Therapeutic microspheres and methods thereof

Abstract

Methods of modifying the envelope density of therapeutic microspheres can provide therapeutic microspheres for optimal distribution to different targets of therapy. For example, a method of modifying an envelope density of therapeutic microspheres can include electroplating bare microspheres with one or more layers of metal to provide densified microspheres. Surfaces of the densified microspheres can include the one-or-more layers of metal thereover while at least partially maintaining pore structure and availability for loading a therapeutic agent therein. An increase in mass from the one-or-more layers of metal and any loss of the pore structure in densified microspheres can contribute to an increase in the envelope density. The method can also include loading the therapeutic agent into pores of the densified microspheres, thereby providing the therapeutic microspheres for the optimal distribution to one or more targets of therapy.

Description

THERAPEUTIC MICROSPHERES AND METHODS THEREOFBACKGROUND

[0001] Radioembolization is a type of cancer treatment in which radiomicrospheres are locoregionally administered about a tumor by a microcatheter for irradiation of the tumor with beta radiation. Oftentimes, radioembolization is used to treat primary or metastasized hepatic tumors.

[0002] During treatment of a hepatic tumor, the microcatheter is guided through the vasculature to the right, left, or a specifically selected hepatic artery for administration via injection of the radiomicrospheres. The radiomicrospheres are subsequently distributed via blood flow to tumor arteries, where the radiomicrospheres are permanently deposited. The radiomicrospheres, which typically include yttrium-90, then irradiate the tumor with beta particles via beta decay of the yttrium-90 to zirconium-90. Since yttrium-90 irradiates most of its beta particles within a few millimeters of the radiomicrospheres, proper distribution of the radiomicrospheres in the vasculature about the tumor is important.

[0003] There are two commercially available yttrium-90 radiomicrosphere products commonly used for radioembolization, namely TheraSphere™ (Boston Scientific, Marlborough, MA, USA), which includes glass microspheres for substrates, and SIR-Spheres® (Sirtex Medical Ltd, Woburn, MA, USA), which includes polymer microspheres for substrates. While the radiomicrospheres of both brands are configured to irradiate tumors with beta radiation upon locoregional administration to a tumor, the radiomicrospheres of the TheraSphere™ brand of radiomicrospheres has a much greater envelope density than the radiomicrospheres of the SIR-Spheres® brand of microspheres. Indeed, TheraSphere™ radiomicrospheres have an envelope density of approximately 3.2 g / cc, and SIR-Spheres® radiomicrospheres have an envelope density of approximately 1.3 g / cc. This leaves an unexplored range in envelope density between that of the relatively high envelope density of TheraSphere™ radiomicrospheres and the relatively low envelope density of SIR-Spheres® radiomicrospheres, which range in envelope density that can be used to address distribution issues such as settlement of the radiomicrospheres in the microcatheter, settlement of the radiomicrospheres in connections between the microcatheter and a remainder of the delivery system, nonuniform distribution of the radiomicrospheres in the vasculature about the tumor,insufficient distal penetration of the radiomicrospheres in the vasculature about the tumor, stasis, or reflux.

[0004] In view of the foregoing, the ability to modify the envelope density of radiomicrospheres is needed for optimal distribution of the radiomicrospheres in the vasculature about hepatic tumors or other beta-radiation sensitive tumors. Notably, this need extends to therapeutic microspheres other than the foregoing radiomicrospheres for optimal distribution of the therapeutic microspheres in or around their targets of therapy. Disclosed herein are therapeutic microspheres and methods thereof that address the foregoing.SUMMARY

[0005] Disclosed herein are therapeutic microspheres including a microsphere core of a silicate-based glass or a biocompatible polymer. The therapeutic microspheres also include one or more layers of metal electroplated over a surface of the microsphere core for densification thereof. The microsphere core at least partially maintains pore structure and availability for loading one or more therapeutic agents therein despite the one-or-more layers of metal electroplated over the surface of the microsphere. The therapeutic microspheres also include a therapeutic agent loaded into pores of the pore structure, thereby providing the plurality of therapeutic microspheres.

[0006] In some embodiments, the one-or-more layers of metal include at least an underlayer and an overlayer.

[0007] In some embodiments, the underlayer promotes adhesion of the overlayer.

[0008] In some embodiments, the underlayer is copper and the overlayer is gold.

[0009] In some embodiments, the pores include chelation sites including diethylenetriaminepentaacetic acid (“DTP A”) or ethylenediaminetetraacetic acid (“EDTA”).

[0010] In some embodiments, the therapeutic agent is yttrium-90 chelated to the chelation sites including DTPA or EDTA in the pores.

[0011] In some embodiments, yttrium-90 is chelated to about 45-55% of the chelation sites for about 28-32 GBq of radiation activity.

[0012] In some embodiments, each therapeutic microsphere of the therapeutic microspheres has an envelope-density between about 1.8 to about 2.2 g / cc.

[0013] Also disclosed herein is a method of modifying an envelope density of a plurality of therapeutic microspheres. The method includes electroplating a plurality of bare microspheres with one or more layers of metal to provide a plurality of densified microspheres. Surfaces of the densified microspheres include the one-or-more layers of metal thereover while at least partially maintaining pore structure and availability for loading a therapeutic agent therein. An increase in mass from the one-or-more layers of metal and any loss of the pore structure in the plurality of densified microspheres contribute to an increase in the envelope density. The method also includes loading the therapeutic agent into pores of the plurality of densified microspheres, thereby providing the plurality of therapeutic microspheres.

[0014] In some embodiments, the plurality of bare microspheres are formed of either a silicate-based glass or a biocompatible polymer. The polymer is selected from polystyrene, divinylbenzene, a copolymer of polystyrene and divinylbenzene, and a polymer blend of polystyrene and divinylbenzene.

[0015] In some embodiments, electroplating the plurality of bare microspheres includes electrolytically electroplating the plurality of bare microspheres to provide the plurality of densified microspheres.

[0016] In some embodiments, electroplating the plurality of bare microspheres includes electrolessly electroplating the plurality of bare microspheres to provide the plurality of densified microspheres.

[0017] In some embodiments, the one-or-more layers of metal include at least an underlayer and an overlayer.

[0018] In some embodiments, the underlayer promotes adhesion of the overlayer, control over one or more properties of the overlayer, or some combination thereof.

[0019] In some embodiments, the underlayer is copper and the overlayer is gold.

[0020] In some embodiments, loading the therapeutic agent into the pores of the plurality of densified microspheres includes chelating the therapeutic agent at chelation sites in the pores of the plurality of densified microspheres.

[0021] In some embodiments, the chelation sites include DTPA or EDTA, and the therapeutic agent is yttrium-90.

[0022] In some embodiments, the method further includes separating the plurality of therapeutic microspheres into a plurality of microsphere batches having different envelopedensity distributions.

[0023] In some embodiments, the plurality of microsphere batches having the different envelope-density distributions are indicated for optimal distribution to different targets of therapy.

[0024] In some embodiments, each microsphere batch of the plurality of microsphere batches has an envelope-density distribution between about 1.8 to about 2.2 g / cc.

