Computer-Aided Design of Lasso-like Self-Assembling Anticancer Peptides with Multiple Functions for Targeted Self-Delivery and Cancer Treatments

Abstract

Anticancer peptides are promising drug candidates for cancer treatment, but the short circulation time and low delivery efficiency limit their clinical applications. Herein, we designed several lasso-like self-assembling anticancer peptides (LASAPs) integrated with multiple functions by a computer-aided approach. Among these LASAPs, LASAP1 (CRG­DKG­PDC­GKA­FRR­FLG­ALF­KAL­SHLL, 1–9 disulfide bond) was determined to be superior to the others because it can self-assemble into homogeneous nanoparticles and exhibits improved stability in serum. Thus, LASAP1 was chosen for proving the design idea. LASAP1 can self-assemble into nanoparticles displaying iRGD on the surface because of its amphiphilic structure and accumulate to the tumor site after injection because of the EPR effect and iRGD targeting to αVβ3 integrin. The nanoparticles could disassemble in the acidic microenvironment of the solid tumor, and cleaved by the overexpressed hK2, which was secreted by prostate tumor cells, to release the effector peptide PTP-7b (FLG­ALF­KAL­SHLL), which was further activated by the acidic pH. Therefore, LASAP1 could target the orthotopic prostate tumor in the model mice after intraperitoneal injection and specifically inhibit tumor growth, with low systematic toxicity. Combining the multiple targeting functions, LASAP1 represents a promising design of self-delivery of peptide drugs for targeted cancer treatments.

Molecular View on the iRGD Peptide Binding Mechanism: Implications for Integrin Activity and Selectivity Profiles

“…Thus, the Lys 5 –Gly 6 bond is easily accessible for proteolytic cleavage, which releases the NRP-1-recognizing CendR/K sequence (CRGDK). On the other hand, the solvent exposure of the Cys 9 carboxylate explains why the bioconjugation of this group with bulky molecules, for either therapeutic or diagnostic purposes, is safely permitted. − Both of these findings strengthen the reliability and increase the scientific impact of the obtained atomistic i RGD–integrin binding complexes.…”

“…Over the past decade, the tumor-homing i RGD ( 1 ) peptide has emerged as a powerful tool for anticancer therapy, ,,,− due to its high tropism for cancer tissues and the possible coadministration with a plethora of chemotherapeutic agents. In this article, we provide unprecedented data about the biological and structural aspects of i RGD’s mechanism of action.…”

“…For these reasons, anticancer compounds often need to be administered at high doses to exert relevant pharmacological effects, with the rise of serious adverse reactions. − A feasible solution to the tissue penetration problem is represented by smart carriers that can vehicle the desired drug to extravascular cancer tissue. Carriers of different natures have been developed such as gold nanoparticles, − liposomes, , polymer micelles, or receptor-selective peptides. − In this context, Ruoslahti and co-workers identified an RGD integrins-targeting cyclic nonapeptide, namely, i RGD (internalizing RGD, CRGDKGPDC, 1 Chart ), endowed with remarkable tumor-homing properties. , Notably, this peptide can improve the tumor penetration and efficacy of chemotherapeutics through two alternative mechanisms. ,− In fact, i RGD can be either covalently bioconjugatedusually functionalizing the C-terminal Cys 9 to organic and peptidic drugs or attached to the surface of other delivering systems like nanoparticles, liposomes, or oncolytic viruses. − On the other hand, the tumor endocytosis of cytotoxic agents such as cisplatin, gemcitabine, doxorubicin, nab-paclitaxel, and trastuzumab is enhanced by the simple coadministration of 1 . ,, As a result, hundreds of distinct applications involving i RGD have been published during the past decade, − claiming the p...…”

GSH/pH Cascade-Responsive Nanoparticles Eliminate Methicillin-Resistant Staphylococcus aureus Biofilm via Synergistic Photo-Chemo Therapy

“…The DLS test results showed that the hydrodynamic diameter and zeta potential of the SP–Van@IR780 NPs were ∼230 and 15.77 mV, respectively (Figures B, S5). Due to the shrinkage of the nanoparticles in the dry state during TEM sample preparation, the average size from TEM image was smaller than the hydrodynamic diameters measured by DLS. − The size stability of SP–Van@IR780 NPs in a normal physiological environment was evaluated. As shown in Figure C, there was no obvious change in the particle size within 10 days, indicating that the SP–Van@IR780 NPs would have good stability in the in vivo circulation.…”

Advances in biosynthesis of peptide drugs: Technology and industrialization

“…Pei et al designed some lasso-like self-assembling anticancer peptides (LASAPs) which can self-assemble into nanoparticles in solution, combined multiple tumor-targeting strategies for targeted cancer treatment, and the self-assembled LAS-APs showed resistance to various proteases and had longer in vivo half-lives than the effector peptide PTP-7b. [77] Wallace et al [78] demonstrated that a prodrug colistin methanesulfonate with better self-assembling ability showed much higher stability in solution than colistin. Li et al [79] modified the antimicrobial peptide halictines-2 (HAL-2) with cholesterol to obtain a self-assembling peptide HAL-C that can form nanoparticles in solution, and it showed much improved serum stability and in vivo antitumor activity.These researches pave the way to the clinical applications of self-assembling peptide drugs, which could be an effective strategy to solve the stability problem.…”