Polydopamine and dopamine interfere with tetrazolium-based cytotoxicity assays and produce exaggerated cytocompatibility inferences.

Tetrazolium-based assays such as the MTT assay have been commonly employed in evaluating biocompatibility. Here, we show that PDA (or its precursor dopamine (DA)) spontaneously reduces MTT and produces exaggerated cytocompatibility inferences. The extent of interference depends on the method of DA polymerization. We observed that the trypan blue exclusion assay allowed more accurate determination of cell viability in the presence of DA- and PDA-based nanomaterials.

Polydopamine-on-liposomes: stable nanoformulations, uniform coatings and superior antifouling performance.

Polydopamine (PDA), a mussel-inspired synthetic polymer, affords biocompatible and antifouling coatings on a variety of surfaces. However, the traditional protocol of preparing PDA by polymerizing dopamine (DA) under basic conditions yields physically-unstable and non-uniform coatings that are prone to delamination and exhibit compromised antifouling performance in vivo. Here, we show that the high local pH in the vicinity of vesicular self-assemblies formed by a series of acetal-based cationic amphiphiles can be exploited to conveniently polymerise DA under physiological conditions in a gradual manner without requiring any external oxidant. Two of the four PDA-liposome nanoformulations viz. PDA-L1 and PDA-L2 turned out to be highly stable physically and resisted precipitation for more than a month while the other two formulations (PDA-L3 and PDA-L4) were less stable and formed visible precipitates with time. Further, the PDA-liposome formulations had significantly improved haemocompatibility compared to that of pristine liposomes. PDA-L1 formed highly uniform, nanostructured coatings on implants like catheter, cotton and bandages that did not delaminate even after a week of continuous incubation in simulated body fluid, or on exposure to pH change and presence of proteolytic enzymes. The PDA-L1 coated catheter implants resisted biofouling by both Gram-positive and Gram-negative bacteria in vitro and also had superior in vivo performance in mice vis-à-vis the implants coated with traditional base-polymerised PDA formulation (BP-PDA). Thus, these novel liposomal PDA nanoformulations significantly improve the practical utility of PDA-based coatings for antimicrobial applications.

Chirally Twisted Ultrathin Polydopamine Nanoribbons: Synthesis and Spontaneous Assembly of Silver Nanoparticles on Them.

Polydopamine (PDA) is a synthetic polymeric material with immense potential in biomedical and surface functionalization applications. Herein, we have screened self-assemblies formed by Phenylalanine-based amphiphiles (Phe-AMPs) as soft templates for preparing chiral PDA nanostructures. Our study revealed that the amphiphile 2 endowed with a primary amine residue afforded chirally-twisted ultrathin nanoribbons of PDA under optimized conditions. The chirality at the Phe residue of 2 modulated the twist-chirality of the PDA nanoribbons; the l-2 resulted in nanoribbons with right-handed twist, whereas the d-2 induced a left-handed twist to the ribbons. The racemic mixture of these two amphiphiles produced flat, achiral tapes. The PDA ribbon thickness was ≈5.86±0.40 nm, whereas its width and length were ≈133.5±3.2 nm and >5000 nm, respectively. Upon dialysis, hollow PDA nanotubes were obtained due to curling of the PDA nanoribbons. These PDA-nanoarchitectures were employed to spontaneously form and assemble Ag-nanoparticles along the edges of the PDA nanoribbons. In this work we are reporting chirality controlled synthesis of PDA nanostructures for the first time.

A nanogel based oral gene delivery system targeting SUMOylation machinery to combat gut inflammation.

Poor success rates and challenges associated with the current therapeutic strategies of inflammatory bowel disease (IBD) have accelerated the emergence of gene therapy as an alternative treatment option with great promise. However, oral delivery of nucleic acids (NAs) to an inflamed colon is challenged by multiple barriers presented by the gastrointestinal, extracellular and intracellular compartments. Therefore, we screened a series of polyaspartic acid-derived amphiphilic cationic polymers with varied hydrophobicity for their ability to deliver NAs into mammalian cells. Using the most effective TAC6 polymer, we then engineered biocompatible and stable nanogels composed of polyplexes (TAC6, NA) and an anionic polymer, sodium polyaspartate, that were able to deliver the NAs across mammalian cells using caveolae-mediated cellular uptake. We then utilized these nanogels for oral delivery of PIAS1 (protein inhibitor of activated STAT1), a SUMO 3 ligase, encoding plasmid DNA since PIAS1 is a key nodal therapeutic target for IBD due to its ability to control NF-κB-mediated inflammatory signaling. We show that plasmid delivery using TAC6-derived nanogels diminished gut inflammation in a murine colitis model. Therefore, our study presents engineering of orally deliverable nanogels that can target SUMOylation machinery to combat gut inflammation with very high efficacy.

Emerging biomedical applications of polyaspartic acid-derived biodegradable polyelectrolytes and polyelectrolyte complexes.

Polyelectrolytes (PELs) - polymers with charged repeat units - have emerged as a useful class of polymers for biomedical applications due to their high aqueous solubility, low aggregation propensity and the opportunity they afford for polyvalent interactions with surfaces. Biodegradability and biocompatibility of PELs are important prerequisites for their utilization in in vivo applications. PELs that can be chemically functionalized with ease prove advantageous for creating diverse biomaterials. Polyaspartic acid (PASA) is a modular and biocompatible synthetic PEL that has all these features. It also shows many positive biomedical attributes such as bone-tissue targeting, muco-adhesive behavior and extended blood circulation time. Cationic PELs derived from PASA are rapidly internalized by mammalian and bacterial cells, and hence have immense utility in therapeutic delivery applications. Polyelectrolyte complexes (PECs) and multilayers (PEMs) formed from PASA PELs have further expanded their biomedical utility. This mini-review highlights some recent literature examples of unique biomedical applications of PELs, PECs and PEMs prepared through the molecular engineering of PASA. It discusses biomineralization modulators, anti-mycobacterial agents, underwater adhesives, mucoadhesive drug and gene delivery agents, and cell encapsulants fabricated using PASA derived PELs.

Injectable, Self-Healing Chimeric Catechol-Fe(III) Hydrogel for Localized Combination Cancer Therapy.

Conventional intravenous or oral administration of a combination of chemotherapeutics displays poor bioavailability and induces undesirable systemic toxicity. Therefore, localized delivery of such chemotherapeutic combinations using polymeric hydrogels is expected to help in enhancing drug efficacy and reducing systemic toxicity. In this manuscript, we have utilized a chitosan-catechol based hydrogel (CAT-Gel) assembled through catechol-Fe(III) coordinative interactions for localized combination therapy in murine lung and breast cancer models. CAT-Gel offers a unique blend of material properties such as injectability and self-healing along with useful biological attributes like their noncytotoxic and nonhemolytic nature. The amphipathic nature of this hydrogel enabled us to incorporate a recipe of hydrophilic doxorubicin hydrochloride (DOX) and hydrophobic docetaxel (DTX) anticancer drugs. Rheology studies confirmed the self-healing nature of this chimeric hydrogel even after drug loading. CAT-Gel was retained for more than 40 days in mice upon subcutaneous injection. The sequential and sustained release of the entrapped DOX and DTX from the hydrogel resulted in synergistic therapeutic effect with increased median survival against murine lung and breast cancer models. Therefore, CAT-Gel provides a new coordinatively assembled biocompatible scaffold for localized delivery of chemotherapeutic drugs.