[0025] Disclosed herein are therapeutic microspheres including a microsphere core of a silicate-based glass or a biocompatible polymer. The therapeutic microspheres also include one or more metals, one or more metal salts, or a combination thereof deposited into pores of the microsphere core for densification thereof. The microsphere core at least partially maintains pore structure and availability for loading one or more therapeutic agents therein despite the one-or-more metals, the one-or-more metal salts, or the combination thereof deposited into the pores of the microsphere core. The therapeutic microspheres also include a therapeutic agent loaded into the pores of the pore structure, thereby providing the plurality of therapeutic microspheres.

[0026] In some embodiments, the one-or-more metals include gold.

[0027] In some embodiments, the one-or-more metal salts include at least one insoluble salt selected from yttrium phosphate, cerium phosphate, and lanthanum phosphate.

[0028] In some embodiments, the pores include chelation sites including DTPA or EDTA.

[0029] In some embodiments, the therapeutic agent is yttrium-90 chelated to the chelation sites including DTPA or EDTA in the pores.

[0030] In some embodiments, yttrium-90 is chelated to about 45-55% of the chelation sites for about 28-32 GBq of radiation activity.

[0031] In some embodiments, each therapeutic microsphere of the therapeutic microspheres has an envelope-density between about 1.5 to about 1.9 g / cc.

[0032] Disclosed herein is another method of modifying an envelope density of a plurality of therapeutic microspheres. The method includes depositing one or more metals, one or more metal salts, or a combination thereof into pores of a plurality of receptive-pore microspheres to provide a plurality of densified microspheres. The pores of the densified microspheres remain at least partially available for loading a therapeutic agent therein. An increase in mass from the one-or-more metals, one-or-more metal salts, or the combination thereof and any loss of pore structure in the plurality of densified microspheres contribute to an increase in the envelope density. The method also includes loading the therapeutic agent into the pores of the plurality of densified microspheres, thereby providing the plurality of therapeutic microspheres.

[0033] In some embodiments, the plurality of receptive-pore microspheres are formed of either a silicate-based glass or a biocompatible polymer. The polymer is selected from polystyrene, divinylbenzene, a copolymer of polystyrene and divinylbenzene, and a polymer blend of polystyrene and divinylbenzene.

[0034] In some embodiments, depositing the one-or-more metals, the one-or-more metal salts, or the combination thereof into the pores of the plurality of receptive-pore microspheres includes vacuum infiltrating a solution of the one-or-more metal salts into the pores of the receptive-pore microspheres.

[0035] In some embodiments, depositing the one-or-more metals, the one-or-more metal salts, or the combination thereof into the pores of the plurality of receptive-pore microspheres further includes reducing the one-or-more metal salts to the one-or-more metals in the pores of the receptive-pore microspheres with a reducing agent, thereby depositing the one-or-more metals in the pores of the receptive-pore microspheres.

[0036] In some embodiments, the one-or-more metal salts include gold chloride, the reducing agent includes ascorbic acid, and the one-or-more metals include gold.

[0037] In some embodiments, depositing the one-or-more metals, the one-or-more metal salts, or the combination thereof into the pores of the plurality of receptive-poremicrospheres includes chelating one more metal cations at chelation sites in the pores of the receptive-pore microspheres.

[0038] In some embodiments, depositing the one-or-more metals, the one-or-more metal salts, or the combination thereof into the pores of the plurality of receptive-pore microspheres further includes precipitating the one-or-more metal cations as the one-or-more metal salts in the pores of the receptive-pore microspheres with a counterion, thereby depositing the one-or-more metal salts in the pores of the receptive-pore microspheres.

[0039] In some embodiments, the one-or-more metal salts precipitated in the pores of the receptive-pore microspheres include one or more insoluble metal salts.

[0040] In some embodiments, the counterion is phosphate, and the one-or-more insoluble salts are selected from phosphates of yttrium, cerium, and lanthanum.

[0041] In some embodiments, loading the therapeutic agent into the pores of the plurality of densified microspheres includes chelating the therapeutic agent at the chelation sites in the pores of the plurality of densified microspheres.

[0042] In some embodiments, the chelation sites include DTPA or EDTA, and the therapeutic agent is yttrium-90.

[0043] In some embodiments, the method further includes repeating the depositing of the one-or-more metals, the one-or-more metal salts, or the combination thereof into the pores of the plurality of receptive-pore microspheres until a desired envelope-density distribution is achieved.

[0044] In some embodiments, the method further includes separating the plurality of therapeutic microspheres into a plurality of microsphere batches having different envelopedensity distributions.

[0045] In some embodiments, the plurality of microsphere batches having the different envelope-density distributions are indicated for optimal distribution to different targets of therapy.

[0046] In some embodiments, each microsphere batch of the plurality of microsphere batches has an envelope-density distribution between about 1.5 to about 1.9 g / cc.

[0047] Disclosed herein are therapeutic microspheres including a microsphere core of a consolidated silicate-based glass for densification thereof. Pores of the microsphere core remain at least partially available for loading one or more therapeutic agents therein. The therapeutic microspheres also include a therapeutic agent loaded into the pores of the pore structure, thereby providing the plurality of therapeutic microspheres.

[0048] In some embodiments, the silicate-based glass is doped with a dopant for additional densification.

[0049] In some embodiments, the pores include chelation sites including DTPA or EDTA.

[0050] In some embodiments, the therapeutic agent is yttrium-90 chelated to the chelation sites including DTPA or EDTA in the pores.

[0051] In some embodiments, yttrium-90 is chelated to about 45-55% of the chelation sites for about 28-32 GBq of radiation activity.

[0052] In some embodiments, each therapeutic microsphere of the therapeutic microspheres has an envelope-density between about 1.0 to about 2.2 g / cc.

[0053] Disclosed herein is another method of modifying an envelope density of a plurality of therapeutic microspheres. The method includes consolidating a plurality of unconsolidated microspheres with heat to provide a plurality of densified microspheres. Pores of the densified microspheres remain at least partially available for loading a therapeutic agent therein. Any loss of pore structure in the plurality of densified microspheres contributes to an increase in the envelope density. The method also includes loading the therapeutic agent into pores of the plurality of densified microspheres, thereby providing the plurality of therapeutic microspheres.

[0054] In some embodiments, the plurality of unconsolidated microspheres are formed of a silicate-based glass, optionally, doped with a dopant for additional densification.

[0055] In some embodiments, loading the therapeutic agent into the pores of the plurality of densified microspheres includes chelating the therapeutic agent at chelation sites in the pores of the plurality of densified microspheres.

[0056] In some embodiments, the chelation sites include DTPA or EDTA, and the therapeutic agent is yttrium-90.

[0057] In some embodiments, the method further includes separating the plurality of therapeutic microspheres into a plurality of microsphere batches having different envelopedensity distributions.

[0058] In some embodiments, the plurality of microsphere batches having the different envelope-density distributions are indicated for optimal distribution to different targets of therapy.

[0059] In some embodiments, each microsphere batch of the plurality of microsphere batches has an envelope-density distribution between about 1.0 g / cc and about 2.2 g / cc.

[0060] These and other features of the concepts provided herein will become more apparent to those of skill in the art in view of the accompanying drawings and following description, which describe particular embodiments of such concepts in greater detail.DRAWINGS

[0001] FIG. 1 provides a radiographic image after injection of the therapeutic microspheres into the hepatic artery of an animal model, the therapeutic microspheres densified in accordance with some embodiments.

