Optimization of macromolecular prodrugs of the antitumor antibiotic adriamycin

In our earlier work [10] on aminoribosyl-bound prodrugs of adriamycin (ADR) using poly(α-l-glutamic acid) (PGA) grafted in high yield (90–100 mol.%) with various peptide spacers as a plasma-soluble macromolecular carrier we observed rather low cytotoxic activities in L1210 leukemia and B16 melanoma in vitro assays. These results may be tentatively explained by a decreased susceptibility of the spacer-bound adriamycin moiety to hydrolysis by lysosomal enzymes due to the high spacer load. This hypothesis was tested by the study of two conjugates prepared by a different route. Peptide conjugates of adriamycin (Gly-Gly-Leu—ADR and Gly-Gly-Gly-Leu—ADR) were synthesized using the trityl N-protecting group and were coupled to PGA in 4.5 mol.% load according to the method described earlier [11]. However, these conjugates were almost totally devoid of cell growth-inhibiting activity in L1210 and B16 in vitro tests. The data suggest that either the uptake of the polymeric prodrugs into the cell by pinocytosis is highly dependent on spacer load or molecular weight, or that lysosomal digestion is too slow for efficient release of ADR. Possibly, enzymatic degradation of PGA which is known to occur only between pH 4 and 6 is rate-limiting for release of the drug. Current studies include the enzymatic degradation of PGA—peptide spacer—drug systems using p-nitroaniline as a model drug and papain as the enzyme. By variation of the length and load of spacer it can be estimated under which conditions the release of drug (using UV spectrometry) is faster than degradation of the polymer (as determined by viscometry). In addition, the uptake of PGA and derivatives with a fluorescent label into tumor cells is studied using laser flow cytometry and laser microscopy

The synthesis and characterization of polypeptide-adriamycin conjugates and its complexes with adriamycin. Part I

Poly(α-l-glutamic acid) (PGA) was grafted with amino acid and oligopeptide spacers up to 5 amino acids with the use of N,N'-carbonyldiimidazole and 2,3-dihydro-1,2-benz-isothiazole-3-on-1, 1-dioxide (saccharin) as an additive, and these polypeptides were characterized. The antitumor antibiotic adriamycin was covalently coupled via an amide bond onto PGA and onto the grafted polymers with the use of N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ); these conjugates were characterized. The conjugates containing Gly—Gly—l-Leu spacer arms did yield free adriamycin upon digestion with papain. Adriamycin gave fairly stable complexes with PGA—adriamycin and branched poly peptide—adriamycin conjugates; these complexes were characterized

Biodegradable hollow fibres for the controlled release of drugs

Biodegradable hollow fibres of poly-l-lactic acid (PLLA) filled with a suspension of the contraceptive hormone levonorgestrel in castor oil were implanted subcutaneously in rats to study the rate of drug release, rate of biodegradation and tissue reaction caused by the implant. The in vivo drug release was compared with the release in vitro using different release media. Fibres, disinfected with alcohol showed a zero-order release, both in vitro and in vivo, for over 6 months. Fibres, either γ-sterilized or disinfected with alcohol were harvested at time intervals ranging from 1 d to 6 months after implantation. Molecular weights of PLLA, tensile strengths, and remaining amounts of drug were determined as a function of time.\ud \ud The tissue reaction can be described as a very moderate foreign body reaction with the initial presence of macrophages, which are gradually replaced by fibroblasts which form a collagen capsule. Molecular weight determinations of PLLA showed a decrease from an initial Mw of 1.59x10 5 to 5.5 × 10 4 in 4 months (after alcohol sterilization). A gradual decrease in fibre strength with time was observed which did not significantly impair the release rate of levonorgestrel

DSP Prototyping of Blind Adaptive MMSE Multiuser Detection for Cellular Wireless CDMA Systems

Blind adaptive Minimum Mean Square Error (MMSE) detection is theoretically one of the most promising multiuser detection techniques for cellular wireless Code-Division Multiple Access (CDMA) systems, but its implementation has not yet been studied extensively. Therefore the goal of the research described in this paper is to study the implementation of blind adaptive MMSE detection on the current generation of DSPs and to determine the detectedbits-per-second performance that can be achieved by such an implementation. The blind adaptive MMSE detection algorithm is first analyzed in order to determine how it can be implemented. The algorithm is then implemented in a simulator and the simulator is used to study the adaptive behavior of the algorithm. The simulator is also used to verify the correctness of the implementation of the algorithm by comparing the simulation results obtained with the simulator to simulation results published in literature. When the algorithm is shown to be correct it is implemented on and optimized for a floating-point DSP. This DSP implementation is used to determine the detected-bits-per-second performance that can be achieved by blind adaptive MMSE detection on modern DSPs

Implementaion of a combined OFDM-demodulation and WCDMA-equalization module

For a dual-mode baseband receiver for the OFDMWireless LAN andWCDMA standards, integration of the demodulation and equalization tasks on a dedicated hardware module has been investigated. For OFDM demodulation, an FFT algorithm based on cascaded twiddle factor decomposition has been selected. This type of algorithm combines high spatial and tempo- ral regularity in the FFT data-flow graphs with a minimal number of computations. A frequency-domain algorithm based on a circulant channel approximation has been se- lected forWCDMA equalization. It has good performance, low hardware complexity and a low number of computa- tions. Its main advantage is the reuse of the FFT kernel, which contributes to the integration of both tasks. The demodulation and equalization module has been de- scribed at the register transfer level with the in-house developed Arx language. The core of the module is a pipelined radix-23 butterfly combined with a complex mul- tiplier and complex divider. The module has an area of 0.447 mm2 in 0.18 μm technology and a power consump- tion of 10.6 mW. The proposed module compares favorably with solutions reported in literature. Keywords—OFDMdemodulation,WCDMA, frequency- domain equalization, architecture design

Characterization of Poly(A)-Protein Complexes Isolated from Free and Membrane-Bound Polyribosomes of Ehrlich Ascites Tumor Cells

Proteins present in messenger ribonucleoprotein particles were labeled with [35S]-methionine in Ehrlich ascites tumor cells in which synthesis of new ribosomes was inhibited. Poly(A)-protein complexes were isolated from free and membrane-bound polyribosomes by sucrose gradient centrifugation and affinity chromatography on oligo(dT)-cellulose. Both classes of Poly(A)-protein particles contain a poly(A) chain of about 70 adenyl residues and a protein with a molecular weight of 76000 attached to it