Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1992-04-16
1994-02-08
Wityshyn, Michael G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530359, 530409, 514410, 514 2, 514 7, 424450, 540145, A61K 3140, A61K 3700, C07D48722, C07K 1516
Patent
active
052848310
DESCRIPTION:
DESCRIPTION
e in irradiation by about 1 MW-min.
In experiment 1 (Table 2), as well as other (n+ .sup.10 B) therapy experiments, it was noted that "cratering" of the tumor occurred, followed by scabbing and crusting of the skin surface. Animals receiving neutrons alone also showed such reaction. In order to determine if the irradiation itself was producing skin lesions, five non-tumor bearing mice were exposed for 1.8 MW min in a single acute dose (2.7 Gy of densely ionizing particles and less than 1 Gy of photons). The skin response was graded on a scale in which a score of 1 indicates erythema, and 2 to 3 indicates moist desquamation of varying severity. The skin response indicated that the cratering noted was, in fact, a response of the tumor to the irradiation.
It is clear from the these experiments that the presence of BOPP produced a significant therapeutic effect, as for example in experiment 4, where the GDR was extended by almost a factor of 2, from 3.3 (neutrons alone) to 6.3 (neutron +BOPP). Using Equation 3, it can be estimated that the administration of 45 .mu.g .sup.10 B/gbw produces tumor growth retardation similar to that from 4 MW-min of beam alone (i.e., .about.1.3 Gy of densely, ionizing particles, accompanied by .about.0.5 Gy of sparsely ionizing particles).
EXAMPLE 10
BOPP was incubated (4 .mu.m) with fresh human plasma for 30 minutes at 37.degree. C. The plasma lipoprotein fractions were then isolated by density gradient preparative ultracentrifugation and examined for porphyrin content by UV-vis spectrometry. Approximately 55.+-.10% of the administered porphyrin bound to the HDL protein fraction, 25% to LDL and the remaining 20% to VLDL. These three fractions contained 90.+-.10% of the total porphyrin.
We have examined the in vitro uptake of a BOPP-LDL conjugate in human colonic carcimona (LoVo) and human hepatocyte (Chang) cell lines. Both lines are known to express high levels of the LDL receptor. Cell uptake and distribution was observed through microspectrofluorimetric analysis and high sensitivity image analysis. Intracellular boron concentrations exceeding 200 .mu.g .sup.10 B/g were easily achieved.
It is to be understood that while the invention has been described above in conjunction with preferred specific embodiments, the description and examples are intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims.
1. A composition, useful for delivery of boron atoms to cells, comprising: ##STR14## where R.sup.3 is a closo-carborane and R.sup.2 is an alkyl or an aryl having 1 to about 7 carbon atoms; and
2. The composition as in claim 1 wherein R.sup.3 is a substituted or unsubstituted 1,2-icosahedral isomer or a 1,7-icosahedral isomer enriched in .sup.10 boron.
3. The composition as in claim 1 wherein the porphyrin compound is substantially encapsulated by the at least one lipoprotein.
4. The composition as in claim 3 wherein the at least one lipoprotein includes LDL.
5. The composition as in claim 1 wherein R.sup.3 is a substituted or unsubstituted 1,2-icosahedral or 1,7-icosahedral isomer and R.sup.2 is methyl.
6. A method of preparing a cellular drug delivery composition comprising: of the pyrrole rings thereof at pyrrole ring positions 2 and 4, the substituents including a glycol with two hydroxyl groups; and, chloride having the structure ##STR15## wherein R.sup.3 is a closo-carborane, the contacting conducted in the presence of a reaction rate enhancing amount of p-dimethylamino pyridine, to acylate at least one hydroxyl group of each bis-glycol sustituent and to form a porphine reaction product having at least one R.sup.3 group covalently bonded to each of the pyrrole rings at positions 2 and 4.
7. The method as in claim 6 wherein the porphine precursor compound has substituents at pyrrole ring positions 6 and 7, the bis-glycol substituents being at pyrrole ring positions 2 and 4 and the substituents at positions 6 and 7 having the structure --C.sub.2 H.sub.4 --COOR.sup.2 and R.sup.2 is an alkyl or an aryl having 1 to about
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Kahl Stephen B.
Koo Myoung-Seo
Sayala C.
The Regents of the University of California
Wityshyn Michael G.
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