[0002] FIG. 2 provides a radiographic image after injection of lower density therapeutic microspheres into the hepatic artery of the animal model.DESCRIPTION

[0003] Before some particular embodiments are disclosed in greater detail, it should be understood that the particular embodiments disclosed herein do not limit the scope of the concepts provided herein. It should also be understood that a particular embodiment disclosed herein can have features that can be readily separated from the particular embodiment and optionally combined with or substituted for features of any of a number of other embodiments disclosed herein.

[0004] Regarding terms used herein, it should also be understood the terms are for the purpose of describing some particular embodiments, and the terms do not limit the scope of theconcepts provided herein. Ordinal numbers (e.g., first, second, third, etc.) are generally used to distinguish or identify different features or steps in a group of features or steps, and do not supply a serial or numerical limitation. For example, “first,” “second,” and “third” features or steps need not necessarily appear in that order, and the particular embodiments including such features or steps need not necessarily be limited to the three features or steps. In addition, any of the foregoing features or steps can, in turn, further include one or more features or steps unless indicated otherwise. Labels such as “left,” “right,” “top,” “bottom,” “front,” “back,” and the like are used for convenience and are not intended to imply, for example, any particular fixed location, orientation, or direction. Instead, such labels are used to reflect, for example, relative location, orientation, or directions. Singular forms of “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise.

[0005] “About,” as in about a particular magnitude of size, thickness, temperature, time, or the like, is intended to reflect the particular magnitude within rounding or measurement uncertainty as it is defined in metrology.

[0006] “Microspheres” is used herein with the same meaning as commonly understood by those of ordinary skill in the art, which refers to spheres in which the size of each discrete sphere is readily given in microns or micrometers. Indeed, the microspheres can be at least about 1 pm, 10 pm, 20 pm, 30 pm, 40 pm, 50 pm, 60 pm, 70 pm, 80 pm, 90 pm, 100 pm, 200 pm, 300 pm, 400 pm, 500 pm, 600 pm, 700 pm, 800 pm, 900 pm, or 1000 pm in diameter, inclusive of any intervening diameters defined by the so-called ones or tens place. The microspheres can be no more than about 1000 pm, 900 pm, 800 pm, 700 pm, 600 pm, 500 pm, 400 pm, 300 pm, 200 pm, 100 pm, 90 pm, 80 pm, 70 pm, 60 pm, 50 pm, 40 pm, 30 pm, 20 pm, 10 pm, or 1 pm in diameter, inclusive of any intervening diameters defined by the so- called ones or tens place. As such, the microspheres can be at least about 1 pm and no more than about 1000 pm in diameter, including at least about 10 pm and no more than about 100 pm in diameter, such as at least about 10 pm and no more than about 50 pm in diameter, for example, at least about 20 pm and no more than about 30 pm in diameter. Notably, the microspheres are not limited to such diameters.

[0007] “Envelope density” is used herein with the same meaning as commonly understood by those of ordinary skill in the art, which includes the ratio of mass (m) of the therapeutic microspheres to their volume (7) as in p = m / F, notably, with any open or closed pores of the therapeutic microspheres contributing to the volume of the therapeuticmicrospheres. Should the therapeutic microspheres be effectively nonporous, the contribution of any pores to the volume of such nonporous therapeutic microspheres is negligible, and the envelope density of the nonporous therapeutic microspheres approaches the absolute density of the nonporous therapeutic microspheres. As such, it should be understood that the envelope density of any non-porous therapeutic microspheres set forth herein can alternatively be referred to as the absolute density of the non-porous therapeutic microspheres.

[0008] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art.

[0009] As set forth above, the ability to modify the envelope density of therapeutic microspheres is needed for optimal distribution of the therapeutic microspheres in or around their targets of therapy. Disclosed herein are therapeutic microspheres and methods thereof that address the foregoing. Such methods modify the flow and deposition characteristics of the therapeutic microspheres in the vasculature, which is useful for radioembolization, bland embolization, chemoembolization, targeted drug delivery, as well as for diagnostic or imaging applications (e.g., scout dose prior to yttrium-90 radioembolization).

[0010] The therapeutic microspheres include those modified by density-modification methods set forth below for modifying the envelope density of therapeutic microspheres. Such methods include densification methods for increasing the envelope density of therapeutic microspheres as well as rarefaction methods for decreasing the envelope density of therapeutic microspheres, choice of which depends upon starting microsphere substrate and target envelope density of the therapeutic microspheres. Notwithstanding the foregoing, densification methods for increasing the envelope density of therapeutic microsphere are primarily set forth below. The densification methods can include, but are not limited to, deposition methods such as electroplating dense material over microsphere surfaces, depositing dense material in microsphere pores, or both; consolidation methods; or combinations thereof. Indeed, it should be understood that any densification method disclosed herein can be combined with any other densification method disclosed herein to achieve a desired envelope-density distribution for optimal distribution of the therapeutic microspheres in or around their targets of therapy.Deposition methodsElectroplating dense material over microsphere surfaces

[0011] A method of modifying the envelope density of a plurality of therapeutic microspheres can include electroplating a plurality of bare microspheres with one or more layers of metal to provide a plurality of densified microspheres.

[0012] The plurality of bare microspheres upon which the one-or-more layers of metal are electroplated can be formed of either a silicate-based glass or a biocompatible polymer selected from at least polystyrene, divinylbenzene, a copolymer of polystyrene and divinylbenzene, and a polymer blend of polystyrene and divinylbenzene. Such microsphere substrates are biocompatible but not necessarily biodegradable. However, the microsphere substrates can include biodegradable polymer substrates such as polycaprolactone (“PCL”), poly(L-lactic acid) (“PLLA”), or poly(lactic-co-glycolic acid) (“PLGA”), which can be useful in diagnosing or treating a condition.

[0013] Electroplating the plurality of bare microspheres can include electrolytically electroplating the plurality of bare microspheres to provide the plurality of densified microspheres. Alternatively, electroplating the plurality of bare microspheres can include electrolessly electroplating the plurality of bare microspheres to provide the plurality of densified microspheres. Regardless, surfaces of the densified microspheres can include the one- or-more layers of metal thereover while at least partially maintaining pore structure and availability for loading a therapeutic agent therein. An increase in mass from the one-or-more layers of metal and any loss of the pore structure in the plurality of densified microspheres contribute to an increase in the envelope density.

[0014] The one-or-more layers of metal can include a single layer of a single metal, a plurality of layers of the single metal, a single layer of a first metal for an underlayer and a single layer of a second metal for an overlayer, the single layer of the first metal for the underlayer and a plurality of layers of the second metal for the overlayer, a plurality of layers of the first metal for the underlayer and the plurality of layers of the second metal for the overlayer depending upon at least a desired envelope-density distribution. In an example, the one-or-more layers of metal can include gold, platinum, or palladium for the single layer of the single metal or the plurality of layers of the single metal. In another example, the one-or-more layers of metal can include copper for the underlayer and gold, platinum, or palladium for one or more layers of the overlayer. When present, the underlayer can promote adhesion of the overlayer(s), control over one or more properties (e.g., thickness, texture, etc.) of the overlayer(s), or some combination thereof.

