Introduction
Drug delivery technologies have enabled the development of many pharmaceutical products by enhancing the delivery of a therapeutic to its target site, minimizing off-target accumulation and facilitating patient compliance.
In recent decades, the fusion of polymer science and biomedical research has led to groundbreaking advancements, opening up numerous opportunities to enhance therapeutic efficiency. Drug delivery technologies have been expanded beyond small molecules to include nucleic acids, peptides, proteins and antibodies.
Small-molecule drugs (<900 daltons), such as chemotherapeutics, antibiotics, and steroids, have been used since the late 1800s. Their small size allows them to diffuse rapidly through biological fluids and cell membranes, enabling interaction with various tissues and cells. However, their therapeutic utility is limited by poor aqueous solubility, which affects about 90% of preclinical drug candidates (1).
To overcome low bioavailability, strategies have focused on improving drug solubility through pH modifiers and altering the physicochemical properties of the drugs. Drug delivery technologies include three areas: drug modifications, microenvironment modifications and drug delivery systems.
Drug delivery systems refer to all types of formulations
Modifying drugs and their microenvironment can optimize drug activity.
Drug delivery systems combine these strategies by creating an interface between the drug and its surroundings. Early drug delivery research showed that altering the drug release rate can change its pharmacokinetic (PK) parameters, such as biodistribution, half-life, total exposure, and maximum serum concentration (2).
Controlled-release technologies for small molecules paved the way for peptide and protein therapeutics, which require sustained-release systems due to short half-lives. Controlled-release drug delivery systems, such as osmotic release oral systems and transdermal patches, have been developed to achieve predictable drug release and improve patient compliance. These systems include hydrogels, polymeric implants, microparticles, and nanoparticles, providing higher control over these parameters.
Polymeric drug delivery has been defined as a formulation or a device that enables the introduction of a therapeutic substance into the body. Polymeric drug delivery systems control the rate, time, and location of drug release, enhancing safety and efficacy.
Research on polymeric drug delivery has been ongoing since the 1980s, focusing on new delivery systems and modes of action to improve therapeutic efficiency and bioavailability. These systems use mechanisms (3) like dissolution, diffusion, osmosis, and ion exchange to enhance drug half-life and target specific tissues.
Natural polymers like chitosan, dextrin, polysaccharides, and hyaluronic acid, as well as synthetic polymers such as poly (2-hydroxyethyl methacrylate), poly(N-isopropylacrylamide)s, poly(ethylenimine)s, dendritic polymers, biodegradable and bio-absorbable polymers, are being developed for polymeric drug delivery systems.
Synthetic polymers
Given the diversity of existing synthetic macromolecular structures, including linear, grafted, dendritic, star-like, hyperbranched and cyclic architectures. Among the versatile linear polymers which still possess a myriad of opportunities to advance functional materials design, they remain to some extent the foundations of the advanced polymers in the field of drug delivery.
Biodegradable and bio-absorbable polymers
Bio-absorbable drug delivery systems are ideal for applications requiring temporary implants (4). Commonly used synthetic and biodegradable polymers, such as hydrogels made from poly(lactic acid) and poly(glycolic acid), are key components of these systems. Other frameworks (5) include aliphatic polyesters like poly(caprolactone), and poly(dioxanone).
Other potential implant materials include polyanhydrides, and biodegradable polycarbonates. Synthetic biodegradable polymers are usually preferred due to their lower immunogenicity compared to natural polymers.
Nanoparticles and microparticles have been used to address solubility challenges and enable site-specific delivery, reducing off-target side effects. Poly(ethylene glycol) (PEG) coatings have extended the circulation half-life of nanoparticles, leading to the approval of PEGylated liposomal doxorubicin (Doxil®) by the FDA in 1995 (6). Delivery systems are now widely used for small molecules and other therapeutic classes. Recent advances include nano-drug delivery systems that cross the blood-brain barrier (BBB) for treating central nervous system diseases, using transporters for natural nutrients (7).
Water-soluble synthetic polymers are essential tools in biomedical applications, as they significantly enhance drug delivery, tissue engineering, diagnostics, and regenerative medicine. Their key features include biocompatibility, adjustable degradation rates, controlled release mechanisms, and the ability to encapsulate and protect drugs, making them highly versatile for various therapeutic and diagnostic uses.
Dendritic polymers
Dendritic polymers are highly branched with controllable structures, featuring many terminal functional groups, low viscosity, and good solubility. Their size, branching degree, and functionality can be precisely adjusted through synthetic procedures. Research on dendrimers has expanded to include biocompatible dendrimers for applications in drug delivery, immunology, vaccines, antimicrobials, and antivirals. Dendrimers represent a versatile new class of polymer architectures, and bioreducible dendrimer polymers have been investigated for efficient gene delivery (8).
Bio-inspired polymers
The development of drug delivery carriers using natural and synthetic polymers include systems that leverage mechanisms used by pathogens and mammalian cells, such as selective targeting and prolonged circulation. Biomimetic and bioinspired systems show great potential in overcoming obstacles in polymeric drug delivery.
