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Advances in Radiotherapy
& Nuclear Medicine Radionuclide-carrying liposomes

delivered their therapeutic agent. Another advantage is appropriate chelating agent. In the case of radiometals,
that when liposomes are administered intravenously they ionophores can be used to load the radiometal into the
can naturally accumulate in tumors due to the “leaky” liposome, which can then allow for the radiometal to bind
microenvironment created by tumor angiogenesis. The to a chelator inside the liposome. In some cases, if a certain
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phenomenon of microenvironments showing heightened chemotherapy has the adequate potential for chelating a
retention of macromolecular drugs, such as liposomes, is desired radiometal, the same approach can be taken using
commonly described as, “the enhanced permeability and a chemotherapeutic agent as the chelating agent to bolster
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retention effect (EPR).” This ability, paired with lessening the therapeutic effect of the liposome. A paper published
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contact between internal liposomal contents and non- by Goins et al. elucidates how the presence of glutathione
targeted tissue, makes liposomal drug delivery a desirable in liposomes can be used to trap technetium and rhenium
technique in medicine. Liposomal drugs, such as Doxil , radionuclides in liposomes after using a lipophilic
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have proven their usefulness. Doxil , which is made of chelating agent to transport the radionuclide through the
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liposomes that encapsulate doxorubicin, increases drug lipid bilayer where it interacts with the glutathione. It
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concentrations in tumors and causes fewer adverse side should be noted that using chelating agents only within
effects compared to free doxorubicin. It is these critical the liposome as opposed to the surface of the liposome is
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qualities of drug administration that make liposomes an favorable. This is because the presence of chelating agents
ideal candidate for encapsulation and administration of on the surface of the liposome can cause interactions with
radionuclides. proteins in the bloodstream or body tissues after in vivo
Passive targeting with liposomes for cancer therapy, administration, which can impact the biodistribution
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with accumulation through EPR, is limited in some of administered liposomes. Li et al. also showed how
liposomes encapsulating iodine-131 ( I) showed higher
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tumors. EPR occurs due to large gaps in the endothelial levels of cytotoxicity toward cervical cancer cells compared
walls of tumor vessels. Gaps between vascular endothelial to liposomes with I attached to the surface. In general,
131
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cells in normal tissue are approximately 5 – 10 nm. In it is more beneficial to encapsulate radionuclides within
tumor vessels, gaps in vascular endothelial tissue can range the liposomes rather than attach them to the surface. The
between 100 and 700 nm, or in some cases they appear current U.S. FDA-approved liposomal products employ
even larger. Liposomes themselves usually range from a variety of active and passive methods of loading with
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50 nm to 500 nm in diameter, allowing them to selectively therapeutic material. 20
leak into the vascular interstitium in tumors but not into
normal tissue. This phenomenon, however, does not occur Another commonly used method to encapsulate
with all types of tumors, so this type of passive targeting, both chemotherapeutic and radiotherapeutic agents into
while advantageous, cannot always be depended on liposomes is the pH gradient method. In the presence of
because it can lead to a lack of true specificity for tumor a liposomal pH gradient, the concentration of ammonium
tissue. In some cases, it may be possible to circumvent the is higher in the aqueous core than outside of the liposome,
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lack of an EPR effect through the use of active targeting. allowing for the trapping of radionuclides in the liposomes.
For instance, liposomes can be modified by attaching Many anti-cancer chemotherapeutic liposomes have
antibodies to their surface to improve drug targeting to also used the pH gradient method to load drugs into
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specific cancerous sites. 15 liposomes. The pH gradient loading method can also
be used for entrapment of radionuclides. Bao et al. first
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5. Loading radionuclides into liposomes for reported that rhenium and technetium radionuclides
diagnostic and therapeutic applications were transported through the liposome lipid bilayer and
trapped within the interior of the liposome based on the pH
The optimal method for loading radionuclides into gradient in the interior of the liposome. In this method,
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liposomes can also vary between different radionuclides. the radionuclide chelator N,N-bis(2-mercaptoethyl)-N′,N′-
For instance, hydrophilic radiopharmaceuticals can be diethylethylenediamine (BMEDA) can be used to transport
trapped within the core of the liposome while the lipid 99m Tc through the lipid bilayer of the liposome. The complex
bilayer is being formed. 5 can then be entrapped in the liposomes with the aid of pH

Many methods of incorporating drugs and gradient as the aqueous and acidic core of the liposome
radionuclides into different types of liposomes have results in the amino groups of this complex becoming
been explored. These methods include the attachment of protonated and thus entrapped. In summary, a broad
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radionuclides to the liposomal surface and active loading spectrum of techniques can be used to load radionuclides
of radionuclides into the hydrophilic core of the liposome into liposomes, demonstrating the unique versatility that
followed by the trapping of the radionuclides with an liposomes offer in their preparation and function.

Volume 2 Issue 4 (2024) 4 doi: 10.36922/arnm.4373