Magnetic Microspheres: Synthesis of a Novel Parenteral Drug Carrier

Widder, Kenneth J.; Flouret, George; Senyei, Andrew E.

doi:10.1002/jps.2600680124

Cited by 186 publications

(46 citation statements)

References 16 publications

(7 reference statements)

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“…Previous investigators have shown that serum albumin may adsorb at the water/oil interface in the emulsion during the preparation of the albumin microspheres and that serum albumin undergoes a change in conformation so that hydrophobic regions of the protein are preferentially exposed to the oil phase (23). The formation of an adsorbed layer composed of denatured serum albumin results in marginally stable microspheres without heat or chemical crosslinking.…”

Section: Resultsmentioning

confidence: 99%

Preparation and characterization of microspheres of albumin-heparin conjugates

Kwon¹,

Bae²,

Kim³

et al. 1991

Journal of Colloid and Interface Science

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Albumin-heparin microspheres have been prepared as a new drug carrier. A soluble albumin-heparin conjugate was synthesized by forming amide bonds between human serum albumin and heparin. After purification the albumin-heparin conjugate was crosslinked in a water-in-oil emulsion to form albuminheparin microspheres. The composition of the conjugate was determined by amino acid analysis. The swelling properties of albumin-heparin microspheres were investigated as a function of pH and ionic strength and compared with albumin microspheres. Albumin-heparin and albumin microspheres exhibited stimuli-sensitive swelling. Both microsphere systems exhibited low swelling at low pH and high swelling at higher pH caused by ionization of amino acids of serum albumin. The swelling of albumin-hepafin microspheres was more sensitive toward ionic strength than that of albumin microspheres. This was due to the greater negative charge of the albumin-heparin microspheres. Surfaces of albumin-heparin and albumin microspheres were characterized by ESCA, contact angle measurements, electrophoresis, and scanning electron microscopy. Surface analysis indicated the presence of heparin at the albumin-heparin microsphere/water interface.

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Section: Resultsmentioning

confidence: 99%

Preparation and characterization of microspheres of albumin-heparin conjugates

Kwon¹,

Bae²,

Kim³

et al. 1991

Journal of Colloid and Interface Science

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“…Animals were treated after tumor load was evident (6)(7)(8) days after inoculation) and with a single dose of 0.5 mg of doxorubicin per kg as compared to multiple-dose therapy with free doxorubicin at 5 mg/kg.…”

Section: Discussionmentioning

confidence: 99%

“…Magnetic microspheres (average 1 ,um in diameter) were prepared using methods as described (8). Briefly, a phase-emulsion polymerization process was used in which the aqueous phase consists of human serum albumin, doxorubicin, and magnetite (Fe3O4).…”

Section: Methodsmentioning

confidence: 99%

Tumor remission in Yoshida sarcoma-bearing rts by selective targeting of magnetic albumin microspheres containing doxorubicin.

Widder¹,

Morris²,

Poore³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

139

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Magnetically responsive albumin microspheres containing doxorubicin and magnetite (Fe3O,) were selectively targeted to Yoshida sarcoma tumors in rats by utilizing an extracorporeal magnet. Tumor cells were inoculated subcutaneously in the tail ofrats, and the tumors were allowed to grow to an average size of 9 X 45 mm prior to initiating treatment. Drug-bearing microspheres (0.5 mg ofdoxorubicin per kg ofbody weight) were infused proximal to the tumor through the ventral caudal artery while the tumor was exposed to an external magnetic field of 5500 Oe for 30 min. Control animals received free doxorubicin administered either intravenously (5 mg/kg) or infused intraarterially (5 and 0.5 mg/kg), drug-bearing microspheres infused intraarterially (0.5 mg/kg) without the external magnet, or placebo microspheres with magetic localization. Ofthe 12 animals treated with a single dose in the experimental group, 9 exhibited total remission of the tumor, representing a disappearance of tumors as large as 60 mm in length. Marked tumor regression was observed in the remaining three rats, and no deaths or metastases occurred in the experimental group. In contrast, significant increases in tumor size with widespread metastases occurred in all control groups and most rats died. These experiments indicate that targeting of oncolytic agents to solid neoplasms by magnetic microspheres may be a means of increasing the efficacy and decreasing the toxicity of antitumor agents.The ability to selectively target and restrict activity of antineoplastic agents to known foci of tumors has been a continuous challenge in cancer chemotherapy. Encapsulation carriers such as liposomes (1, 2) and albumin microspheres (3, 4) offer promise for attaining target-site specificity. However, the unrestricted circulation of liposomes and other carriers results in their rapid clearance by the, reticuloendothelial system if injected intravascularly. Moreover, neither modality has demonstrated a significant degree oftarget-site specificity. The various modalities for the targeting of drugs have recently been extensively reviewed (5) and will not be discussed here.With the goal of circumventing the reticuloendothelial system and achieving high target-area concentrations of drug carrier, we designed small (1-,m average diameter) magnetically responsive albumin microspheres capable of responding to extracorporeal magnetic fields (6). Virtually any water-soluble drug can be entrapped in these microspheres. By varying magnetic parameters, we have shown in vitro that the microspheres could be selectively retained at capillary-level flow rates (7). Retention ofthe drug carrier in capillaries is important, as maximum drug diffusion occurs at this level ofthe circulation. In addition, one ideally would like to remove the carrier from the vascular system into the extravascular compartment, producing a depot for sustained release ofantineoplastic agents. We have demonstrated that as early as 30 min after drug-carrier lo-

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“…Preparation of Microspheres-Microspheres were prepared by a modification of methods described previously (7). Essentially, a phaseseparation emulsion-polymerization method was employed.…”

Section: Methodsmentioning

confidence: 99%