP plasma levels could protect against seizures without causing memory impairment. Hence, the adverse cognitive effects might be avoided by stabilizing plasma levels of the drug.
[Show abstract][Hide abstract] ABSTRACT: Drug low solubility and stability in physiological environment constitutes a main hurdle in attaining the appropriate bioavailability. Several polymer-based nanotechnologies are being intended in order to optimize the technological (e.g., solubility, stability, bioavailability, etc.) aspects of drugs. Among them, polymeric nanoparticles, dendrimers, polymeric micelles and polymersomes appear as the most attractive and promising. Concomitant with efforts in the academic arena that aim at overcoming these drawbacks and, strongly motivated by a constant search for innovative therapeutic strategies, a very rich intellectual property has been produced in the last years. This phenomenon has been moved forward by the fact that aiming at registering off-patent or about to be off patent products, pharmaceutical companies develop new formulations of old products. Another ambit of research is the design of more sophisticated drug delivery devices (e.g., targeting, localized delivery) in order to minimize adverse effects that make the administration of certain drugs risky or to enhance the patient compliance. A recent report by Cientifica Ltd. foresees a critical expansion in the nano-based drug delivery market from its current $3.4B (about 10% of the total drug delivery market) to about $26B by 2012, being this only a promising beginning for the $220B forecasted by 2015. Given the present circumstances, we are probably witnessing a new revolution in therapeutics that will take treatment to a different dimension. The goal of the present review is to provide a comprehensive and updated patent compilation of the most recent inventions relying on polymer-based nanoparticulated carriers (polymeric nanoparticles, dendrimers, polymeric micellles and polymersomes) for the optimization of the technological aspects of therapeutic agents. This article also includes a thorough review of the patents made public in recent years (2003-2007).
Recent Patents on Biomedical Engineering. 01/2010; 1(1).
[Show abstract][Hide abstract] ABSTRACT: Tuberculosis (TB) is the second most deadly infectious disease. Despite potentially curative pharmacotherapies being available for over 50 years, the length of the treatment and the pill burden can hamper patient lifestyle. Thus, low compliance and adherence to administration schedules remain the main reasons for therapeutic failure and contribute to the development of multi-drug-resistant (MDR) strains. Pediatric patients constitute a high risk population. Most of the first-line drugs are not commercially available in pediatric form. The design of novel antibiotics attempts to overcome drug resistance, to shorten the treatment course and to reduce drug interactions with antiretroviral therapies. On the other hand, the existing anti-TB drugs are still effective. Overcoming technological drawbacks of these therapeutic agents as well as improving the effectiveness of the drug by targeting the infection reservoirs remains the central aims of Pharmaceutical Technology. In this framework, nanotechnologies appear as one of the most promising approaches for the development of more effective and compliant medicines. The present review thoroughly overviews the state-of-the-art in the development of nano-based drug delivery systems for encapsulation and release of anti-TB drugs and discusses the challenges that are faced in the development of a more effective, compliant and also affordable TB pharmacotherapy.
Advanced drug delivery reviews 11/2009; 62(4-5):547-59. · 11.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose. Intravenous or periocular topotecan has been proposed as new treatment modality for patients with advanced intraocular retinoblastoma, but systemic topotecan lactone exposure induced by both approaches may cause toxicity. The purpose of this study was to develop a topotecan-loaded ocular delivery system to minimize systemic exposure and achieve selective transscleral penetration. Methods. Biocompatible polymer implants containing low (0.3 mg) or high (2.3 mg) topotecan load were manufactured and characterized in vitro. Adrenaline (500 mug) was coloaded to induce local vasoconstriction in vivo in 2 of 4 animal groups. Implants were inserted into the episclera of rabbits, and topotecan (lactone and total) concentrations in ocular tissues and plasma were determined over a period of 48 hours. Results. In vitro, implants released 30% to 50% of the loaded drug within 48 hours and 45% to 70% by day 10. In vivo, topotecan lactone was highly accumulated in locally exposed ocular tissues (ranging from 10(5) to 10(6) ng/g in sclera and choroid and 10(2) to10(3) ng/g in retina) over 48 hours with all the formulations studied. Low vitreous topotecan lactone levels (approximately 5 ng/mL) were found in animals receiving concomitant local vasoconstriction and high load implants. Topotecan lactone concentrations in plasma and in contralateral eyes were minimal or undetectable as a marker of tissue selectivity of the proposed strategy. Conclusions. These studies may contribute to improving the efficacy and safety of chemotherapy treatments for retinoblastoma and may support the role of the local vasculature and tissues promoting drug clearance and local accumulation during transscleral drug delivery.
