Octa-arginine modified poly(amidoamine) dendrimers for improved delivery and cytotoxic effect of paclitaxel in cancer

<p>Cell penetrating peptides (CPP) have the ability to penetrate the cell membrane and have been associated with various cargos for their facile intracellular translocation. The current study involves the synthesis of a CPP, octa-arginine (R8)-modified poly(amidoamine) dendrimer of generation 4 (G4), which has additionally been PEGylated and conjugated to the poorly soluble anticancer drug, paclitaxel (PTX). The synthesized dendrimer conjugates were characterized by proton nuclear magnetic resonance (1H-NMR) Spectroscopy and zeta potential measurements and evaluated <i>in vitro</i> in cell monolayers and 3D spheroids. Cellular uptake study in human cervical cancer cell line (HeLa) revealed that R8 modification significantly improved the cell association of conjugates. G4-PTX- polyethylene glycol (PEG)-R8 conjugate demonstrated enhanced cytotoxic potential and higher induction of apoptosis compared to free PTX and G4-PTX-PEG. Further, the penetrability of fluorescently labeled F-G4-PTX-PEG-R8 was evaluated in 3D spheroids of HeLa at various depths by using confocal microscopy. G4-PTX-PEG-R8 induced cell death and inhibited the growth in 3D spheroids as competently as in monolayers. The enhanced intracellular translocation of R8-modified dendrimers resulted in improved anticancer efficacy of PTX. Therefore, the newly developed dendrimer system is efficient for the intracellular delivery of PTX in cancer cells and has a strong potential to be utilized as an effective chemotherapeutic agent for cancer.</p

Cholesterol-conjugated poly(D, L-lactide)-based micelles as a nanocarrier system for effective delivery of curcumin in cancer therapy

<p>Polymeric micelles have been widely explored preclinically as suitable delivery systems for poorly soluble chemotherapeutic drugs in cancer therapy. The present study reported the development of cholesterol (Ch)-conjugated poly(D,L-Lactide) (PLA)-based polymeric micelles (mPEG–PLA-Ch) for effective encapsulation and delivery of curcumin (CUR) at the tumor site. Cholesterol conjugation dramatically affected the particle size and improved drug loading (DL) and encapsulation efficiency (EE). mPEG–PLA-Ch-CUR showed bigger hydrodynamic diameter (104.6 ± 2.1 nm, and 169.3 ± 1.52 nm for mPEG–PLA and mPEG–PLA-Ch, respectively) due to increased size of the hydrophobic core. The newly developed polymer exhibited low critical micelles concentration (CMC) (25 μg/mL) which is close to lipid-based polymer, PEG-phosphatidyl ethanolamine (12.5 μg/mL) compared to mPEG–PLA (50 μg/mL). mPEG–PLA-Ch micelles exhibited relatively higher EE (93.74 ± 1.6%) and DL (11.86 ± 0.8%) compared to mPEG–PLA micelles (EE 91.89 ± 1.2% and DL 11.06 ± 0.8%). mPEG–PLA-Ch micelles were internalized by the cancer cells effectively and exhibited higher cytotoxicity compared to free CUR in both, murine melanoma (B16F10) and human breast cancer (MDA-MB-231) cells. mPEG–PLA-Ch exhibited satisfactory hemocompatibility indicating their potential for systemic application. Further, mPEG–PLA-Ch-CUR demonstrated higher rate of reduction of tumor volume in B16F10-xenografted tumor-bearing mice compared to free CUR. At the end of 22 days, the tumor reduced to 1.87-fold (627.72 ± 0.9 mm³ versus 1174.68 ± 1.64 mm³) compared to the treatment with free CUR. In conclusion, the experimental data <i>in vitro</i> and <i>in vivo</i> indicated that the newly developed CUR-mPEG–PLA-Ch micelles may have promising applications in solid tumors.</p

Supplementary materials for machine learning-driven multifunctional peptide engineering for sustained ocular drug delivery

The research notebook contains the code of the machine learning pipeline developed in the project, which involves a super learner-based methodology for multifunctional peptide engineering. The main pipeline consists of variable reduction and model training. The code functionality details can be found in the Methods section of the paper "Machine learning-driven multifunctional peptide engineering for sustained ocular drug delivery."Sustained drug delivery strategies have many potential benefits for treating a range of diseases, particularly chronic diseases that require treatment for years. For many chronic ocular diseases, patient adherence to eye drop dosing regimens and the need for frequent intraocular injections are significant barriers to effective disease management. Here, we utilize peptide engineering to impart melanin binding properties to peptide-drug conjugates to act as a sustained-release depot in the eye. We developed a super learning-based methodology to engineer multifunctional peptides that efficiently enter cells, bind to melanin, and have low cytotoxicity. When the lead multifunctional peptide (HR97) was conjugated to brimonidine, an intraocular pressure (IOP)-lowering drug that is prescribed for three times per day topical dosing, IOP reduction was observed for up to 18 days after a single intracameral HR97-brimonidine injection in rabbits. Further, the cumulative IOP-lowering effect was increased ~17-fold compared to free brimonidine injection. Engineered multifunctional peptide-drug conjugates are a promising approach for providing sustained therapeutic delivery in the eye and beyond.National Institutes of Health (NIH) (grant nos. R01EY026578 and R01EY031041; National Eye Institute Training Grant (T32EY007143); National Science Foundation Award (DGE-1632976