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Controlled local delivery of chemotherapeutic agents for treating solid tumors

a chemotherapeutic agent and local delivery technology, applied in the direction of drugs, peptide/protein ingredients, prosthesis, etc., can solve the problems of poor bioavailability and/or short half-lives in vivo, and achieve the effects of preserving bioactivity and bioavailability of the agent, short half-lives, and poor bioavailability

Inactive Publication Date: 2001-10-16
MASSACHUSETTS INST OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

A method and devices for localized delivery of a chemotherapeutic agent to solid tumors, wherein the agent does not cross the blood-brain barrier and is characterized by poor bioavailability and/or short half-lives in vivo, are described. The devices consist of reservoirs which release drug over an extended time period while at the same time preserving the bioactivity and bioa

Problems solved by technology

A method and devices for localized delivery of a chemotherapeutic agent to solid tumors, wherein the agent does not cross the blood-brain barrier and is characterized by poor bioavailability and / or short half-lives in vivo, are described.

Method used

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  • Controlled local delivery of chemotherapeutic agents for treating solid tumors
  • Controlled local delivery of chemotherapeutic agents for treating solid tumors
  • Controlled local delivery of chemotherapeutic agents for treating solid tumors

Examples

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example 1

In Vitro Efficacy of Paclitaxel

Cell culture. Tumor sensitivity to paclitaxel was measured by the clonogenic assay described by Rosenblum, et al., Cancer 41:2305-2314 (1978) and Salcman, et al., Neurosurgery 29:526-531 (1991) with rat glioma (9L, F98), human glioma (H80, U87, U373), and human medulloblastoma (D324) cell lines. Cells were grown and propagated in minimum essential medium (MEM) supplemented with 10% fetal bovine serum, L-glutamine, penicillin, and streptomycin and incubated at 37.degree. C. in an atmosphere containing 5% CO.sub.2. At the start of each assay, 600 tumor cells in 2 ml of medium were plated on Falcon 6-well tissue-culture plates (Becton-Dickenson, Lincoln Park, N.J.). After incubating for 24 h, the medium was removed from the places and replaced with 2 ml of medium containing paclitaxel and 0.1% dimethylsulfoxide (DMSO). The treatment solutions were prepared as described by Roytta et al., Prostate 11:95-106 (1987). The paclitaxel treatment solution was then...

example 2

Preparation of Paclitaxel Implant

Solid paclitaxel, obtained from Napro Biotherapeutics (Boulder, Colo.) or from the National Cancer Institute (Bethesda, Md.), was mixed with poly[bis(p-carboxyphenoxy)propane-sebacic acid] copolymer (PCPP-SA) (20:80) synthesized according to the method of Domb, A. J., and R. Langer (J. Polym. Sci. 25:3373-3386 (1987)), the teachings of which are incorporated herein by reference, to give a mixture containing 0, 20, 30, or 40% paclitaxel by weight. The paclitaxel-polymer mixture was dissolved in methylene chloride (Fluka, Switzerland) to give a 10% solution (w:v). The solvent was evaporated with a nitrogen stream to yield a dry powder. Paclitaxel-polymer discs (10 mg final weight) were prepared by compression molding 11 mg of the paclitaxel-polymer powder with a stainless steel mold (internal diameter, 2.5 mm) under light pressure from a Carver Press at 200 psi. The discs were sterilized under UV light for 45 minutes.

example 3

Demonstration of Paclitaxel Delivery from a Biodegradable Matrix into the Surrounding Medium in Vitro

The efficiency of the delivery of paclitaxel incorporated into a biodegradable polymer into the surrounding medium was assessed in vitro as follows.

Preparation of polymer discs. Polymer discs were prepared as described above except that .sup.3 H-labeled paclitaxel (Atomic Energy Commission, Nuclear Research Center, Beer Sheva, Israel) was used in the polymer preparation. The .sup.3 H-labeled paclitaxel had a final specific activity of 0.019 .mu.Ci / mg and was obtained by mixing .sup.3 H-labeled paclitaxel at 6.2 Ci / mmol with 100 mg of unlabeled paclitaxel (Napro Biotherapeutics, Boulder, Colo.; or National Cancer Institute, Bethesda, Md.) in methanol and then evaporating the solvent.

Protocol. The paclitaxel-loaded polymer discs were placed in a microporous polyethylene specimen capsule (8.times.8 mm internal diameter and height), which was immersed in 7 ml of 0.1M phosphate buffer, pH...

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Abstract

A method and devices for localized delivery of a chemotherapeutic agent to solid tumors, wherein the agent does not cross the blood-brain barrier and is characterized by poor bioavailability and / or short half-lives in vivo, are described. The devices consist of reservoirs which release drug over an extended time period while at the same time preserving the bioactivity and bioavailability of the agent. In the most preferred embodiment, the device consists of biodegradable polymeric matrixes, although reservoirs can also be formulated from non-biodegradable polymers or reservoirs connected to implanted infusion pumps. The devices are implanted within or immediately adjacent the tumors to be treated or the site where they have been surgically removed. The examples demonstrate the efficacy of paclitaxel and camptothecin delivered in polymeric implants prepared by compression molding of biodegradable and non-biodegradable polymers, respectively. The results are highly statistically significant.

Description

The U.S. government has rights in this invention by virtue of a grant from the National Cancer Institute, cooperative agreement number U01 CA 52857; and N.I.H. grant numbers U01 CA52857 to Henry Brem and Robert S. Langer and T32 CA09574.BACKGROUND OF THE INVENTIONThis invention is in the field of localized delivery of chemotherapeutic agents to solid tumors.One-third of all individuals in the United States alone will develop cancer. Although the five-year survival rate has risen dramatically to nearly fifty percent as a result of progress in early diagnosis and the therapy, cancer still remains second only to cardiac disease as a cause of death in the United States. Twenty percent of Americans die from cancer, half due to lung, breast, and colon-rectal cancer.Designing effective treatments for patients with cancer has represented a major challenge. The current regimen of surgical resection, external beam radiation therapy, and / or systemic chemotherapy has been partially successful i...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K9/20A61K31/282A61K31/28A61K31/337A61K31/4738A61K31/4745A61K9/22A61K31/47A61K38/00A61K39/395A61K45/00A61K47/34
CPCA61K9/0085A61K9/2027A61K9/2031A61K9/204A61K31/337A61K31/4745A61K31/555A61P35/00
Inventor BREM, HENNYLANGER, ROBERT S.DOMB, ABRAHAM J.
Owner MASSACHUSETTS INST OF TECH
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