Polymers that undergo reversible or irreversible changes as a result of interactions with non-destructive, small environmental changes including heat, light, magnetic or electrical field, pH, etc., are called stimuli-responsive polymers. These polymers adapt to their surroundings by altering their structure through weak intermolecular interactions, similar to biological systems like proteins and nucleic acids. These materials are designed to mimic the adaptive and responsive behaviors found in natural systems. Responsive polymer systems often include sensitive monomeric units that react to environmental changes, forming structures like hydrogels, micelles, or polymer brushes. These changes can affect the entire polymer structure, such as protonation in varying pH or bond breakage due to temperature. Thermoresponsive polymers have attracted much attention because of their potential biological and medical applications such as drug and gene delivery (9). Thus, creating selective and responsive materials that allow personalized treatment is of considerable interest for the scientific community.
Below are highlighted 2 examples of stimuli-responsive polymers synthesis.
Case study 1: poly(N-isopropylacrylamide)(10)
Temperature is a commonly used stimulus for stimuli-responsive polymers due to its easy controllability in both in vitro and in vivo procedures. Thermo-responsive polymers exhibit a critical solution temperature, which is a key characteristic. The lower critical solution temperature (LCST) is the point below which the polymer and solvent form a single phase, while above this temperature, phase separation occurs. These transition temperatures depend on the concentration of the polymer, which influences the phase separation temperature.
Poly(N-isopropylacrylamide) (PNIPAM) is one of the most studied thermoresponsive polymer that exhibits a coil-globule transition in aqueous solution at the lower critical solution temperature (LCST) of around 32 °C. This has endowed PNIPAM derivates with LCST near human body temperature together with applications in bioengineering fields (11).
Several well-defined PNIPAM polymers with identical molecular weight and different bifunctional end-groups have been prepared by the conjunction of RAFT polymerization and click chemistry.
RAFT is a well-established radical polymerization technique that allows the synthesis of polymeric architectures of controlled molecular weight and functionality. It can tolerate various functional groups like azide and alkyne, which are useful for further functionalization. The copper(I)-catalyzed cycloaddition of azide and alkyne, known for its efficiency and versatility, is used in bioconjugate synthesis and surface modifications. Combining RAFT polymerization with click chemistry allows the preparation of PNIPAM analogs with different end groups.
RAFT polymerization was carried out using N-Isopropylacrylamide (NIPAM) monomer with bisalkyne derivative (EMEB) as a chain transfer agent (CTA) and AIBN as the initiator in 1,4-dioxane at 60°C.
Monomer conversion and polymer molecular weight were monitored during the polymerization process. Subsequent click reaction producing PNIPAM with triazole-linked end-groups containing phenyl, octyl, hydroxyl, and amino groups.
The modified polymers have been characterized by NMR and FTIR spectroscopy and MALDI-TOF MS.
Four PNIPAMs samples with the same molecular weight but with different end-groups (benzyl, octyl, hydroxyl, amino) were synthesized using RAFT polymerization and click reaction.
Thanks to the hydrophilic groups the ordering of solvating water decrease, with greater effects observed at chain ends rather than midchain. Hydrophobic groups (like aromatic rings and alkyl chains) and polar groups (like hydroxyl and amino) affect the thermal transitions (LCST) of PNIPAM.
This method provides the opportunity to study end-groups effects on LCST, and therefore adjust PNIPAM’s thermoresponsive properties without needing diverse initiators or different polymerization processes, providing better control over molecular weight and end-group effects on thermal transitions.
Case study 2: Poly(2-oxazoline) as Stimuli-Responsive Materials (12)
Among the different examples of well-defined biostable and biodegradable polymers widely used in the medical field such as poly(ethylene glycol) (PEG) or N-(2-hydroxypropyl)methacrylamide (HPMA), another class of high-quality polymers is polyoxazolines.
The poly(2-oxazoline) polymers are obtained within the cationic ring-opening polymerization (CROP) of 2-oxazoline monomers.
The polymerization of 2-oxazolines, resulting in poly(2-alkyl/aryl-2-oxazoline) (PAOx). The obtained PAOx is an organic class of poly(amide)s that can be regarded as pseudo-peptides due to their structural similarities to naturally occurring peptides (Figure 1).
The obtained biocompatibility, stealth behavior, nonionic character, stability, high functionalization possibilities, low dispersity, and solubility in water and organic solvents have allowed poly(2-oxazoline) to find many biomedical applications.
The CROP (Cationic Ring-Opening Polymerization) follows a typical chain-growth polymerization mechanism including initiation, propagation, and termination, which is presented in Scheme 3. The main steps of the polymerization reaction are: initiation by electrophilic medium addition, propagation caused by nucleophilic substitution, and final termination with the nucleophile chemical compound.
The CROP reaction of 2-oxazoline monomers can proceed in a living or quasi-living manner under suitable conditions. Achieving living polymerization requires extreme purity and dryness of solvents, initiators, and monomers, as nucleophilic species and strong bases must be avoided to prevent irreversible termination and chain transfer reactions. Following these guidelines enables living polymerization, making post-polymerization modification of poly(2-oxazoline) derivatives a promising research area.
