Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
2001-02-16
2003-04-15
Mendez, Manuel (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C604S501000
Reexamination Certificate
active
06547777
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an apparatus and method for reducing interstitial fluid pressure, enhancing radiation therapy, and enhancing delivery and effectiveness of therapeutic agents in tissue, particularly in tumors.
BACKGROUND OF THE INVENTION
Throughout this application various publications are referenced and citations are provided in the Reference section. The disclosure of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Cancer is the second leading cause of death in this country and still continues to be a public health problem of increasing significance.
1
Cancer therapy may be categorized into three major approaches: surgical excision, radiotherapy, and chemotherapy. Chemotherapy is defined as the treatment of cancer by a systemic administration of drugs.
Unfortunately, most drugs which showed promising effects in vitro have failed to be as effective in vivo, particularly in solid tumors. It has been proposed that one of the major reasons for this failure is the impediment of drug transport into tumors. In particular, a physiological barrier created by raised interstitial fluid pressure appears to be responsible. The interstitial fluid pressure is raised in tumors primarily because of the lack of lymphatics in tumors and growth of tumor cells in confined spaces. The raised interstitial fluid pressure in tumors is a principal transport-retarding factor for the delivery of drugs such as macromolecules, i.e., large molecular weight molecules such as monoclonal antibodies (MoAb), tumor necrosis factor, and other chemotherapeutic agents.
Jain et al. suspected that elevated interstitial fluid pressure is a principal transport retarding factor in MoAb delivery because of the lack of lymphatics in the tumor.
2,3
In normal tissue, maintenance of the fluid balance within the tissue spaces is dependent upon the interplay of hydrostatic and colloid osmotic pressures operating on a vascular network with uneven permeability and with dissimilar exchange area with the aid of the lymphatic system. The lymphatics are responsible for returning extravasated fluids and macromolecules to circulation throughout the body. Most macromolecules, including proteins, cannot return to circulation without the lymphatic system after they percolate through the endothelial wall.
4
Accordingly, lymphatic drainage is a factor of primary importance in maintaining fluid balance.
5
Once the equilibrium is disrupted, dehydration or edema in the tissue would result from the imbalanced colloid osmotic and hydrostatic vascular pressure. These relations are well described by Starling's hypothesis.
6
A functioning lymphatic system as an anatomical entity has not been demonstrated in the tumor. The absence of lymphatics affords no alternative way by which macromolecules can re-enter the circulation after their extravasation through the capillaries. The potential of fluid flow into the tumor is hindered by an opposing force with equivalent magnitude from interstitial fluid pressure. This opposing force increases until all the forces in Starling's Law are balanced. The convective component of drug transport from capillary to interstitial space is blocked and the predominant mechanism is molecular diffusion. Fluid oozes out toward the tumor surface because of the lower effective pressure at the tumor periphery resulting from draining advantage by lymphatics of the normal tissue at the tumor periphery. This outward fluid velocity from the tumor center to the tumor periphery additionally hinders the diffusional movement of treatment molecules into the tumor center.
2
Decreased intravascular pressure and/or increased interstitial pressure in tumors has been demonstrated by several investigators.
7-12
Findings to date indicate that elevated interstitial fluid pressure has been attributed to the absence of a well-defined lymphatic system in the tumor,
3, 13
and to increased permeability of tumor vessels.
14, 15
Researchers reported that interstitial fluid pressure increases with tumor size.
16-19
The increase in interstitial fluid pressure has also been shown to correlate with reduction in tumor blood flow (lower blood perfusion rate) and the development of necrosis in a growing tumor.
16-18, 20
Jain et al. presented a mathematical model describing the possible relationship between the distribution of macromolecules, e.g., monoclonal antibodies (MoAbs) and elevated interstitial pressure.
21
They proposed that increased interstitial fluid pressure might be responsible for the poor penetration of MoAbs into tumors including the heterogeneous blood perfusion, hindered diffusion in the interstitium, and extravascular binding of MoAbs. Furthermore, they stated that the elevated interstitial pressure principally reduces the driving force for extravasation of fluid and macromolecules in tumors, and leads to an experimentally verifiable, radially outward convection which opposed the inward diffusion. They have presented results from several mathematical models and the models' implications to support their hypothesis.
2, 3, 22, 23
A variety of approaches have been tried to enhance delivery of therapeutic agents to tumors. For example, U.S. Pat. No. 5,484,399 to DiResta et al. (“DiResta '399 patent”), the contents of which are incorporated herein by reference, discloses a process and device to reduce interstitial fluid pressure in tissue. Briefly, the DiResta '399 patent discloses an artificial lymphatic system (ALS) which includes a plurality of aspiration tubes, each having a plurality of aspiration holes, and a manifold for connecting the tubes to a vacuum source. Experimental studies have shown that the ALS has resulted in reduced interstitial fluid pressure within tumors, increased blood flow within tumors, and enhanced uptake of chemotherapeutic drugs into the tumors. Specifically, by reducing interstitial fluid pressure, blood flow, pH, and pO
2
all increase to more normal levels. These changes increase delivery of drugs to the tissue and drug uptake into the cells. The increase in tissue pH enhances the reaction kinetics of drugs whose pH optimum is in the normal range. Increasing pO
2
enhances radiation therapy because oxygen is the most potent radiationsensitizing agent currently known.
Despite these promising findings, there are limitations to the ALS. Specifically, the small holes in the ALS may tend to become blocked with time. As a result, long term use of the ALS could potentially be problematic. Long term use of the ALS may further be complicated by the lack of a mechanism to secure the drains of the ALS to the tissue so that the drains remain spatially fixed. Finally, the ALS had no features that facilitate use with adjunct therapies that enhance drug delivery. Use of various other therapies to enhance efficacy of the ALS would be desirable. However, until now, no other adjunct therapy has been used in conjunction with the ALS.
Electroporation is another therapy that has been used to enhance delivery of therapeutic agents to tumors. Recent studies have demonstrated that electroporation may be beneficial in the treatment of accessible solid tumors. Electroporation is a technique that uses pulsed electric fields to create transient pores within cell membranes to temporarily increase the membrane's permeability to exogenous molecular agents. The electric fields are created between pairs of needle electrodes inserted into a tissue region of interest. The electrode separation distance is typically fixed and a grid array of electrodes is used to treat tissue regions.
As electroporation requires that the desired drugs be within the tissue region to be treated when the electric field is induced, the major problem with the successful use of electroporation is the need for an adequate quantity of the therapeutic agent in the region at which the electric field will be generated. Blood flow is low in many solid tumors
DiResta Gene R.
Healey John Henry
Han Mark
Mendez Manuel
Sloan-Kettering Institute for Cancer Research
LandOfFree
Apparatus and method for reducing interstitial fluid... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Apparatus and method for reducing interstitial fluid..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Apparatus and method for reducing interstitial fluid... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3036347