[0015] Advantageously, the one-or-more layers of metal can impart additional functionality to the plurality of densified microspheres and, ultimately, the plurality of therapeutic microspheres prepared therefrom. In an example, the one-or-more layers of metal can impart radiopacity to the plurality of therapeutic microspheres, thereby enabling the therapeutic microspheres to be highly visible by radiographic methods such as X-ray or angiography. Such radiopacity can be particularly useful when the therapeutic microspheres cannot be visualized by other means such as when the therapeutic microspheres are configured for bland embolization, chemoembolization, targeted drug delivery, or the like, which do not utilize radiation activity.

[0016] As alluded to by the plurality of layers of the single metal, the first metal, or the second layer above, the method can include continuing or repeating the electroplating of the plurality of densified microspheres until a desired envelope-density distribution is achieved. Indeed, the electroplating of the one-or-more layers of metal can be continued or repeated until each layer of the one-or-more layers is at least 0.1 pm, 0.2 pm, 0.3 pm, 0.4 pm, 0.5 pm, 0.6 pm, 0.7 pm, 0.8 pm, 0.9 pm, or 1.0 pm thick. The electroplating of the one-or-more layers of metal can be continued or repeated until each layer of the one-or-more layers is no more than about 1.0 pm, 0.9 pm, 0.8 pm, 0.7 pm, 0.6 pm, 0.5 pm, 0.4 pm, 0.3 pm, 0.2 pm, or 0.1 pm thick. As such, the electroplating of the one-or-more layers of metal can be continued or repeated until each layer of the one-or-more layers is at least about 0.1 pm and no more than 1.0 pm thick, including at least about 0.1 pm and no more than 0.5 pm thick, such as at least about 0.1 pm and no more than 0.4 pm thick, for example, at least about 0.1 pm and no more than 0.3 pm thick. In an example, the one-or-more layers can include copper for the underlayer at a thickness of about 0.25 pm and gold for the overlayer at a thickness of about 0.25 pm, which increases the plurality of therapeutic microspheres from an envelope-density distribution of about 1.1 g / cc to about 2.0 g / cc.

[0017] Therapeutic microspheres prepared in accordance with the foregoing can include a microsphere core such as that of a bare microsphere of the silicate-based glass or the biocompatible polymer. The therapeutic microspheres can also include the one-or-more layers of metal electroplated over a surface of the microsphere core for densification thereof. As above, the microsphere core at least partially maintains the pore structure and availability for loading the one or more therapeutic agents therein despite the one-or-more layers of metal electroplated over the surface of the microsphere. Indeed, the therapeutic microspheres caninclude a therapeutic agent loaded into the pores of the pore structure as set forth below, thereby providing the plurality of therapeutic microspheres.Depositing dense materials in microsphere pores

[0018] A method of modifying the envelope density of a plurality of therapeutic microspheres can include depositing one or more metals, one or more metal salts, or a combination thereof into pores of a plurality of receptive-pore microspheres to provide a plurality of densified microspheres. However, it should be understood that the one-or-more metals, the one-or-more metal salts, or the combination thereof can be deposited on surfaces of the receptive-pore microspheres as well.

[0019] The plurality of receptive-pore microspheres within which the one-or-more metals, one-or-more metal salts, or the combination thereof are deposited can be formed of either a silicate-based glass or a biocompatible polymer selected from at least polystyrene, divinylbenzene, a copolymer of polystyrene and divinylbenzene, and a polymer blend of polystyrene and divinylbenzene. As above, such microsphere substrates are biocompatible but not necessarily biodegradable. However, the microsphere substrates can include biodegradable polymer substrates such as PCL, PLLA, or PLGA, which can be useful in diagnosing or treating a condition.

[0020] Depositing the one-or-more metals, the one-or-more metal salts, or the combination thereof into the pores of the plurality of receptive-pore microspheres can include vacuum infiltrating a solution of the one-or-more metal salts into the pores of the receptive- pore microspheres. Further, depositing the one-or-more metals, the one-or-more metal salts, or the combination thereof into the pores of the plurality of receptive-pore microspheres can include reducing the one-or-more metal salts to the one-or-more metals in the pores of the receptive-pore microspheres with a reducing agent in another solution subsequently vacuum infiltrated into the pores of the receptive-pore microspheres, thereby depositing the one-or- more metals in the pores of the receptive-pore microspheres. The pores of the densified microspheres can remain at least partially available for loading the therapeutic agent therein. An increase in mass from the one-or-more metals, one-or-more metal salts, or the combination thereof trapped in the pores and any loss of pore structure in the plurality of densified microspheres contributes to an increase in the envelope density.

[0021] The one-or-more metal salts can include at least a gold salt such as gold chloride, which results in at least gold for the one-or-more metals.

[0022] The reducing agent can include, but is not limited to, ascorbic acid or a salt thereof, citric acid or a salt thereof, sodium borohydride, potassium borohydride, or sodium hydrosulfite; however, the reducing agent is not limited thereto.

[0023] In an alternative to the foregoing, depositing the one-or-more metals, the one- or-more metal salts, or the combination thereof into the pores of the plurality of receptive-pore microspheres can include chelating one or more metal cations at chelation sites in the pores of the receptive-pore microspheres such as by vacuum infiltrating a solution of the one-or-more metal salts into the pores of the receptive-pore microspheres. (Notably, the chelation sites can include DTPA or EDTA, as set forth below.) Further, depositing the one-or-more metals, the one-or-more metal salts, or the combination thereof into the pores of the plurality of receptive- pore microspheres can include precipitating the one-or-more metal cations as the one-or-more metal salts in the pores of the receptive-pore microspheres with an counter in another solution subsequently vacuum infiltrated into the pores of the receptive-pore microspheres, thereby depositing the one-or-more metal salts in the pores of the receptive-pore microspheres. The pores of the densified microspheres can remain at least partially available for loading a therapeutic agent therein. An increase in mass from the one-or-more metals, one-or-more metal salts, or the combination thereof trapped in the pores and any loss of pore structure in the plurality of densified microspheres contributes to an increase in the envelope density.

[0024] The one-or-more metal salts precipitated in the pores of the receptive-pore microspheres can include one or more insoluble metal salts selected from at least phosphates of yttrium, cerium, and lanthanum. In accordance with the foregoing, the counterion used to precipitate the one-or-more metal salts can be phosphate, but neither the counterion of the one- or-more insoluble metal salts are limited thereto.

[0025] Notably, when the plurality of receptive-pore microspheres are formed of a silicate-based glass, heating of the plurality of densified microspheres including the insoluble metal phosphate salts of yttrium, cerium, or lanthanum to temperature above 300 °C can transform such insoluble metal salts into more crystalline versions thereof. The more crystalline versions of the phosphate salts of yttrium, cerium, or lanthanum can have lower solubilitiesresulting in less leaching of free yttrium-90 from the plurality of therapeutic microspheres in vitro or in vivo.

[0026] The method can include repeating the depositing of the one-or-more metals, the one-or-more metal salts, or the combination thereof into the pores of the plurality of receptive- pore microspheres until a desired envelope-density distribution is achieved. Indeed, whether depositing the one-or-more metals (e.g., gold) or the one-or-more metal salts (e.g., YPO4, CePO4, or LaPO4) as set forth above, the pores and any chelation sites thereof can remain receptive to vacuum infiltrating additional solutions of the one-or-more metal salts into the pores of the receptive-pore microspheres for subsequent deposition.

