Why are nanoliposome encapsulated antibiotics still so unavailable despite being so effective?

Question

I wasnt sure how the phrase the headline question really nor if this is the right place to ask it, but i'm primarily interested in the chemical synthesis aspect and the experience of chemists regarding this subject.

In the antimicrobial literature specific liposome or nano particle encapsulations of antibiotics have been shown over and over again to show immense potential for quite a long time by now, enhancing efficacy, pharmacokinetics while at the same time reducing toxicities. My question basically is, why is this not being used really? Advanced liposomes can be found in some vaccines for example and the likes of it. But we continue to pump e.g. Aminogylcosides like Gentamicin into people which while very effective against certain hard to treat organisms can fail due to 1. pharmacokinetic limitations (low intracellular penetration etc.) and 2. toxicity and damage.

Im not interested in the discussion about efficacy for treatment in people, as that wouldnt be on the subject of chemistry and that has already been shown, but rather what is it that makes it so hard about this being available? I found literature ranging from 20 years ago showing specific PH sensitive liposome encapsulations of Gentamicin vastly increased efficacy against gram negative intracellular infections in vitro and in vivo and immensely reduced toxicity towards human cells - yet its just nowhere to be seen.

Is it that hard to synthesize/make these compounds? Does it cost a castle made of gold to produce a single vial of it? I would like to hear chemists views on the complexity/cost ratio of the production if possible. I do no have an advanced background in chemistry but it is just hard for me to imagine it would take half the world to produce some specifically charged or ph sensitive liposomes - especially if the science on what and how has already been done.

Answer 1

Liposomes are the first nano-drug delivery systems that have been successfully translated into real-time clinical applications. So far, all liposomal drugs are designed for intravenous applications with control release. Most of them are designed to certain targets such as cancer cells. That's why most of liposomal drugs are used in chemotherapy (Ref.1):

The main fact is those liposomal drugs are used mostly in hospitals with control of appropriate medical personals. For example, all seven liposomal drugs so far in chemotherapy are Doxil®, Depocyt®, DaunoXome®, Mepact®, Marqibo®, Myocet®, and Onivyde® as listed in Ref.1 used in cancer patients (in- or out-patients, but under the supervision of their medical doctors). Morphine sulfate extended-release liposome injection, DepoDur™, and non-opioid, bupivacaine liposome (trade name Exparel®) are analgesics used in pain management, specially after postsurgical procedures (e.g., bupivacaine liposome is a postsurgical analgesic used in the management of postsurgical pain and It can also numb an area of the body to relieve pain during surgery or medical procedures). In addition, VYXEOS® is recently FDA approved (First approved August 3, 2017) liposomal drug for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). VYXEOS®, a liposomal daunorubicin/Cytarabine, is a fixed-dose combination of liposomal bound cytarabine and daunorubicin that delivers the two medications in a 5:1 molar ratio. Further, it is the ONLY treatment recommended by National Comprehensive Cancer Network® (NCCN®) for induction in sAML patients $\ge \pu{60 years}$. Also, in addition to its use in chemotherapy for leukemia, DaunoXome®, a liposomal daunorubicin, is also FDA approved to treat AIDS related Kaposi's sarcoma.

Based on these facts, therefore, it is safe to say that liposomal drugs are in use without aware of general public. Regardless to say that those treatments are very expensive as you have guessed.

I think main drawback to not available liposomal antibiotics is their high vulnerability to acidic conditions, thus no oral applications available (almost all liposome broke open in the stomach). So far, only literature available for acid stable liposome is Ref.2 and 3. However, we have to stop the development in that direction due to the lack of funding. Therefore, do not believe what you are hearing. Liposomal applications and their oral applications are coming pretty soon (someone else may follow our direction). Nonetheless, now we have a vaccine for COVID-19 within a year, don't we?

References:

1. Upendra Bulbake, Sindhu Doppalapudi, Nagavendra Kommineni, Wahid Khan, "Liposomal Formulations in Clinical Use: An Updated Review," Pharmaceutics 2017, 9(2), 12 (33 pages) (doi: 10.3390/pharmaceutics9020012)(PDF).
2. Adelphe M. Mfuh, Mathew P. D. Mahindaratne, Maritza V. Quintero, Frederick J. Lakner, Ande Bao, Beth A. Goins, William T. Phillips, George R. Negrete, "Novel asparagine-derived lipid enhances distearoylphosphatidylcholine bilayer resistance to acidic conditions," Langmuir 2011, 27(8), 4447-4455 (DOI: https://doi.org/10.1021/la105085k).
3. George R. Negrete, Mathew P. D. Mahindaratne, Adelph M. Mfuh, Maritza V. Quintero, "Compositions and Methods Related to Acid Stable Lipid Nanospheres," US20110268653A1 (https://patents.google.com/patent/US20110268653A1/en) (PDF).

Answer 2

The FDA and other regulatory agencies require that formulations are subjected to a variety of tests. Clinical trials are laborious and expensive. Studies demonstrating efficacy in vitro, in small animal studies, or in human pre-clinical trials still have to be translated into human clinical trials. This can be a stumbling block. Quoting a reference posted by Mathew Mahindaratne:

Several liposomes were successfully translated into the clinic and other liposomal formulations are in different phases of clinical investigation. Although many of these products have been proven to be beneficial in preclinical trials, only formulations that show efficacy in clinical trials will make their way into the clinic.

Efficacy and toxicity are only part of the testing. Stability is also important. In addition you have to find a way to prepare the formulations on an appropriate scale, in a cost-effective way. Ref 1. (a little dated and from a non-mainstream journal but open access) summarizes some of the potential disadvantages with liposome formulations (distribution in the body, proneness to oxidation and/or hydrolysis, and scale-up of production).

References

1. Sharma Vijay K, Mishra D N, Sharma A K,Srivastava. Liposomes: Present Prospective and Future Challenges. International Journal of Current Pharmaceutical Review and Research Volume 1, Issue 2, August - October 2010 http://impactfactor.org/PDF/IJCPR/1/IJCPR,Vol1,Issue2,Article2.pdf