Surgical delivery of drug releasing poly(lactic-co-glycolic acid)/poly(ethylene glycol) paste with in vivo effects against glioblastoma

Introduction

The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma.

Methods

Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model.

Results

Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour.

Conclusions

Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models.     

Congestive Heart Failure: A Case of Protein Misfolding

This article describes an interesting case of a patient presenting with congestive heart failure found to have restrictive cardiomyopathy with initial laboratory evaluation showing hypogammaglobuminemia without a monoclonal band on serum and urine electrophoresis. This case highlights the clinically significant cardiac manifestation caused by protein misfolding, a defect in protein homeostasis. In addition, the utility of a relatively newer laboratory test, serum free light chains as well as the importance of clinical and pathophysiologic correlation is also discussed. We present a relatively uncommon cause of heart disease, cardiac amyloidosis in a patient with a systemic plasma cell dyscrasia, and multiple myeloma.     

Diagnosing pneumonia in rural Thailand: Digital cameras versus film digitizers for chest radiograph teleradiology.

BACKGROUND: Accurate surveillance for pneumonia requires standardized classification of chest radiographs. Digital imaging permits rapid electronic transfer of data to radiologists, and recent improvements in digital camera technology present high quality, yet cheaper, options. METHODS: We evaluated the comparative utility of digital camera versus film digitizer in capturing chest radiographs in a pneumonia surveillance system in rural Thailand using a panel of radiologists; the gold standard was the hard-copy radiograph. We calculated sensitivity and specificity and conducted a receiver operator characteristics (ROC) analysis. RESULTS: Of the 192 radiographs from patients with clinical pneumonia, 166 (86%) were classified as pneumonia on the hard copies. Sensitivity and specificity for identifying pneumonia were 89% and 73% for the camera and 90% and 65% for the digitizer. In the ROC analysis, there was no statistically significant difference in the area under the curve (camera, 0.86; film digitizer, 0.91, p = 0.29). The digital camera set cost 965 dollars compared to 3000 dollars for the film digitizer. CONCLUSION: Detection of pneumonia was not measurably compromised by using digital cameras compared with film digitizers. The 3-fold lower cost of the digital camera makes this technology an affordable and widely accessible alternative for surveillance systems, vaccine trials, and perhaps clinical use.     

IgG Against Dengue Virus in Healthy Blood Donors,Zanzibar, Tanzania

We conducted a seroprevalence survey among 500 healthy adult donors at Zanzibar National Blood Transfusion Services. Dengue virus IgG seroprevalence was 50.6% and independently associated with age and urban residence. These data will aid in building a surveillance, preparedness, and response plan for dengue virus infections in the Zanzibar Archipelago.Key words: dengue, seroprevalence, Zanzibar, viruses, vector-borne infections     

Outcome of living donor renal allograft survival in children with focal segmental glomerulosclerosis

Abstract:  FSGS is the most frequent GN that may recur in a renal allograft. Compared with adults, the impact of FSGS on graft survival appears to be more significant in children. Thus we decided to assess graft survival and complications after renal transplantation in children with FSGS. Outcome of renal transplantation in 25 children with FSGS who received a renal transplant at Labafi Nejad Hospital was studied and compared with 75 patients as a control group. The mean follow-up duration was 68.16 (s.d. = 41.93) months. Other than demographics, variables such as DGF, acute rejection, number of acute rejection episodes, and graft failure in both groups were evaluated. Acute rejection was seen in 22/25 (88%) of FSGS group, compared to 40/75 (53.3%) in the control group. This difference was statistically significant (p = 0.001). DGF was seen in 4/25 (16%) and 13/75 (17.3%) in the FSGS and control groups, respectively (p = N.S.). The mean graft survival time was 115.61 (s.e.m. = 12.56) and 155.56 (s.e.m. = 7.16) month in FSGS and control group, respectively (p = N.S.). We demonstrated that graft function and survival were not significantly different in the FSGS and control patients. However, acute rejection episodes were more common in FSGS patients but without a significant impact on graft survival.     

Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1

The gene for retinitis pigmentosa 3 (RP3), the most frequent form of X- linked RP (XLRP), has been mapped previously to a chromosome interval of less than 1000 kbp between the DXS1110 marker and the OTC locus at Xp21.1-p11.4. Employing a novel technique, YAC Representation Hybridization (YRH)', we have recently identified a small XLRP associated microdeletion in this interval, as well as several putative exons including the 3' end of a gene that was truncated by the deletion. cDNA library screening and sequencing of a cosmid centromeric to the deletion has now enabled us to identify numerous additional exons and to detect several point mutations in patients with XLRP. The predicted gene product shows homology to RCC1, the guanine-nucleotide- exchange factor (GEF) of the Ras-like GTPase Ran. Our findings suggest that we have cloned the long-sought RP3 gene, and that it may encode the GEF of a retina-specific GTP-binding protein.      

Multifunctional unimolecular micelles for cancer-targeted drug delivery and positron emission tomography imaging

A multifunctional unimolecular micelle made of a hyperbranched amphiphilic block copolymer was designed, synthesized, and characterized for cancer-targeted drug delivery and non-invasive positron emission tomography (PET) imaging in tumor-bearing mice. The hyperbranched amphiphilic block copolymer, Boltorn(?) H40-poly(L-glutamate-hydrazone-doxorubicin)-b-poly(ethylene glycol) (i.e., H40-P(LG-Hyd-DOX)-b-PEG), was conjugated with cyclo(Arg-Gly-Asp-D-Phe-Cys) peptides (cRGD, for integrin α(v)β(3) targeting) and macrocyclic chelators (1,4,7-triazacyclononane-N, N', N'-triacetic acid [NOTA], for (64)Cu-labeling and PET imaging) (i.e., H40-P(LG-Hyd-DOX)-b-PEG-OCH(3)/cRGD/NOTA, also referred to as H40-DOX-cRGD). The anti-cancer drug, doxorubicin (DOX) was covalently conjugated onto the hydrophobic segments of the amphiphilic block copolymer arms (i.e., PLG) via a pH-labile hydrazone linkage to enable pH-controlled drug release. The unimolecular micelles exhibited a uniform size distribution and pH-sensitive drug release behavior. cRGD-conjugated unimolecular micelles (i.e., H40-DOX-cRGD) exhibited a much higher cellular uptake in U87MG human glioblastoma cells due to integrin α(v)β(3)-mediated endocytosis than non-targeted unimolecular micelles (i.e., H40-DOX), thereby leading to a significantly higher cytotoxicity. In U87MG tumor-bearing mice, H40-DOX-cRGD-(64)Cu also exhibited a much higher level of tumor accumulation than H40-DOX-(64)Cu, measured by non-invasive PET imaging and confirmed by biodistribution studies and ex vivo fluorescence imaging. We believe that unimolecular micelles formed by hyperbranched amphiphilic block copolymers that synergistically integrate passive and active tumor-targeting abilities with pH-controlled drug release and PET imaging capabilities provide the basis for future cancer theranostics.