[0027] Advantageously, the one-or-more metals, the one-or-more metal salts, or the combination thereof can impart additional functionality to the plurality of densified microspheres and, ultimately, the plurality of therapeutic microspheres prepared therefrom. In an example, the one-or-more metals, the one-or-more metal salts, or the combination thereof can include technetium-99 (e.g., "TC5+or99Tc6+), thereby enabling the therapeutic microspheres to be highly visible by gamma-ray-detecting cameras for bone, brain, lung, or thyroid scans. In another example, the one-or-more metals, the one-or-more metal salts, or the combination thereof can include gadolinium (e.g., Gd3+), thereby enabling the therapeutic microspheres to be highly visible by magnetic resonance imaging (“MRI”).

[0028] The method can include drying the plurality of densified microspheres after the desired envelope-density distribution is achieved therefor.

[0029] Table 1 set forth below provides densities for some densified microspheres in accordance with the foregoing.Table 1. Densities of some densified microspheres.

[0030] Therapeutic microspheres prepared in accordance with the foregoing can include a microsphere core such as that of a receptive-pore microsphere of a silicate-based glass or a biocompatible polymer. The therapeutic microspheres can also include the one-or- more metals, one-or-more metal salts, or the combination thereof deposited into the pores of the microsphere core for densification thereof. As above, the microsphere core at least partially maintains the pore structure and availability for loading the one-or-more therapeutic agents therein despite the one-or-more metals, the one-or-more metal salts, or the combination thereof deposited into the pores of the microsphere core. The therapeutic microspheres can also include a therapeutic agent loaded into the pores of the pore structure as set forth below, thereby providing the plurality of therapeutic microspheres.Consolidation methodsConsolidating microspheres with heat

[0031] A method of modifying the envelope density of a plurality of therapeutic microspheres can include consolidating a plurality of unconsolidated microspheres with heat to provide a plurality of densified microspheres.

[0032] The plurality of unconsolidated microspheres that are consolidated with heat can be formed of a silicate-based glass, optionally, doped with a dopant (e.g., barium titanate) for additional densification. Notably, the plurality of unconsolidated microspheres can be a plurality of undensified therapeutic microspheres already containing a radionuclide such as yttrium-90 or some other plurality of microspheres set forth herein. While any organiccompounds such as DTPA or EDTA are destroyed via thermal decomposition (e.g., pyrolysis, carbonization, etc.) while heating the foregoing plurality of undensified therapeutic microspheres, radionuclides such as yttrium-90 remain trapped in the pores of the densified therapeutic microspheres.

[0033] Consolidating the plurality of unconsolidated microspheres can include heating the plurality of unconsolidated microspheres at one or more temperatures for one or more periods of time in accordance with a heating profile ranging from a relatively simple heating profile to a relatively complex heating profile for providing the plurality of densified microspheres. In an example with a relatively simple heating profile, the plurality of unconsolidated microspheres can be heated at a temperature of about 850 °C for about 60 minutes to provide the plurality of densified microspheres. The plurality of densified microspheres (d = 25 pm) can be reduced in diameter by approximately 15% from that of the plurality of unconsolidated microspheres (d = 29 pm) under the foregoing conditions, resulting in a density of about 1.9 g / cc with a porosity of about 25%. Notably, as in the foregoing example, the pores of the densified microspheres can remain at least partially available for loading the therapeutic agent therein. That said, the pores of the densified microspheres can be mostly, if not entirely, eliminated depending on the heating profile used for the heating of the plurality of unconsolidated microspheres, thereby precluding the loading of the therapeutic agent. Any loss of pore structure in the plurality of densified microspheres contributes to an increase in the envelope density.

[0034] The one-or-more temperatures at which the unconsolidated microspheres can be heated include a temperature of at least about 200 °C, 400 °C, 600 °C, 800 °C, or 1000 °C, inclusive of any intervening temperature defined by the so-called tens or hundreds places. The one-or-more temperatures at which the unconsolidated microspheres can be heated include a temperature of no more than about 1000 °C, 800 °C, 600 °C, 400 °C, or 100 °C, inclusive of any intervening temperature defined by the so-called tens or hundreds places. As such, the one- or-more temperatures at which the unconsolidated microspheres can be heated include a temperature of at least about 200 °C and no more than about 1000 °C, including at least about 400 °C and no more than about 1000 °C, such as at least about 600 °C and no more than about 1000 °C, for example, at least about 800 °C and no more than about 1000 °C.

[0035] The one-or-more periods of time for which the unconsolidated microspheres can be heated include a period of time of at least about 15, 30, 45, 60, 75, 90, 105, or 120minutes inclusive of any intervening period of time defined by the so-called ones or ten places. The one-or-more periods of time for which the unconsolidated microspheres can be heated include a period of time of no more than about 120, 105, 90, 75, 60, 45, 30, or 15 minutes inclusive of any intervening period of time defined by the so-called ones or ten places. As such, the one-or-more periods of time for which the unconsolidated microspheres can be heated include a period of time of at least about 15 minutes and no more than about 120 minutes, including at least about 30 minutes and no more than about 105 minutes, such as at least about 45 minutes and no more than about 90 minutes, for example, at least about 45 minutes and no more than about 75 minutes.

[0036] Therapeutic microspheres prepared in accordance with the foregoing can include a microsphere core of a consolidated silicate-based glass for densification thereof. Pores of the microsphere core can remain at least partially available for loading the one-or- more therapeutic agents therein. The therapeutic microspheres can also include a therapeutic agent loaded into the pores of the pore structure as set forth below, thereby providing the plurality of therapeutic microspheres.Additional aspects of the methods

[0037] Following on from any densification method of the foregoing densification methods, methods can also include loading the therapeutic agent into the pores of the plurality of densified microspheres, thereby providing the plurality of therapeutic microspheres.

[0038] The therapeutic agent can be any desired therapeutic agent for diagnosing or treating a condition. Indeed, the therapeutic microspheres can include one or more radionuclides selected from at least strontium-89, yttrium-90, technetium-99, and samarium- 153; one or more anticancer drugs selected from at least doxorubicin, paclitaxel, mitoxantrone, an histone deacetylase inhibitor, and an isothiocyanate; one or more antibiotics selected from at least vancomycin, gentamicin, ciprofloxacin, and rifampicin; one or more peptides or polypeptides selected from at least insulin, interferon, a growth factor, and an antibody; one or more nucleic acids selected from at least an antisense oligonucleotide, a small interfering RNA, and a DNA vaccine; one or more imaging agents for diagnostic purposes; one or more magnetic particles for magnetic drug targeting; or some combination thereof.

[0039] In accordance with the therapeutic agent being any desired therapeutic agent for diagnosing or treating a condition, loading the therapeutic agent into the pores of the pluralityof densified microspheres can vary. When the therapeutic agent is chelatable such as a radionuclide, loading the therapeutic agent into the pores of the plurality of densified microspheres can include chelating the therapeutic agent at chelation sites in the pores of the plurality of densified microspheres such as by vacuum infiltrating a solution of the therapeutic agent (e.g.,90Y3+) into the pores of the receptive-pore microspheres. The chelation sites can include DTPA or EDTA. Notably, it is advantageous to load a therapeutic agent such as a radionuclide into the pores of the plurality of densified microspheres after their densification as opposed to before any such densification in order to reduce health or safety risks in handling radiomicrospheres as well as to ensure the plurality of therapeutic microspheres maintain as much activity as possible. However, a therapeutic agent such as a radionuclide can be loaded into the pores of the plurality of densified microspheres prior to densification as desired or needed.