The termination step can be used for introducing the desired functionalities into the polymer structure. The initiation step allows also the modification of the structure, thus both of these processes provide a possibility of introducing a variety of end groups.
One of the most popular end-group modifications of poly(2-oxazoline)-based materials is the nucleophilic substitution made by azides. As reported, the azides have been widely used and applied in poly(2-oxazoline) functionalization through click chemistry.
Generally, many end-functionalities are suitable for post-polymerization modification using click chemistry and can be easily introduced at the termination step. Below are presented the most popular end-groups (scheme 4).
Compared to other biocompatible polymers, poly(2-oxazoline)s are characterized by low toxicity, relatively fast decomposition time, and flexibility regarding the synthesis of the desired structure. Their properties can be easily tuned with the implementation of various functional groups (13).
For effective drug delivery, it’s crucial to understand how the compound behaves in the physiological environment. Within the development of poly(2-oxazoline)-based DDS, physiological stimuli (temperature, pH, redox) have been used for controlled drug release, which varies between inflammatory and normal tissue.
Polyoxazolines as homopolymers are characterized by pH- and thermoresponsive properties, they are also included in copolymers that are sensitive to other types of external environmental impacts.
Concluding remarks
Drug delivery has evolved from small molecules to proteins, peptides, nucleic acids, and live-cell therapies. Delivery challenges for each therapeutic class have been addressed through drug and microenvironment modifications. Multifunctional delivery systems combine these strategies to improve control over drug action. Established delivery approaches, like controlled-release systems, have been adapted for new therapeutic modalities and vice versa. For example, PEG conjugation was first used for proteins and later for small molecules.
Environmental modifiers, like cytokines and antibiotics, have been repurposed across therapeutic classes. Therapeutic antibodies have facilitated site-specific delivery of cytotoxic compounds. Despite advancements, challenges remain in targeted delivery, overcoming biological barriers, and developing responsive drug delivery systems.
The development of polymeric drug delivery systems is rapidly advancing in particularly in cancer treatment using biocompatible and bio-related copolymers and dendrimers. Combining synthetic and biological perspectives offers a new paradigm for designing polymeric drug and gene delivery systems.
The development in polymer-based chemistry has allowed to design a broad diversity in structures with remarkable performances. The precise control over the synthesis of conjugated polymer is of great significance for the synthesis of functional polymer with a specific structure, which paves a way for manufacturing high-performance devices.
References and notes
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- P. Törmälä et al. Bio-absorbable polymers: materials technology and surgical applications. Proc Inst Mech Eng. 1998, 212, 101–11.
- AM. Vargason et al. The evolution of commercial drug delivery technologies. Nat Biomed Eng , 2021, 5, 951–967.
- Barenholz Y. Doxil®- The first FDA-approved nano-drug: lessons learned. J. Control. Release, 2012, 160, 117–134
- H. Park H et al. Evolution of drug delivery systems: From 1950 to 2020 and beyond. J Control Release. 2022, 342, 53-65.
- HY. Nam et al. Dendrimer type bio-reducible polymer for efficient gene delivery. J Control Release, 2012, 160, 3, 592-600.
- Schmaljohann D. Thermo- and pH-responsive polymers in drug delivery. Adv. Drug Delivery Rev. 2006, 58, 1655–1670
- Z. Liu et al. Well-defined poly(N-isopropylacrylamide) with a bifunctional endgroup: synthesis, characterization, and thermoresponsive properties, Designed Monomers and Polymers, 2013, 16:5, 465-474
- Matsuda T, Saito Y, Shoda K. Cell sorting technique based on thermoresponsive differential cell adhesiveness. Biomacromolecules. 2007, 8, 2345–2349
- Lusina, A.; Nazim, T.; Cegłowski, M. Poly(2-oxazoline)s as Stimuli-Responsive Materials for Biomedical Applications: Recent Developments of Polish Scientists. Polymers 2022, 14, 4176.
- Polyoxazoline: Chemistry, Properties, and Applications in Drug Delivery, Bioconjugate Chem. 2011, 22, 5, 976–986.
- S. Jana, M. Uchman, Poly(2-Oxazoline)-Based Stimulus-Responsive (Co)Polymers: An Overview of Their Design, Solution Properties, Surface-Chemistries and Applications. Prog. Polym. Sci. 2020, 106, 101252.
- C. Xu et al. Precise control of conjugated polymer synthesis from step-growth polymerization to iterative synthesis, Giant, Volume 14, 2023, 100154.
Figure 1. Representation of polymeric architectures.
Scheme 1. Synthesis of PNIPAM with triazole-linked end-groups including: phenyl, octyl, hydroxyl, and amino groups via 1) RAFT polymerization, followed by 2) click chemistry.
Scheme 2. Polymerization of 2-oxazolines and their structural similarity with poly(amino acid)s
Scheme 3. General mechanism of the living cationic ring-opening polymerization (CROP) of 2-oxazoline monomers.
Scheme 4. Examples of structures with the most common end-groups.
Table 1. Examples of structures of thermos-responsive poly(2-oxazoline) homopolymers.
