Novel gallium(III) complexes transported by MDR1 P-glycoprotein: potential PET imaging agents for probing P-glycoprotein-mediated transport activity in vivo

AbstractBackground: Multidrug resistance (MDR) mediated by expression of MDR1 P-glycoprotein (Pgp) represents one of the best characterized barriers to chemotherapy in cancer patients. Positron emission tomography (PET) agents for analysis of Pgp-mediated drug transport activity in vivo would enable noninvasive assessment of chemotherapeutic regimens and MDR gene therapy.Results: Candidate Schiff-base phenolic gallium(III) complexes were synthesized from their heptadentate precursors and gallium(III)acetylacetonate. Crystal structures demonstrated a hexacoordinated central gallium with overall trans-pseudo-octahedral geometry. Radiolabeled 67Ga-complexes were obtained in high purity and screened in drug-sensitive (Pgp−) and MDR (Pgp+) tumor cells. Compared with control, lead compound 6 demonstrated antagonist-reversible 55-fold lower accumulation in Pgp-expressing MDR cells. Furthermore, compared with wild-type control, quantitative pharmacokinetic analysis showed markedly increased penetration and retention of 6 in brain and liver tissues of mdr1a/b(−/−) gene disrupted mice, correctly mapping Pgp-mediated transport activity at the capillary blood–brain barrier and hepatocellular biliary cannalicular surface in vivo.Conclusions: These results indicate that gallium(III) complex 6 is recognized by MDR1 Pgp as an avid transport substrate, thereby providing a useful scaffold to generate 68Ga radiopharmaceuticals for molecular imaging of Pgp transport activity in tumors and tissues in vivo using PET

Analysis of the Ex Vivo and In Vivo Antiretroviral Activity of Gemcitabine

Replication of retroviral and host genomes requires ribonucleotide reductase to convert rNTPs to dNTPs, which are then used as substrates for DNA synthesis. Inhibition of ribonucleotide reductase by hydroxyurea (HU) has been previously used to treat cancers as well as HIV. However, the use of HU as an antiretroviral is limited by its associated toxicities such as myelosuppression and hepatotoxicity. In this study, we examined the ribonucleotide reductase inhibitor, gemcitabine, both in cell culture and in C57Bl/6 mice infected with LP-BM5 murine leukemia virus (LP-BM5 MuLV, a murine AIDS model). Gemcitabine decreased infectivity of MuLV in cell culture with an EC50 in the low nanomolar range with no detectable cytotoxicity. Similarly, gemcitabine significantly decreased disease progression in mice infected with LP-BM5. Specifically, gemcitabine treatment decreased spleen size, plasma IgM, and provirus levels compared to LP-BM5 MuLV infected, untreated mice. Gemcitabine efficacy was observed at doses as low as 1 mg/kg/day in the absence of toxicity. Higher doses of gemcitabine (3 mg/kg/day and higher) were associated with toxicity as determined by a loss in body mass. In summary, our findings demonstrate that gemcitabine has antiretroviral activity ex vivo and in vivo in the LP-BM5 MuLV model. These observations together with a recent ex vivo study with HIV-1[1], suggest that gemcitabine has broad antiretroviral activity and could be particularly useful in vivo when used in combination drug therapy

A retrospective study of Human Immunodeficiency Virus transmission, mortality and loss to follow-up among infants in the first 18 months of life in a prevention of mother-to-child transmission programme in an urban hospital in KwaZulu-Natal, South Africa

<p>Abstract</p> <p>Background</p> <p>Follow up of Human Immunodeficiency Virus (HIV)-exposed infants is an important component of Prevention of Mother-to-Child Transmission (PMTCT) programmes in order to ascertain infant outcomes post delivery. We determined HIV transmission, mortality and loss to follow-up (LTFU) of HIV-exposed infants attending a postnatal clinic in an urban hospital in Durban, South Africa.</p> <p>Methods</p> <p>We conducted a retrospective cohort study of infants born to women in the PMTCT programme at McCord Hospital, where mothers paid a fee for service. Data were abstracted from patient records for live-born infants delivered between 1 May 2008 and 31 May 2009. The infants’ LTFU status and age was based on the date of the last visit. HIV transmission was calculated as a proportion of infants followed and tested at six weeks. Mortality rates were analyzed using Kaplan-Meier (K-M), with censoring on 15 January 2010, LTFU or death.</p> <p>Results</p> <p>Of 260 infants, 155 (59.6%) remained in care at McCord beyond 28 weeks: one died at < 28 days, three died between one to six months; 34 were LTFU within seven days, 60 were LTFU by six months. K-M mortality rate: 1.7% at six months (95% confidence interval (CI): 0.6% to 4.3%). Of 220 (83%) infants tested for HIV at six weeks, six (2.7%, 95% CI: 1.1% to 5.8%) were HIV-infected. In Cox regression analysis, late antenatal attendance (≥ 28 weeks gestation) relative to attending in the first trimester was a predictor for infant LTFU (adjusted hazards ratio = 2.3; 95% CI: 1.0 to 5.1; p = 0.044).</p> <p>Conclusion</p> <p>This urban PMTCT programme achieved low transmission rates at six weeks, but LTFU in the first six months limited our ability to examine HIV transmission up to 18 months and determinants of mortality. The LTFU of infants born to women who attended antenatal care at 28 weeks gestation or later emphasizes the need to identify late antenatal attendees for follow up care to educate and support them regarding the importance of follow up care for themselves and their infants.</p