[0040] Subsequent to loading a chelatable therapeutic agent such as a radionuclide into the pores of the plurality of densified microspheres, at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of the chelation sites can include the therapeutic agent chelated at the chelation sites. Alternatively, no more than about 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, or 25% of the chelation sites can include the therapeutic agent chelated at the chelation sites subsequent to loading the chelatable therapeutic agent into the pores of the plurality of densified microspheres. As such, subsequent to loading the chelatable therapeutic agent into the pores of the plurality of densified microspheres, at least about 25% of the chelation sites and no more than about 75% of the chelation sites, including at least about 30% of the chelation sites and no more than about 70% of the chelation sites, such as at least about 35% of the chelation sites and no more than about 65% of the chelation sites, for example, at least about 40% of the chelation sites and no more than about 60% of the chelation sites, can include the therapeutic agent chelated at the chelation sites.

[0041] Further, subsequent to loading a chelatable therapeutic agent including a radionuclide into the pores of the plurality of densified microspheres, the therapeutic microspheres can have a radiation activity of at least about 15 GBq, 20 GBq, 25 GBq, 30 GBq, 35 GBq, 40 GBq, or 45 GBq, inclusive of any intervening radiation activity defined by the so- called ones place. Alternatively, the therapeutic microspheres can have a radiation activity of no more than about 45 GBq, 40 GBq, 35 GBq, 30 GBq, 25 GBq, 20 GBq, or 15 GBq, inclusive of any intervening radiation activity defined by the so-called ones place. As such, subsequentto loading the chelatable therapeutic agent including the radionuclide into the pores of the plurality of densified microspheres, the therapeutic microspheres can have a radiation activity of at least about 15 GBq and no more than 45 GBq, including at least about 20 GBq and no more than 40 GBq, such as at least about 25 GBq and no more than 35 GBq, for example, at least about 28 GBq and no more than 32 GBq.

[0042] The method can also include separating the plurality of therapeutic microspheres into a plurality of microsphere batches having different envelope-density distributions; however, it should be understood that the separating can alternatively be performed on the plurality of densified microspheres followed by loading the therapeutic agent into the pores of the plurality of densified microspheres so separated. Regardless, the plurality of microsphere batches having the different envelope-density distributions can be indicated for optimal distribution to different targets of therapy.

[0043] Each microsphere batch of the plurality of microsphere batches can have an envelope-density distribution of at least about 1.0 g / cc, 1.1 g / cc, 1.2 g / cc, 1.3 g / cc, 1.4 g / cc, 1.5 g / cc, 1.6 g / cc, 1.7 g / cc, 1.8 g / cc, 1.9 g / cc, 2.0 g / cc, 2.1 g / cc, 2.2 g / cc, 2.3 g / cc, 2.4 g / cc, 2.5 g / cc, 2.6 g / cc, 2.7 g / cc, 2.8 g / cc, 2.9 g / cc, 3.0 g / cc, 3.1 g / cc, 3.2 g / cc, 3.3 g / cc, 3.4 g / cc, 3.5 g / cc, 3.6 g / cc, 3.7 g / cc, 3.8 g / cc, 3.9 g / cc, or 4.0 g / cc. Each microsphere batch of the plurality of microsphere batches can have an envelope-density distribution of no more than about 4.0 g / cc, 3.9 g / cc, 3.8 g / cc, 3.7 g / cc, 3.6 g / cc, 3.5 g / cc, 3.4 g / cc, 3.3 g / cc, 3.2 g / cc, 3.1 g / cc, 3.0 g / cc, 2.9 g / cc, 2.8 g / cc, 2.7 g / cc, 2.6 g / cc, 2.5 g / cc, 2.4 g / cc, 2.3 g / cc, 2.2 g / cc, 2.1 g / cc, 2.0 g / cc, 1.9 g / cc, 1.8 g / cc, 1.7 g / cc, 1.6 g / cc, 1.5 g / cc, 1.4 g / cc, 1.3 g / cc, 1.2 g / cc, 1.1 g / cc, or 1.0 g / cc. As such, each microsphere batch of the plurality of microsphere batches can have an envelope-density distribution of at least about 1.0 g / cc and no more than about 4.0 g / cc, including at least about 1.0 g / cc and no more than about 2.2 g / cc, such as at least about 1.5 g / cc and no more than about 2.2 g / cc, for example, at least about 1.8 g / cc and no more than about 2.2 g / cc. In an example, each microsphere batch of the plurality of microsphere batches can have an envelope-density distribution between about 1.8 to about 2.2 g / cc as a result of electroplating the plurality of bare microspheres with the one-or-more layers of metal as set forth above. In another example, each microsphere batch of the plurality of microsphere batches can have an envelope-density distribution between about 1.5 to about 1.9 g / cc as a result of depositing the one-or-more metals, the one-or-more metal salts, or the combination thereof into the pores of the plurality of receptive-pore microspheres as set forth above. Inanother example, each microsphere batch of the plurality of microsphere batches can have an envelope-density distribution between about 1.0 to about 2.2 g / cc as a result of consolidating a plurality of unconsolidated microspheres with heat as set forth above.

[0044] Notably, any envelope-density distribution set forth herein with a magnitude and units of g / cc or the like should be understood as being centered or skewed around that magnitude with an uncertainty inherent to the technological limitations in separating the plurality of therapeutic microspheres into the plurality of microsphere batches, measuring the envelope-density distributions of the plurality of microsphere batches, or a combination thereof. Any ranges of the envelope-density distribution set forth herein (e.g., an envelopedensity distribution of at least about 1.0 g / cc and no more than about 4.0 g / cc) should be understood as ranges within which the magnitude of the envelope-density distribution lies; such ranges do not relate to the uncertainty inherent to the technological limitations in separating the plurality of therapeutic microspheres into the plurality of microsphere batches, measuring the envelope-density distributions of the plurality of microsphere batches, or the combination thereof.Advantages

[0045] By way of any one or more density-modification methods set forth herein, the therapeutic microspheres can be customized with a desired envelope-density distribution for optimal distribution of the therapeutic microspheres in or around their targets of therapy. In an example, the one-or-more density-modification methods can be used to customize the therapeutic microspheres such that the therapeutic microspheres have an envelope-density distribution or, simply, envelope density, greater than that of blood (e.g., 1.06 g / cc), which mitigates distribution issues such as stasis and reflux. In another example, the one-or-more density-modification methods can be used to customize therapeutic microspheres such that the therapeutic microspheres have an envelope-density distribution or, simply, envelope density, less than or equal to about three time that of blood, which mitigates distribution issues such as settlement of the therapeutic microspheres in microcatheters, settlement of the therapeutic microspheres in connections between the microcatheters and their delivery systems, nonuniform distribution of the therapeutic microspheres in the vasculature about tumors or other targets of therapy, insufficient distal penetration of the therapeutic microspheres in the vasculature about the tumors of other targets of therapy.EXAMPLESExample 1 : Depositing dense materials in microsphere pores

