Tumor-Targeted Fluorescent Proteinoid Nanocapsules Encapsulating Synergistic Drugs for Personalized Cancer Therapy

Abstract

Personalized cancer treatment based on specific mutations offers targeted therapy and is preferred over “standard” chemotherapy. Proteinoid polymers produced by thermal step-growth polymerization of amino acids may form nanocapsules (NCs) that encapsulate drugs overcoming miscibility problems and allowing passive targeted delivery with reduced side effects. The arginine-glycine-glutamic acid (RGD) sequence is known for its preferential attraction to αvβ3 integrin, which is highly expressed on neovascular endothelial cells that support tumor growth. Here, tumor-targeted RGD-based proteinoid NCs entrapping a synergistic combination of Palbociclib (Pal) and Alpelisib (Alp) were synthesized by self-assembly to induce the reduction of tumor cell growth in different types of cancers. The diameters of the hollow and drug encapsulating poly(RGD) NCs were 34 ± 5 and 22 ± 3 nm, respectively; thereby, their drug targeted efficiency is due to both passive and active targeting. The encapsulation yield of Pal and Alp was 70 and 90%, respectively. In vitro experiments with A549, MCF7 and HCT116 human cancer cells demonstrate a synergistic effect of Pal and Alp, controlled release and dose dependence. Preliminary results in a 3D tumor spheroid model with cells derived from patient-derived xenografts of colon cancer illustrate disassembly of spheroids, indicating that the NCs have therapeutic potential.

Low frequency electrical waves in ensembles of proteinoid microspheres

“…Glutamic acid is also involved in the formation of disulfide bonds 11 , 12 which are essential for the stability of proteinoids. The process of self-assembly is a key factor in the formation of both polystyrene formation 13 , 14 and proteinoids 15 , 16 . However, there are some key differences in the way the two materials form.…”

Low frequency electrical waves in ensembles of proteinoid microspheres

“…Glutamic acid is also involved in the formation of disulfide bonds [11,12] which are essential for the stability of proteinoids. The process of self-assembly is a key factor in the formation of both polystyrene formation [13,14] and proteinoids [15,16]. However, there are some key differences in the way the two materials form.…”

Tumor‐Targeted Poly(ArgGlyAsp) Nanocapsules for Personalized Cancer Therapy – In Vivo Study

“…[1,2] The combination of palbociclib (Pal, a CDK4/6 inhibitor) and alpelisib (Alp, a P13K inhibitor) was shown to have a significant synergistic effect on tumor growth in different types of tumors both in vitro and in vivo. [3,4] Pal and Alp are approved by the Food and Drug Administration (FDA) as a treatment for hormone receptor (HR)+ human epidermal growth factor receptor 2 (HER2)− advanced/metastatic breast cancer in combination with hormonal therapy, but not in combination with each other. [5,6] Patient-derived xenografts (PDX) are models of cancer created by implanting tissue/cells from a tumor of a specific patient into an immunodeficient mouse.…”

“…[32,36] P(RGD) proteinoid polymers were recently prepared in our lab by step-growth polymerization of R, G, and D at 170 °C under N 2 atmosphere. [4,[28][29][30] NMR showed that the frequency of the RGD sequence in the proteinoid polymer was about 13%. Gel permeation chromatography (GPC) illustrated that the molecular weight and polydispersity index (PDI) of the formed P(RGD) are 66 and 1.03 kDa, respectively.…”

“…Hollow and P(RGD)/Pal,Alp NCs containing different drugs/proteinoid weight ratios (1, 5, 10, 25, and 50 w%) were produced by selfassembly as described in our recent manuscript. [4] For in vitro cell viability study, we chose to work with P(RGD) encapsulated with 25% drugs (12.5% of each drug). [4] The effect of NCs loaded with Pal and Alp on cell lines including MCF7 (breast adenocarcinoma), HCT116 (colon carcinoma) and A549 (lung carcinoma) demonstrated controlled release, synergy of the combination and dose dependence.…”