Lipoprotein Preparations: A Potential Routes for Cell-Targeted Delivery of Polyphenols and other drugs

Hanna Lewandowska

The potential of lipoproteins as drug delivery systems is presently underestimated. Lipoproteins may be of great use in drug delivery due to their unique characteristics: Cells have lipoprotein receptors, more or less specific for each type of lipoprotein, which (especially LDL receptors) are particularly strongly expressed in rapidly proliferating cells. Another advantage connected to the application of lipoproteins as a drug carriers is their large (several to several dozen nm diameter) size. While normal tissue is not permeable to big particles, tumor tissue tends to accumulate macromolecules and especially lipids. This phenomenon has been characterized and termed the tumor-selective enhanced permeability and retention (EPR) effect [1]. The next attractive feature of lipoproteins as a bio carrier is their biosafety. While synthetic materials can cause toxicology problems, the lipoproteins are fully biodegradable in the body by way of natural mechanisms. As solid particles, they have greater structural stability than, for example, the liposomes that are currently a very popular medium in medical preparations [2]. It is also worth to mention, lipoproteins are easily isolated from blood plasma. Taking into account the above-described findings and conclusions, it seems a reasonable scientific goal to look into the potential of lipoproteins as carriers of polyphenolics, metals, and other drugs, and into the effects that modified lipoproteins have in cells.

Polyphenols (PPs) were shown to be able to exhibit numerous regulatory functions in mammalian cells. Nevertheless, the potential regulatory effects of native PPs that are shown in vitro in numerous papers, are not likely to occur in the tissue, due to the poor ADMET (absorption, distribution, metabolism, excretion, and toxicology) qualities of PPs [3]. Especially, the issue are their poor water solubility and a high potential for modification by both first and second phase metabolism. Therefore many attempts are made to make polyphenols more available.  Apart from chemical modifications of the PPs many attempts have focused on looking for the appropriate drug carriers. Among the successful solutions are the liposomes, polymeric micelles, phospholipids, and other nanoparticle-based drug delivery systems [4]. For instance, a highly absorptive curcumin dispersed with colloidal nano-particles, was demonstrated to yield more than 30-fold higher bioavailability via oral administration compared with conventional curcumin in rat models [5]. Хотите провести приятно время? Заходите https://escorteurogirls.com по ссылке

As an alternative to the above-mentioned synthetic and semi-synthetic vehicles for PPs delivery, we proposed [6] a fully natural carrier capable of carrying the lipophilic payload, the LDL particle. Highly enhanced uptake of LDL in cancer, potentially makes it an ideal carrier for PP, which has been shown in the literature to have beneficial antioxidant effects at low concentrations, while pro-oxidative and cytostatic at higher doses [7].

In our recent work work [6], new polyphenol-containing LDL nano-preparations were prepared. Modulation of lipophilicity through the use of carriers allowed for excellent improvement of the therapeutic properties of such drugs as paclitaxel and doxorubicin (Abraxane [8], Doxil [9]). The proposed series of popular PPs, with increasing lipophilic properties, applied with a fully natural lipophilic carrier, are an attempt to find optimal conditions for the administration of drugs with different lipophilicity on the specific example of popular dietary supplements. The procedure for the synthesis of PP-saturated LDL nanoparticles, and their anti- and pro-oxidative activity and toxicity to human cancer cells will be presented. Along with the short summary of the obtained results, the possibility to use lipoproteins in drug delivery (including e.g. metal complexes, potential nanozymes) will be further discussed.

The work was supported by the National Science Centre, Poland (grant no. 2018/31/B/NZ7/03083).

 

  1. Maeda, H. The Enhanced Permeability and Retention (EPR) Effect in Tumor Vasculature: The Key Role of Tumor-Selective Macromolecular Drug Targeting. Advances in Enzyme Regulation 2001, 41, 189–207, doi:10.1016/S0065-2571(00)00013-3.
  2. Feng, T.; Wei, Y.; Lee, R.J.; Zhao, L. Liposomal Curcumin and Its Application in Cancer. International journal of nanomedicine 2017, 12, 6027–6044.
  3. Nelson, K.M.; Dahlin, J.L.; Bisson, J.; Graham, J.; Pauli, G.F.; Walters, M.A. The Essential Medicinal Chemistry of Curcumin: Miniperspective. Journal of Medicinal Chemistry 2017, 1620–1637.
  4. Gera, M.; Sharma, N.; Ghosh, M.; Huynh, D.L.; Lee, S.J.; Min, T.; Kwon, T.; Jeong, D.K. Nanoformulations of Curcumin: An Emerging Paradigm for Improved Remedial Application. Oncotarget 2017, 8, 66680–66698.
  5. Sasaki, H.; Sunagawa, Y.; Takahashi, K.; Imaizumi, A.; Fukuda, H.; Hashimoto, T.; Wada, H.; Katanasaka, Y.; Kakeya, H.; Fujita, M. Innovative Preparation of Curcumin for Improved Oral Bioavailability. Biological and Pharmaceutical Bulletin 2011, 34, 660–665.
  6. Lewandowska, H.; Kalinowska, M. New Polyphenol-Containing LDL Nano-Preparations in Oxidative Stress and DNA Damage: A Potential Route for Cell-Targeted PP Delivery. Materials 2020, 13, 5106.
  7. Martin, K.R.; Appel, C.L. Polyphenols as Dietary Supplements: A Double-Edged Sword. Nutrition and Dietary Supplements 2009, 2, 1–12.
  8. Abraxane (Paclitaxel Protein-Bound Particles for Injectable Suspension) Available online: https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/3061-abraxane-paclitaxel-protein-bound-particles-for-injectable-suspension (accessed on 24 January 2020).
  9. Doxil (Doxorubicin HCl Liposome Injection) Available online: https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/3407-doxil-doxorubicin-hcl-liposome-injection (accessed on 24 January 2020).

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