Alternative Solutions to Further
Assess and Evaluate:
1. Adjust
the number and positioning of the microbubbles in order to rupture the capsule
- One of
the main problems with using a polymer shell as a transport vehicle for drugs
is that scientists have been unable to rupture the capsule by microbubble
cavitation. Existing research has demonstrated that microbubble cavitations
near solid walls generate jets of water in the direction of the wall. This
results from the pressure difference on each side of the microbubble. By
varying the number and location of microbubbles along with the above principle,
it may be possible to concentrate the force on a specific area to break through
the polymer shell.
2. Incorporate
antibodies throughout the polymer shell of microbubbles
- The
advantage of antibodies on the polymer coating is that this would help the
microbubbles to stick and attach to the targeted designated site more
efficiently, such as a cancer tumor. It would also weaken the microbubble shell
so that it will be able to be ruptured easily using ultrasound and release the
medicine that are inside the microbubbles. Research has been done in analyzing
the attachment of specific antibodies to the phosphatidylserine (PS) layer of
Sonozoid (which consists of perfluorobutane gas microbubbles stabilized by a
membrane of hydrogenated egg phosphatidylserine). The attachment of antibodies
was used to detect the PS layer specifically for “targeted molecular imaging”.
However, this has not been implemented in the process of actual drug delivery.
- Phosphatidylserine
(PS) exists and is exposed on the outer membrane of cells during the apoptosis
stage, or the cell death stage. PS also has been found on cancer cells, which
ironically prevents the death of these cells. As a probable solution, the idea
of having microbubbles covered with specific antibodies or contrasting agents
would be used to detect and attach to the PS layer of cancer tumor cells,
instead of the microbubbles being covered by PS. This would eventually help in
safely and directly releasing the medicine into the cancer cell, as the
microbubbles are ruptured by the ultrasound. In the study mentioned above, the
possible antibodies or agents that was utilized on Sonozoid were
Fluorescein-Labeled Annexin V, PE-streptavidin with PE Biotinylated Annexin V
(Avidin-Biotin binding), or the Avidin -Biotin binding along with a
biotinylated Alexa488–IgG antibody. These antibodies/agents may be suitable for
a new design of polymer-covered microbubbles, if they are sufficiently
effective, do not cause any side effects in the body, and if it is not costly
to be developed. It may also be convenient if the microbubbles had a
phospholipid bilayer with PS already on its membrane.
- http://search.proquest.com/biologicalscience/docview/855954465/1368E50A5FB1528C1FD/6?accountid=10559
3.
Composite materials for coating the
microbubbles
- Magnetic/PLA
composite microbubble with various structures and controllable average size can
be prepared by a modified double emulsion solvent evaporation. Certain
amount of manganese phosphide and pla are mixed and dissolved in
dichloromethane. Then 2-3 milliliters of deionized water is added. The obtained
emulsion is then poured into poly vinyl alcohol solution and homogenized for a
certain amount of time. The resultant double emulsion is then stirred with 2%
isopropanol solution and after waiting for couple of hours, the resultant
microbubbles can be obtained.
- http://www.springerlink.com/content/h0831787r1n35838/fulltext.html#Sch1
4.
Polylactic Acid
- Nowadays,
some protein especially albumin based microbubbles are being used commercially
for drug delivery. But polymeric microbubbles have some advantages over albumin
based one. Since polymeric shells are thick and sturdy, it can possess a higher
loading capacity. It is also stable and flexible. For this purpose, polylactic
acid or PLA can be used to make microbubbles. This is also a biodegradable and
biocompatible polymer. Another great advantage of PLA is the bubbles can be
stored inside the polymeric shell for quite a long time and both hydrophobic
and hydrophilic drugs can be incorporated.
5.
Albumin and other drugs cross linked with
microbubbles
- Albumin
chosen as nanomaterial not only has some benefits as mentioned previously but
also was easy to link to the protein ultrasound microbubbles for the purpose of
targeting.There are two different methods for nanoparticles to carry genes. One
of them is the single-step method, in which a gene is added to the albumin
solution before the nanoparticles are prepared, and the gene DNA is
encapsulated in the matrix of the nanoparticles. This method has some advantages
because of the higher concentration of the drug, delayed and controllable
release, enzyme resistance, and a longer time to transfect the gene. Another
method is the two-step method, in which the albumin nanoparticles are prepared
before the gene is added, and the pH value of the solution is adjusted to be
acidic, which makes a more positive charge on the surface of the nanoparticles
and links easily to the gene DNA with the negative charge. The nanoparticles
made this way are equal in size, and the particle diameter is changed easily
but without the advantages mentioned previously Albumin can be crosslinked to
another protein by glutaraldehyde.The microbubbles carried with albumin
nano-tPa plasmid could not escape from blood in the circulation because of
their size (2–5 μm in diameter).
- For
breast cancer:
- Several drugs that interfere with estrogen
binding to the ER has been approved by the FDA for the treatment of ER-positive
breast cancer. Drugs called selective estrogen receptor modulators (SERMs), including
tamoxifen and toremifene (Fareston®), bind
to the ER and prevent estrogen binding. Another drug, fulvestrant (Faslodex®),
bind to the ER and promotes its destruction, thereby reducing ER levels inside
cells.
6.
Liposomes and Microbubbles together
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