‘Magic bullets’ could strike down tumours and HIV
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VIEWS & REVIEWS 'Magic bullets' could strike down tumours and mv . -Amanda Hunt- A new type of microsphere delivery system is being developed by scientists at the John Hopkins Medical Institutions in Baltimore, US. They hope that it will enable improved targetting of therapy for patients with cancer and HIV, reducing toxicity. Drs Kam Leong and Vu Truong presented results of their work with the microspheres at the recent Experimental Biology '93 conference, held in New Orleans, US, at the end of March. Homing in OIl tumours The microsphere is designed to allow targetted delivery of high drug concentrations to the specific sites where they are required, reducing systemic toxicity. Antibodies on the surface enable 'homing' of the capsule to the target tissue, where enzymes denature the protein coat of the microsphere, enabling local drug release. Release rates from the capsules can be controlled by increasing the degree of capsule cross-linking, resulting in greater stabilisation and slower release. The drug can be released intra- or extracellularly, depending on the cell type. Some cells endocytose the drug, while at other sites, extracellular enzymes degrade the microsphere and allow local drug release. While the idea is not new, the construction technique appears to be a breakthrough. Drs Truong and Leong have used a protein-based polymer system composed of substances which occur naturally in the body, gelatin and chondroitin sulfate, cross-linked with glutaraldehyde l . Other researchers have been working on liposome-based technologies for the last 2 decades, but Drs Truong and Leong say that these seem to be plagued by difficulties of instability, low drug-loading levels and a limited range of functional groups available on the liposome surface. The capsules designed by Drs Truong and Leong can contain a wide variety of compounds, including cytotoxic drugs and biologically active agents such as cytokines, peptides and antisense RNAs. An increasing number of these new bioactive compounds under development are highly unstable in vivo and require specialised delivery vehicles. Unless suitable vehicles are available, the commercial viability of many of these compounds will be limited. The microspheres are designed for systemic injection, and could also be used to transport radioisotopes and imaging agents. 'This system is ideal for encapsulating polypeptides. .. and polynucieotides ... which are expected to comprise the bulk of newer generation therapeutic agents' Drs Vu L Truong and Kam W Leong, John Hopkins Medical Institutions to manufacture An additional advantage of the microspheres, says Dr Truong, is that they are relatively easy to manufacture, requiring few components or processing steps. Also, the microsphere surface is 'universally adaptable' to linkage to a wide range of antibodies or other ligands. At this stage, the researchers are not sure if the protein coat of the microsphere will be immuno- genic. It seems unlikely, they say, as gelatin-based drug-delivery products are used in many surgical procedures without complications. Overcoming drug resNance Monoclonal antibodies attached to the microsphere allow targetting of the drug. In particular, Drs Truong and Leong have worked with microspheres targetted to the P-glycoprotein, a transmembrane protein responsible for anti- neoplastic drug resistance in many tumours. P-glycoprotein is involved in drug efflux from tumour cells. A microsphere targetted towards this protein would enable delivery of high drug concentrations to the tumour, increasing the likelihood of overcoming resistance. The researchers also propose that HIV-specific therapy would be possible with the microspheres, although they have not undertaken this work yet. Drs Truong and Leong have been working with a variety of antibodies. However, they are more interested in refining the microsphere technology, than in targetting specific cell lines. Dr Truong believes that many groups will be interested in picking up the technology once it is ready, and 'specific applications willfollow'. I. Leong KM, et aI. P-glycoprotein-specific binding of immuno- microspheres to drug-resistant KB-V-l cells. FASEB Joumal7: 690, Part II, 23 Feb 1993 Il00'9'9911 INPHARMA i8 17 Apr 1993 3
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Transcript of ‘Magic bullets’ could strike down tumours and HIV
VIEWS & REVIEWS
'Magic bullets' could strike down tumours and mv .
-Amanda Hunt-
A new type of microsphere delivery system is being developed by scientists at the John Hopkins Medical Institutions in Baltimore, US. They hope that it will enable improved targetting of therapy for patients with cancer and HIV, reducing toxicity. Drs Kam Leong and Vu Truong presented results of their work with the microspheres at the recent Experimental Biology '93 conference, held in New Orleans, US, at the end of March.
Homing in OIl tumours The microsphere is designed to allow targetted
delivery of high drug concentrations to the specific sites where they are required, reducing systemic toxicity. Antibodies on the surface enable 'homing' of the capsule to the target tissue, where enzymes denature the protein coat of the microsphere, enabling local drug release.
Release rates from the capsules can be controlled by increasing the degree of capsule cross-linking, resulting in greater stabilisation and slower release. The drug can be released intra- or extracellularly, depending on the cell type. Some cells endocytose the drug, while at other sites, extracellular enzymes degrade the microsphere and allow local drug release.
While the idea is not new, the construction technique appears to be a breakthrough. Drs Truong and Leong have used a protein-based polymer system composed of substances which occur naturally in the body, gelatin and chondroitin sulfate, cross-linked with glutaraldehyde l
. Other researchers have been working on liposome-based technologies for the last 2 decades, but Drs Truong and Leong say that these seem to be plagued by difficulties of instability, low drug-loading levels and a limited range of functional groups available on the liposome surface.
The capsules designed by Drs Truong and Leong can contain a wide variety of compounds, including cytotoxic drugs and biologically active agents such as cytokines, peptides and antisense RNAs. An increasing number of these new bioactive compounds under development are highly unstable in vivo and require specialised delivery vehicles. Unless suitable vehicles are available, the commercial viability of many of these compounds will be limited.
The microspheres are designed for systemic injection, and could also be used to transport radioisotopes and imaging agents.
'This system is ideal for encapsulating polypeptides. .. and polynucieotides ... which
are expected to comprise the bulk of newer generation therapeutic agents'
Drs Vu L Truong and Kam W Leong, John Hopkins
Medical Institutions
~ to manufacture An additional advantage of the microspheres,
says Dr Truong, is that they are relatively easy to manufacture, requiring few components or processing steps. Also, the microsphere surface is 'universally adaptable' to linkage to a wide range of antibodies or other ligands.
At this stage, the researchers are not sure if the protein coat of the microsphere will be immunogenic. It seems unlikely, they say, as gelatin-based drug-delivery products are used in many surgical procedures without complications.
Overcoming drug resNance Monoclonal antibodies attached to the
microsphere allow targetting of the drug. In particular, Drs Truong and Leong have worked with microspheres targetted to the P-glycoprotein, a transmembrane protein responsible for antineoplastic drug resistance in many tumours. P-glycoprotein is involved in drug efflux from tumour cells. A microsphere targetted towards this protein would enable delivery of high drug concentrations to the tumour, increasing the likelihood of overcoming resistance. The researchers also propose that HIV-specific therapy would be possible with the microspheres, although they have not undertaken this work yet.
Drs Truong and Leong have been working with a variety of antibodies. However, they are more interested in refining the microsphere technology, than in targetting specific cell lines. Dr Truong believes that many groups will be interested in picking up the technology once it is ready, and 'specific applications willfollow'.
I. Leong KM, et aI. P-glycoprotein-specific binding of immunomicrospheres to drug-resistant KB-V-l cells. FASEB Joumal7: 690, Part II, 23 Feb 1993 Il00'9'9911
INPHARMAi8 17 Apr 1993
3