[Show abstract][Hide abstract] ABSTRACT: Topotecan is a substrate of the ATP-binding cassette transporters P-glycoprotein (P-gp/MDR1) and breast cancer resistance protein (BCRP). To define the role of these transporters in topotecan penetration into the ventricular cerebrospinal fluid (vCSF) and brain parenchymal extracellular fluid (ECF) compartments, we performed intracerebral microdialysis on transporter-deficient mice after an intravenous dose of topotecan (4 mg/kg). vCSF penetration of unbound topotecan lactone was measured as the ratio of vCSF-to-plasma area under the concentration-time curves. The mean +/- SD ratios for wild-type, Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice were 3.07 +/- 0.09, 2.57 +/- 0.17, 1.63 +/- 0.12, and 0.86 +/- 0.05, respectively. In contrast, the ECF-to-plasma ratios for wild-type, Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice were 0.36 +/- 0.06, 0.42 +/- 0.06, and 0.88 +/- 0.07. Topotecan lactone was below detectable limits in the ECF of Mdr1a/b(-/-) mice. When gefitinib (200 mg/kg) was preadministered to inhibit Bcrp1 and P-gp, the vCSF-to-plasma ratio decreased to 1.29 +/- 0.09 in wild-type mice and increased to 1.13 +/- 0.13 in Mdr1a/b(-/-)Bcrp1(-/-) mice, whereas the ECF-to-plasma ratio increased to 0.74 +/- 0.14 in wild-type and 1.07 +/- 0.03 in Mdr1a/b(-/-)Bcrp1(-/-) mice. Preferential active transport of topotecan lactone over topotecan carboxylate was shown in vivo by vCSF lactone-to-carboxylate area under the curve ratios for wild-type, Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice of 5.69 +/- 0.83, 3.85 +/- 0.64, 3.61 +/- 0.46, and 0.78 +/- 0.19, respectively. Our results suggest that Bcrp1 and P-gp transport topotecan into vCSF and out of brain parenchyma through the blood-brain barrier. These findings may help to improve pharmacologic strategies to treat brain tumors.
Cancer Research 07/2009; 69(14):5885-92. · 9.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Worldwide, over 40 million people are infected with the Human Immunodeficiency Virus (HIV). The High Activity Antiretroviral Therapy (HAART) combines at least three antiretroviral (ARV) drugs and, for over a decade, has been used to extend the lifespan of the HIV-infected patients. Chronic intake of HAART is mandatory to control HIV infection. The frequent administration of several drugs in relatively high doses is a main cause of patient incompliance and a hurdle toward the fulfillment of the pharmacotherapy. High adherence to HAART does not lead to complete HIV virus elimination from the host. Intracellular and anatomical viral reservoirs are responsible for the perpetuation of the infection. Active transport mechanisms involving proteins of the ATP-binding cassette superfamily prevent the penetration of ARV drugs into the brain and may account for the limited bioavailability after oral administration. A new research that addresses from simple organoleptic or technological problems to more complex issues involving the targeting of specific tissues and organs has emerged. With the aim to reduce dosing frequency, to improve the compliance of the existing pharmacotherapy and to target viral reservoirs, the design of drug delivery systems (DDS) is becoming complementary to new drug discovery. Based on the common molecular features that characterize the different families of ARV drugs, the present review describes state-of-the-art ARV DDS and thoroughly discusses the challenges in the development of medicines with enhanced biopharmaceutical properties. In addition, a number of specific issues such as pediatric HAART, preventive pharmacotherapy and specific HIV-associated ethical issues are addressed in an integrative manner. Finally, the impact of such novel drug development on the Pharmaceutical Technology field is discussed.
Journal of Controlled Release 06/2009; 138(1):2-15. · 7.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this work was to develop indinavir pediatric anti-HIV/AIDS formulations enabling convenient dose adjustment, ease of oral administration, and improved organoleptic properties by means of the generation of drug-loaded microparticles made of a polymer that is insoluble under intake conditions and dissolves fast in the stomach in order to completely release the active agent. Indinavir-loaded microparticles made of a pH-dependent polymeric excipient soluble at pH < 5, Eudragit E100, were prepared using a double emulsion solvent diffusion technique and the in vitro release profiles characterized. Finally, taste masking properties were evaluated in blind randomized sensory experiments by ten healthy human volunteers. The use of a w/o/o emulsion system resulted in indinavir loads around 90%. Thermal analysis of the microparticles by differential scanning calorimetry revealed that indinavir appeared mainly dispersed at the molecular level. Concentrations of residual organic solvents as determined by gas chromatography were below the upper limits specified by the European Pharmacopeia for pharmaceutical oral formulations. Then, the behavior of drug-containing microparticles in aqueous media at different pH values was assessed. While they selectively dissolved in gastric-like medium, in tap water (intake conditions), the matrix remained almost unchanged and efficiently prevented drug dissolution. Finally, sensoring taste tests performed by volunteers indicated that systems with indinavir loads approximately 15% displayed acceptable taste. This work explored the production of indinavir-containing microparticles based on a common pharmaceutical excipient as a means for the improvement of medicines of drugs involved in the treatment of HIV/AIDS. For systems containing about 15% drug, taste studies confirmed the acceptability of the formulation. In pediatric regimes, this composition would require an acceptable amount of formulation (0.7-1.5 g).