[0046] 25 pm polystyrene / divinylbenzene microspheres with DTPA chelation sites were treated with commercially available solutions to create “activated” microspheres with palladium nanoparticles on the available surfaces (e.g., those of the pores and the outer surfaces). The activated microspheres were then exposed to a solution of gold chloride to coat the available surfaces with gold cations, which are attracted to the palladium nanoparticles. The gold cations were then reduced with a solution of ascorbic acid to deposit elemental gold in the pores and on the outer surfaces of the microspheres. The microspheres were rinsed to remove any elemental gold particles not adhered to the microspheres. The foregoing method can be repeated until the desired density is obtained. For example, 10 cycles can be performed to obtain a density in the range 1.8-2.2g / cc. The microspheres can then be used to bind cationic yttrium-90 to the DTPA chelation sites, followed by phosphate precipitation and subsequent rinsing.Example 2: Consolidating microspheres with heat

[0047] 25 pm porous silica microspheres with EDTA chelation sites were labeled with yttrium-90 in accordance with Example 1. The yttrium-containing microspheres (also containing cerium phosphate) were rinsed with water and subjected to a temperature between 550 °C and 900 °C. Notably, lower temperatures resulted in “black” microspheres due to the EDTA not completely decomposing. Higher temperatures resulted in microspheres sticking to one another. Consolidating microspheres with heat in this way reduces microsphere size by approximately 15%, resulting in an increase in envelope density from about 1.5 g / cc to about 1.9 g / cc.Example 3: Injecting densified microspheres

[0048] FIG. 1 provides a radiographic image after injection of the therapeutic microspheres into the hepatic artery of an animal model, the therapeutic microspheres densified in accordance with some embodiments. FIG. 2 provides a radiographic image after injection of lower density therapeutic microspheres (1.2 g / cc) into the hepatic artery of an animal model.

[0049] In vitro models show lower density (1.2 g / cc) microspheres exhibit better flow uniformity and deposition in the distal branches of the hepatic artery than more dense microspheres. However, during animal trials as shown in FIG. 2, partial blood flow stasis and reflux were seen at the hepatic artery after the injection of 1.2 g / cc therapeutic microspheres. Lengthy investigation indicated the root cause was the density of the microspheres. While densified therapeutic microspheres (e.g., 1.8-2.4g / cc) get to the distal branches of the hepatic artery more slowly, and, thereby, lead to a more gradual embolic effect, the densified therapeutic microspheres eliminate the issues with stasis and reflux while providing better penetration as shown in FIG. 1.

[0050] While some particular embodiments have been disclosed herein, and while the particular embodiments have been disclosed in some detail, it is not the intention for the particular embodiments to limit the scope of the concepts provided herein. Additional adaptations or modifications can appear to those of ordinary skill in the art, and, in broader aspects, these adaptations or modifications are encompassed as well. Accordingly, departures may be made from the particular embodiments disclosed herein without departing from the scope of the concepts provided herein.

Claims

CLAIMSWhat is claimed is:

1. Therapeutic microspheres, comprising: a microsphere core of a silicate-based glass or a biocompatible polymer; one or more layers of metal electroplated over a surface of the microsphere core for densification thereof, the microsphere core at least partially maintaining pore structure and availability for loading one or more therapeutic agents therein despite the one-or-more layers of metal electroplated over the surface of the microsphere; and a therapeutic agent loaded into pores of the pore structure, thereby providing the plurality of therapeutic microspheres.

2. The therapeutic microspheres of claim 1, wherein the one-or-more layers of metal include at least an underlayer and an overlayer.

3. The therapeutic microspheres of claim 2, wherein the underlayer promotes adhesion of the overlayer.

4. The therapeutic microspheres of either claim 2 or 3, wherein the underlayer is copper and the overlayer is gold.

5. The therapeutic microspheres of any claim of claims 1-4, wherein the pores include chelation sites including diethylenetriaminepentaacetic acid (“DTP A”) or ethylenediaminetetraacetic acid (“EDTA”).

6. The therapeutic microspheres of claim 5, wherein the therapeutic agent is yttri um-90 chelated to the chelation sites including DTPA or EDTA in the pores.

7. The therapeutic microspheres of claim 6, wherein yttrium-90 is chelated to about 45-55% of the chelation sites for about 28-32 GBq of radiation activity.

8. The therapeutic microspheres of any claim of claims 1-7, wherein each therapeutic microsphere of the therapeutic microspheres has an envelopedensity between about 1.8 to about 2.2 g / cc.

9. A method of modifying an envelope density of a plurality of therapeutic microspheres, comprising: electroplating a plurality of bare microspheres with one or more layers of metal to provide a plurality of densified microspheres in which surfaces of the densified microspheres include the one-or-more layers of metal thereover while at least partially maintaining pore structure and availability for loading a therapeutic agent therein, an increase in mass from the one-or- more layers of metal and any loss of the pore structure in the plurality of densified microspheres contributing to an increase in the envelope density; and loading the therapeutic agent into pores of the plurality of densified microspheres, thereby providing the plurality of therapeutic microspheres.

10. The method of claim 9, wherein the plurality of bare microspheres are formed of either a silicate-based glass or a biocompatible polymer selected from polystyrene, divinylbenzene, a copolymer of polystyrene and divinylbenzene, and a polymer blend of polystyrene and divinylbenzene.

11. The method of either claim 9 or 10, wherein electroplating the plurality of bare microspheres includes electrolytically electroplating the plurality of bare microspheres to provide the plurality of densified microspheres.

12. The method of either claim 9 or 10, wherein electroplating the plurality of bare microspheres includes electrolessly electroplating the plurality of bare microspheres to provide the plurality of densified microspheres.

13. The method of any claim of claims 9-12, wherein the one-or-more layers of metal include at least an underlayer and an overlayer.

14. The method of claim 13, wherein the underlayer promotes adhesion of the overlayer, control over one or more properties of the overlayer, or some combination thereof.

15. The method of either claim 13 or 14, wherein the underlayer is copper and the overlayer is gold.

16. The method of any claim of claims 9-15, wherein loading the therapeutic agent into the pores of the plurality of densified microspheres includes chelating the therapeutic agent at chelation sites in the pores of the plurality of densified microspheres.

17. The method of claim 16, wherein the chelation sites include diethylenetriaminepentaacetic acid (“DTP A”) or ethylenediaminetetraacetic acid (“EDTA”) and the therapeutic agent is yttrium-90.

18. The method of any claim of claims 9-17, further comprising separating the plurality of therapeutic microspheres into a plurality of microsphere batches having different envelope-density distributions.

19. The method of claim 18, wherein the plurality of microsphere batches having the different envelope-density distributions are indicated for optimal distribution to different targets of therapy.

20. The method of either claim 18 or 19, wherein each microsphere batch of the plurality of microsphere batches has an envelope-density distribution between about 1.8 to about 2.2 g / cc.

21. Therapeutic microspheres, comprising: a microsphere core of a silicate-based glass or a biocompatible polymer; one or more metals, one or more metal salts, or a combination thereof deposited into pores of the microsphere core for densification thereof, the microsphere core at least partially maintaining pore structure and availability for loading one or more therapeutic agents therein despite the one-or-more metals, the one-or-more metal salts, or the combination thereof deposited into the pores of the microsphere core; and a therapeutic agent loaded into the pores of the pore structure, thereby providing the plurality of therapeutic microspheres.

