An Idea - use Nanovesicles to deliver rapamycin

Review the following:

The nanovesicles extracted from the plant and herbal decoctions are identified as a new class of nanomedicine. They are involved in interspecies chemical communication across the plant and animal kingdoms and display a therapeutic potential against a variety of diseases. Herein, we review the recent progress made in the medical applications of plant-derived nanovesicles in the aspects of anti-inflammation, anti-cancer, tissue regeneration, and modulating commensal microbiota. We further summarize the cellular and molecular mechanisms underlying the physiological functions of plant-derived nanovesicles. Overall, plant-derived nanovesicles provide an alternative to conventional synthetic drugs and present exciting opportunities for future research on disease therapy.


Lipid-based nanovesicles such as liposomes, niosomes, and ethosomes are now well recognized as potential candidates for drug delivery and theranostic applications. Some of them have already stepped forward from laboratory to market. The property to entrap lipophilic drugs in their bilayers and hydrophilic drugs in the aqueous milieu makes them a unique carrier for drug delivery. Delivery of drugs/diagnostics to various organs/tissues/cells via nanovesicles is considered to be a topic of long-standing interest with new challenges being posed to formulation scientists with new developments. The key challenge in this context is the physiological and pathological conditions, which make the delivery of drugs extremely difficult at the disease locus and makes their precise delivery ineffective. This chapter gives an insight into the role of novel nanovesicles in the field of drug delivery. We present an overview of the formulation and characterization and role of diverse nanovesicles. A comprehensive update about their application and current as well as potential challenges have also been discussed.

Another Skunk Works Project?


There are many research labs already working on this, it could open up Rapamycin to wider therapeutic availability.

Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

Standard oral rapamycin (i.e. Rapamune®) administration is plagued by poor bioavailability and broad biodistribution. Thus, this pleotropic mTOR inhibitor has a narrow therapeutic window, numerous side effects and provides inadequate protection to transplanted cells and tissues. Furthermore, the hydrophobicity of rapamycin limits its use in parenteral formulations. Here, we demonstrate that subcutaneous delivery via poly(ethylene glycol)-b-poly(propylene sulfide)(PEG- b-PPS) polymersome (PS) nanocarriers significantly alters rapamycin’s cellular biodistribution to repurpose its mechanism of action for tolerance instead of immunosuppression while minimizing side effects. While oral rapamycin inhibits naïve T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes (rPS) modulate antigen presenting cells in lieu

of T cells significantly improving maintenance of normoglycemia in a clinically relevant, MHC- mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of a rationally designed nanocarrier to re-engineer the immunosuppressive mechanism of a drug by controlling cellular biodistribution.

Progress in Nanomedicine: Approved and Investigational Nanodrugs

Nanomedicine is a relatively new and rapidly evolving field combining nanotechnology, biomedical, and pharmaceutical sciences.1–3 Nanomedicine encompasses nanopharmaceuticals, nanoimaging agents, and theranostics.1,6 This article will discuss only nanopharmaceuticals (i.e., “nanodrugs”).

Nanodrug formulations can impart many physical and biological advantages, such as improved solubility and pharmacokinetics (PK), enhanced efficacy, reduced toxicity, and increased tissue selectivity, compared with conventional medicines.1–6 Some controversy exists regarding the definition of nanodrugs. However, the Food and Drug Administration (FDA) considers the products it regulates (including drugs and biologics) to incorporate nanotechnology if they contain or are manufactured with: NPs that range from 1 to 100 nano- meters (nm), which due to their small size and high surface area exhibit key differences in comparison to bulk materials; or materials outside of this range that exhibit related dimension- dependent properties or phenomena.1,3,6 NPs can change the biochemical, electronic, magnetic, and/or optical properties of a drug formulation in a way that can then be applied for therapeutic purposes.1,3,7 NPs used in nanodrug formulations currently include liposomes, polymers, micelles, nanocrystals, metals/metal oxides and other inorganic materials, and proteins, although research is being conducted with other types of NPs, such as carbon nanotubes (Figure 1).1–3

From the paper you posted;

“Absorption is variably affected by food, especially high-fat meals that decrease the oral bioavailability⁶”

⁶MacDonald A, Scarola J, Burke JT, et al. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Ther. 2000;22 Suppl B:B101–B121.

High-fat meals decrease the oral bioavailability?

Postings on here/other threads state the opposite.

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Agreed, I think they are in error:

The oral availability of sirolimus was increased to a modest extent (35%) and in a uniform manner when administered with a high-fat meal; the geometric mean ratio of the fed/fasting AUC values was 1.35, with a 90% confidence interval of 1.26 to 1.46. Food had no effect on the terminal half-life of sirolimus (mean values of 67 to 68 hours). The 35% increase in AUC obtained after a high-fat meal appears small relative to the intersubject and intrasubject variabilities observed in clinical trials”

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There are numerous companies doing liposomal version of supplements for increased bioavailability. It does seem that Rapamycin might benefit from this “packaging” approach, but sadly as soon as you start doing this for compounds classified as “drugs” (as rapamycin is) you’re suddenly into FDA approval processes, that take forever.

I’m not familiar with the technologies of liposomal “encapsulation” or what is required to do this - but it seems that this is likely more of a “company” type activity than a biohacking endeavor - but I may be wrong on this. Perhaps someone with more expertise in this area can comment. Perhaps there are companies out there that provide this as a service?

A new paper - related to Tissue Specific mTOR inhibitors - perhaps a way to compliment regular rapamycin - though perhaps more likely just a way to target specific organs for cancer therapy without systemic side effects?

Tissue-Restricted Inhibition of mTOR Using Chemical Genetics

It remains unclear how mTOR signaling in individual tissues contributes to whole-organism processes because mTOR inhibitors, like the natural product Rapamycin, are administered systemically and target multiple tissues simultaneously. We developed a chemical-genetic system, termed selecTOR, that restricts the activity of a Rapamycin analog to specific cell populations through targeted expression of a mutant FKBP12 protein. This analog has reduced affinity for its obligate binding partner FKBP12, which reduces its ability to inhibit mTOR in wild-type cells and tissues. Expression of the mutant FKBP12, which contains an expanded binding pocket, rescues the activity of this Rapamycin analog. Using this system, we show that selective mTOR inhibition can be achieved in S. cerevisiae and human cells, and we validate the utility of our system in an intact metazoan model organism by identifying the tissues responsible for a Rapamycin-induced developmental delay in Drosophila.

Full pre-print paper:

Interesting biographical note on one of the paper authors:

K.M.S. is an inventor on patents owned by UCSF covering mTOR targeting small molecules licensed to Calithera Biosciences and Revolution Medicines.


“Pharmaceutical Nanotechnology Basic Protocols”

“Nanovesicles for Nanomedicine: Theory and Practices”

See pages 13 to 29

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Wow. My head is swimming. I appreciate the fact that you can understand these and translate them into common sense steps to take for the rest of us!

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Truth Passes Through Three Stages: First, It Is Ridiculed. Second, It Is Violently Opposed. Third, It Is Accepted As Self-Evident

~Arthur Schopenhauer

There are many, small one off batch they are not interested in, high cost for one off.

Liposomal Nanovesicles for Efficient Encapsulation of Staphylococcal Antibiotics