[Show abstract][Hide abstract] ABSTRACT: To identify the maximum tolerated dose and dose-limiting toxicity of periocular topotecan in patients with relapsed or resistant intraocular retinoblastoma who are facing imminent enucleation.
For this phase I study, a starting dose of 0.5 mg of periocular topotecan administered through a 25-gauge needle was given with intrapatient escalation at a rate of 0.5 mg/cycle according to toxicity, up to a maximum dose of 2 mg. Two courses separated by 2 weeks were scheduled. Plasma levels of topotecan were measured by high-performance liquid chromatography in patients with available intravenous catheters.
Seven eyes of five patients were treated with a total of 14 courses of periocular topotecan. Only mild orbital edema occurred, and grade 1 vomiting developed in the first patient that was controlled with ondansetron for the following courses. Dose-limiting toxicity was not reached and the maximum tolerated dose was set at the target dose of 2 mg (n=5 eyes). Lactone topotecan systemic exposure was lower than 55 ng/mL x h and it correlated linearly with dose in this small cohort. Even though the study was not designed to assess response, one eye was preserved after a partial response, but the remaining six were enucleated, either after a short period of disease stabilization followed by further therapy with other agents in five patients or by rapidly progressive disease in one.
The dose limiting toxicity was not reached. Up to 2 mg of periocular topotecan could be given safely, but further studies are necessary to determine its effect on retinoblastoma (ClinicalTrials.gov number, NCT00460876).
[Show abstract][Hide abstract] ABSTRACT: Gabapentin (GBP) is a water soluble low molecular weight drug with anticonvulsivant and antinociceptive activity. In animal models, systemic administration regimes resembling chronic exposure to this drug (50mg/kg, twice a day during one week), induce memory impairment. Aiming to gain further insight on the mechanisms involved in this process, a monolithic implant that releases constant plasma levels during one-week was designed. GBP-loaded poly(epsilon-caprolactone) matrices were produced by means of a simple and reproducible melt-molding/compression procedure. In vitro release studies firstly comprised uncoated implants that displayed release profiles according to a pseudo-first order model. In order to further regulate the release, two-sided coated implants where drug-free layers would perform as membranes controlling the delivery rate were prepared. A more moderated burst effect and a relatively linear (zero-order) release between days 1 and 7 were apparent. Implants were investigated in vivo and the plasma levels monitored during 10 days. Findings indicated that after a more pronounced release during day 1 and the achievement of the levels in blood comparable to a twice-a-day intraperitoneal management, relatively constant levels were attained until day 7. Overall results support the usefulness of this manufacturing method for the production of implants to attain more prolonged GBP release profiles in memory animal studies.
European Journal of Pharmaceutics and Biopharmaceutics 07/2008; 70(2):666-73. · 3.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the extent and the mechanism by which topotecan, a candidate agent for the treatment of retinoblastoma, gains access to the vitreous when administered by periocular injection or intravenous infusion.
In vivo experiments were conducted in which albino rabbits received 1 mg topotecan by periocular injection (POI group; n = 30) or as a 30-minute intravenous infusion (IV group; n = 16). Plasma and vitreal topotecan concentrations were analyzed during the 10 hours after administration. A population pharmacokinetic model was fit to the data. Additionally, periocular injections were performed postmortem to study the effect of removing the blood vasculature barrier.
Potentially active lactone topotecan levels were detected in the vitreous in the POI and IV groups. Both administration schedules induced high total topotecan plasma exposures because of absorption from the periocular depot, though plasma lactone area under the curve (AUC) was significantly higher in the IV group. Similar vitreal concentrations were found in treated and control eyes in the POI group. The transfer from the periocular compartment to the vitreous was negligible. The absence of drug levels in the control eye of the postmortem-injected rabbits confirmed the systemic delivery of topotecan. Local toxicity was not observed.
As a consequence of a favored passage across the blood-retinal barrier, considerable topotecan vitreous levels were detected in a rabbit model after systemic or periocular administration. Transscleral entry in vivo was constrained by rapid clearance from the administration site.