Silk Sericin-Polylactide Protein–Polymer Conjugates as Biodegradable Amphiphilic Materials and Their Application in Drug Release Systems

Abstract

Silk sericin (SS) is a by-product of silk production. In order to transform it into value-added products, sericin can be used as biodegradable and pH-responsive building block in drug delivery materials. To this end, amphiphilic substances were synthesized via the conjugation of hydrophobic polylactide (PLA) to the hydrophilic sericin using a bis-aryl hydrazone linker. PLA was esterified with terephthalaldehydic acid to obtain aromatic aldehyde terminated PLA (PLA-CHO). In addition, lysine groups of SS were modified with the linker succinimidyl-6-hydrazinonicotinamide (S-HyNic). Then, both macromolecules were mixed to form the amphipilic proteinpolymer conjugate in buffer-DMF solution. The formation of bis-aryl hydrazone linkages was confirmed and quantified by UV-Vis spectroscopy. SS-PLA conjugates self-assembled in water into spherical multicompartment micelles with a diameter of around 100 nm. Doxorubicin (DOX) was selected as a model drug for studying the pH-dependent drug release from SS-PLA 2 nanoparticles. The release rate of the encapsulated drug was slower than that of the free drug and dependent on pH; faster at pH 5.0 and resulted in a larger cumulative amount of drug released than at physiological pH of 7.4. The SS-PLA conjugate of high PLA branches showed smaller particle size and lower loading capacity than the one with low PLA branches. Both SS-PLA conjugates had negligible cytotoxicity whereas, after loading with DOX, the SS-PLA micelles were highly toxic for the human liver carcinoma immortalized cell line HepG2. Therefore the SS-based biodegradable amphiphilic material showed great potential as a drug carrier for cancer therapy.

Protein-Based Hydrogels: Promising Materials for Tissue Engineering

“…Wang and co-workers prepared a PBH with anti-freezing, biocompatible, and tunable features, which was modified in two steps: (1) the addition of anti-freezing proteins associated with the natural fish, and (2) the employment of a chemical cross-linking method to obtain a polymeric hydrogel system [75]. Indeed, the structure of PBHs is modifiable, and polymers, owning cross-linking or modifying roles, can improve the hydrogel characteristics, since they form covalent bonds with proteins [76,77]. Polymers, as cross-linking agents, are capable of modifying the amine and carboxyl ends of proteins, resulting in fatigue-resistant hydrogels [77].…”

Manipulating Cell Fates with Protein Conjugates

“…For example, bovine serum albumin (BSA) is a commonly used protein scaffold for conjugation with hydrophobic polymers, and the resulting BSA-polymer nanoparticles have been used to deliver drugs, such as doxorubicin and camptothecin . Likewise, silk sericin-polylactide protein–polymer conjugates have been constructed for the intracellular delivery of doxorubicin . It is of note that protein–lipid conjugates can also be incorporated into liposomes as targeting elements to direct the liposomes to cancer cells for drug delivery purposes. , …”

“…Various cancer chemotherapeutics, including mertansine and auristatin derivatives, have been designed and synthesized to incorporate maleimide functional groups facilitating conjugation to cysteines to a cancer-specific targeting protein. ,,, Similarly, primary amines on proteins can also be coupled with NHS ester-functionalized drugs or reacted with acrylic acid NHS ester for polymerization initialization to form protein–polymer conjugates as drug vehicles . Bifunctional linkers, such as Sulfo-SMCC or succinimidyl-6-hydrazino-nicotinamide (S-HyNic), have also been utilized to cross-link free amines on proteins to thiol-functionalized oligonucleotides , or aldehyde-modified polymers …”

“…Accordingly, anti-HER2 protein conjugates were used to treat HER2-positive ovarian cancer , and anti-EpCAM protein conjugates were prepared to target EpCAM-overexpressing colon adenocarcinoma and breast cancer . EGFR-overexpressing triple-negative breast cancer, epidermoid carcinoma, and lung adenocarcinoma can be targeted with the corresponding anti-EGFR protein-drug conjugates. ,, Other cancer-associated antigens, including PDGFRβ, CD38, and FGFR1 have also been targeted to treat colorectal cancer, myeloma, and lung carcinoma, respectively. ,, For some protein-polymer-based nanoparticles, no specific targeting elements were involved, and the localization of the drug at tumor tissues was dependent on the enhanced permeability and retention (EPR) effect or the pH-responsive property of the protein-polymer conjugates. , …”

Nanohybrids as Protein-Polymer Conjugate Multimodal Therapeutics

“…Non-specificity in permeation is a major challenge that can result in potential toxicity due to the accumulation of conjugates at undesired or off-target locations in chronic administration (110)(111)(112)134). The administration route should be holistically analyzed and approached sequentially in dealing with the absorption barriers first, followed by circulatory, tissue-level, and cellular-level barriers (133).…”