22. The therapeutic microspheres of claim 21, wherein the one-or-more metals include gold.

23. The therapeutic microspheres of claim 21, wherein the one-or-more metal salts include at least one insoluble salt selected from yttrium phosphate, cerium phosphate, and lanthanum phosphate.

24. The therapeutic microspheres of any claim of claims 21-23, wherein the pores include chelation sites including diethylenetriaminepentaacetic acid (“DTP A”) or ethylenediaminetetraacetic acid (“EDTA”).

25. The therapeutic microspheres of claim 24, wherein the therapeutic agent is yttri um-90 chelated to the chelation sites including DTPA or EDTA in the pores.

26. The therapeutic microspheres of claim 25, wherein yttrium-90 is chelated to about 45-55% of the chelation sites for about 28-32 GBq of radiation activity.

27. The therapeutic microspheres of any claim of claims 21-26, wherein each therapeutic microsphere of the therapeutic microspheres has an envelopedensity between about 1.5 to about 1.9 g / cc.

28. A method of modifying an envelope density of a plurality of therapeutic microspheres, comprising: depositing one or more metals, one or more metal salts, or a combination thereof into pores of a plurality of receptive-pore microspheres to provide a plurality of densified microspheres in which the pores of the densified microspheres remain at least partially available for loading a therapeutic agent therein, an increase in mass from the one-or-more metals, one-or-more metal salts, or the combination thereof and any loss of pore structure in the plurality of densified microspheres contributing to an increase in the envelope density; and loading the therapeutic agent into the pores of the plurality of densified microspheres, thereby providing the plurality of therapeutic microspheres.

29. The method of claim 28, wherein the plurality of receptive-pore microspheres are formed of either a silicate-based glass or a biocompatible polymer selected from polystyrene, divinylbenzene, a copolymer of polystyrene and divinylbenzene, and a polymer blend of polystyrene and divinylbenzene.

30. The method of either claim 28 or 29, wherein depositing the one-or-more metals, the one-or-more metal salts, or the combination thereof into the pores of the plurality of receptive-pore microspheres includes vacuum infiltrating a solution of the one-or-more metal salts into the pores of the receptive-pore microspheres.

31. The method of claim 30, wherein depositing the one-or-more metals, the one- or-more metal salts, or the combination thereof into the pores of the plurality of receptive-pore microspheres further includes reducing the one-or-more metal salts to the one-or-more metals in the pores of the receptive-pore microspheres with a reducing agent, thereby depositing the one-or-more metals in the pores of the receptive-pore microspheres.

32. The method of claim 31, wherein the one-or-more metal salts include gold chloride, the reducing agent includes ascorbic acid, and the one-or-more metals include gold.

33. The method of either claim 28 or 29, wherein depositing the one-or-more metals, the one-or-more metal salts, or the combination thereof into the pores of the plurality of receptive-pore microspheres includes chelating one or more metal cations at chelation sites in the pores of the receptive-pore microspheres.

34. The method of claim 33, wherein depositing the one-or-more metals, the one- or-more metal salts, or the combination thereof into the pores of the plurality of receptive-pore microspheres further includes precipitating the one-or-more metal cations as the one-or-more metal salts in the pores of the receptive-pore microspheres with a counterion, thereby depositing the one-or-more metal salts in the pores of the receptive-pore microspheres.

35. The method of claim 34, wherein the one-or-more metal salts precipitated in the pores of the receptive-pore microspheres include one or more insoluble metal salts.

36. The method of claim 35, wherein the counterion is phosphate and the one-or- more insoluble salts are selected from phosphates of yttrium, cerium, and lanthanum.

37. The method of any claim of claims 33-36, wherein loading the therapeutic agent into the pores of the plurality of densified microspheres includes chelating the therapeutic agent at the chelation sites in the pores of the plurality of densified microspheres.

38. The method of any claim of claims 33-36, wherein the chelation sites include diethylenetriaminepentaacetic acid (“DTP A”) or ethylenediaminetetraacetic acid (“EDTA”) and the therapeutic agent is yttrium-90.

39. The method of any claim of claims 28-38, further comprising repeating the depositing of the one-or-more metals, the one-or-more metal salts, or the combination thereof into the pores of the plurality of receptive-pore microspheres until a desired envelope-density distribution is achieved.

40. The method of any claim of claims 28-39, further comprising separating the plurality of therapeutic microspheres into a plurality of microsphere batches having different envelope-density distributions.

41. The method of claim 40, wherein the plurality of microsphere batches having the different envelope-density distributions are indicated for optimal distribution to different targets of therapy.

42. The method of either claim 40 or 41, wherein each microsphere batch of the plurality of microsphere batches has an envelope-density distribution between about 1.5 to about 1.9 g / cc.

43. Therapeutic microspheres, comprising: a microsphere core of a consolidated silicate-based glass for densification thereof, pores of the microsphere core remaining at least partially available for loading one or more therapeutic agents therein; and a therapeutic agent loaded into the pores of the microsphere core, thereby providing the plurality of therapeutic microspheres.

44. The therapeutic microspheres of claim 43, wherein the silicate-based glass is doped with a dopant for additional densification.

45. The therapeutic microspheres of any claim of either claim 43 or 44, wherein the pores include chelation sites including diethylenetriaminepentaacetic acid (“DTP A”) or ethylenediaminetetraacetic acid (“EDTA”).

46. The therapeutic microspheres of claim 45, wherein the therapeutic agent is yttri um-90 chelated to the chelation sites including DTPA or EDTA in the pores.

47. The therapeutic microspheres of claim 46, wherein yttrium-90 is chelated to about 45-55% of the chelation sites for about 28-32 GBq of radiation activity.

48. The therapeutic microspheres of any claim of claims 43-47, wherein each therapeutic microsphere of the therapeutic microspheres has an envelopedensity between about 1.0 to about 2.2 g / cc.

49. A method of modifying an envelope density of a plurality of therapeutic microspheres, comprising: consolidating a plurality of unconsolidated microspheres with heat to provide a plurality of densified microspheres in which pores of the densified microspheres remain at least partially available for loading a therapeutic agent therein, any loss of pore structure in the plurality of densified microspheres contributing to an increase in the envelope density; and loading the therapeutic agent into pores of the plurality of densified microspheres, thereby providing the plurality of therapeutic microspheres.

50. The method of claim 49, wherein the plurality of unconsolidated microspheres are formed of a silicate-based glass, optionally, doped with a dopant for additional densification.

51. The method of either claim 49 or 50, wherein loading the therapeutic agent into the pores of the plurality of densified microspheres includes chelating the therapeutic agent at chelation sites in the pores of the plurality of densified microspheres.

52. The method of claim 51, wherein the chelation sites include diethylenetriaminepentaacetic acid (“DTPA”) or ethylenediaminetetraacetic acid (“EDTA”) and the therapeutic agent is yttrium-90.

53. The method of any claim of claims 49-52, further comprising separating the plurality of therapeutic microspheres into a plurality of microsphere batches having different envelope-density distributions.

54. The method of claim 52, wherein the plurality of microsphere batches having the different envelope-density distributions are indicated for optimal distribution to different targets of therapy.

55. The method of either claim 53 or 54, wherein each microsphere batch of the plurality of microsphere batches has an envelope-density distribution between about 1.0 g / cc and about 2.2 g / cc.

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