Core-shell tectodendrimers

Details Core-shell tectodendrimers Core-shell tectodendrimers

2002-01-24

2003-10-21

Woodward, Ana (Department: 1711)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

C424SDIG001

Reexamination Certificate

active

06635720

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a new class of materials generally comprising a core dendrimer molecule and a plurality of shell dendrimer molecules chemically bonded to the surface of the core dendrimer molecule.
BACKGROUND OF THE INVENTION
Dendritic macromolecules have received substantial attention during the past two decades on account of their unusual structural and chemical properties, such as their almost perfect isomolecularity (i.e., polydispersity near unity, e.g., 1.0003 to 1.0005 for dendrimers having a molecular weight of about 10,000), their well defined morphology (i.e., uniform size and shape), and their unusually high chemical functionality; and because of their actual and potential utility in diverse applications, such as in biomedicine, pharmaceuticals, personal care, industry, material science, materials engineering, and research. Known dendritic structures include various dendrimers, regular dendrons, controlled hyperbranched polymers, dendrigrafts, random hyperbranched polymers, bridged dendrimers, and others.
It is widely recognized that dendrons and dendrimers constitute a significant subclass of “dendritic polymers” and represent a unique combination of very high structural complexity, together with extraordinary structural control. The assembly of reactive monomers, branch cells or dendrons around atomic or molecular cores to produce dendrimers according to divergent or convergent dendritic branching principles is well known (see for example M. K. Lothian-Tomalia, D. M. Hedstaand, D. A. Tomalia, A. B. Padias, and H. K. Hall, Jr., Tetrahedron 53, 15495 (1997); D. A. Tomalia, A. M. Naylor and W. A. Goddard III, Angew. Chem. Int. Ed. Engl. 29(2), 138 (1990); and C. J. Hawker and J. M. J. Frechet, J. Am. Chem. Soc. 112, 7638 (1992). Systematic filling of space around cores with branch cells, as a function of generational growth stages, to provide discrete, quantized bundles of mass has been shown to be mathematically predictable (see D. A. Tomalia, Adv. Mater. 6, 529 (1994); P. R. Dvornic, D. A. Tomalia,
Chemistry In Britain
, 30(8), 641 (1994) and P. R. Dvornic, D. A. Tomalia, Macromol. Symp., 98, 403 (1995)). Predicted theoretical molecular weights have been confirmed by mass spectroscopy and other analytical methods. The resulting dendritic architectures have allowed the systematic control of molecular structural parameters such as size, shape, surface functionality, and interior functionality at the lower end of the nanoscale region, e.g., from about 1 to about 15 nanometers. It is well established that dendritic structures can be utilized to define confined spaces at the lower end of the nanoscale region (see for example R. Esfand and D. A. Tomalia,
Chemistry and Industry
, 11, 416 (1997)).
Divergent dendritic growth can be precisely controlled to form ideal dendritic polymers which obey mathematical formulas, at least through the first several generations of growth. However, because the radii of dendrimer molecules increase in a linear manner as a function of generation during ideal divergent growth, whereas the surface cells amplify according to geometric progression law, ideal dendritic growth does not extend indefinitely. There is a critical generation at which the reacting dendrimer surface does not have enough space to accommodate incorporation of all of the mathematically required new units. This stage in ideal dendritic growth is referred to as the de Gennes dense-packed stage. At this stage, the surface becomes so crowded with terminal functional groups that, although the terminal groups are chemically reactive, they are sterically prohibited from participating further in ideal dendritic growth. In other words, the de Gennes dense-packed stage is reached in divergent synthesis when the average free volume available to the reactive surface group decreases below the molecular volume required for the transition state of the desired reaction to extend the growth to the next generation. Nevertheless, the appearance of the de Gennes dense-packed stage in divergent synthesis does not preclude further dendritic growth beyond this point. It has been demonstrated by mass spectrographic studies that further increase in the molecular weight can occur beyond the de Gennes dense-packed stage. In the case of an ammonia core polyamidoamine (PAMAM) dendrimer, dendritic growth has been observed to generation
12
. However, at that generational level, experimentally observed molecular weights are lower than the mathematically calculated values. Products resulting from continuation of dendritic growth beyond the dense-packed stage are “imperfect” in structure, because some of the surface groups in the precursor generation are sterically precluded from undergoing further reaction. The number of functional groups on a dendrimer which has been grown past the de Gennes dense-packed stage will not correspond to the ideal, mathematically predicted value for that generation. In the case of PAMAM dendrimers (NH
3
core), a gradual digression from theoretical masses occurs for generations
5
-
8
, followed by a substantial break (i.e., about 23%) between generation
8
and generation
9
PAMAM dendrimers. This discontinuity is interpreted as a signature for the de Gennes dense-packed stage. It should be noted that the digression from theoretical masses for successive generations continues to decline monotonically with each successive generation beyond generation
9
. A similar trend is noted for other dendrimers.
In addition to the deviation from expected molecular weight, the interior of dendritic polymers of higher generations beyond the de Gennes dense-packed stage becomes less accessible to guest molecules. For example, it has been shown that the interior of hydroxyl terminated (ethylene diamine core) PAMAM dendrimers from generation
1
to generation
6
are completely accessible to copper(II) ions, whereas the interior of generation
7
through
10
PAMAM dendrimers is not accessible to copper(II) ions. Subsequent treatment of solutions containing copper(II) ions and generations
1
through
10
dendrimers, with hydrogen sulfide resulted in copious precipitates for solutions containing PAMAM dendrimers of generations
1
through
3
, completely soluble solutions with generations
4
through
6
, and precipitates with generations
7
through
10
. Analysis (TEM) of the solutions containing generations
4
through
10
PAMAM dendrimers confirmed that the generations
4
through
6
dendrimers contained copper sulfide within their interiors, and were functioning as host container molecules. Similar analyses indicated that generations
7
through
10
dendrimers were functioning as surface scaffolding for copper(II) ions, with essentially no copper in the interior.
In various applications, particularly in biomedical applications, it may be desirable to provide larger dendritic polymer structures, having a high loading capacity (i.e., the ability to contain drugs and/or diagnostic compounds), and having relatively predictable sizes, shapes and chemical valency to ensure consistent, controllable performance. However, the largest known dendrimer diameter is about 30 nanometers. The larger dendrimers have relatively dense surfaces which can be impermeable to a variety of drugs and/or diagnostic compounds. Accordingly, the ability of the higher generation dendrimers to act as carriers for drugs and/or diagnostic compounds is generally limited to their ability to retain such compounds by coordination with surface functional groups.
Although bridged dendrimers and dendrimer clusters are known, these structures are generally limited to random branched and/or crosslinked structures of non-uniform size, shape and polydispersity. Accordingly, known bridged dendrimers, crosslinked dendrimers, and dendrimer clusters do not exhibit sufficient predictability, regularity and/or uniformity for use in certain applications, such as a carrier for drug delivery and/or delivery of diagnostic compounds.
U.S. Pat. No. 4,737,550 discloses bridged dense star polymers. The p

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