Polymers in Clinical Trials for Cancer Therapeutics

As per the World Health Organization, Cancer remains the leading cause of death worldwide, resulting in about 10 million deaths in 2020. Worldwide, nearly one in six deaths are attributed to cancer. Further, it is estimated that there will be over 35 million new cancer cases in 2050. To address the increasing cancer burden, the World Health Assembly passed a new resolution, “Resolution Cancer Prevention and Control,” in an attempt to reduce the increasing mortality due to cancer worldwide [1]. Besides enabling medical access and increasing political commitments, this resolution also seeks to enhance basic research on human cancer. Novel polymeric materials for the delivery of new therapeutics remain one of the foremost areas of research owing to the advances in polymer sciences enabling accurate tuning of structure and properties of the polymers. Due to the properties of biocompatibility and controlled degradation within the bodily environment, polymers are extensively used in clinical medicine to treat, diagnose, and evaluate many diseases [2-4]. Specifically, the last two decades have shown immense advancements and studies using polymeric nanoparticles as delivery agents in cancer therapeutics [5-10]. Yet the use of polymers for drug delivery in devices or technologies investigated under clinical trials for cancer therapeutics remains limited. The majority of the ongoing clinical trials are interventional, with only a few observational trials aiming to reduce the cancer burden. Controlled polymer degradation is one of the primaries deciding factors for the use of polymers in biomedical applications.

Polymer degradation results from various conditions that alter a polymer’s physical properties. The key factors that are responsible for polymer degradation are,
a. Thermal changes, such as the effect of elevated temperatures, cause damage to the polymer chains.
b. Exposure to UV light can cause photo-oxidation of the polymer, resulting in chain scission.
c. Oxidative stress can result when the polymeric chains are exposed to oxygen, causing damage to the polymeric chains.
d. Hydrolysis occurs when a reaction with water causes polymeric chains to break down.
e. Mechanical stresses, such as shear stresses can break down polymeric chains
f. Radiative damage can occur, causing crosslinking or chain scission, such as when exposed to gamma rays.

Of the above six types of degradation, the bodily fluids and the body environment are conducive to degradation due to hydrolysis, oxidative stress, and, occasionally, mechanical stresses. The extent of hydrolysable functional groups affects the degradation behavior of polymers. The common hydrolysable functional groups include amides, esters, lactones, and urethanes. As a result, the biomedical industry has formulated many biocompatible polymers with controlled degradation through structural variations and placement of the functional groups. Many biodegradable polymers have shown extensive applications in the biomedical industry for cancer drug delivery due to their tunability, degradation characteristics, and biocompatibility with various human cells [11-13]. Hundreds of polymeric structures are investigated for biomedical applications, yet only a handful are elevated to be used in clinical trials for drug delivery systems for cancer. Table 1 shows the polymeric materials that are used in clinical trials for cancer therapeutics.

Table 1:List of polymeric materials used in clinical trials (Data obtained from Clinical Trials.gov).

As seen in (Table 1), several biodegradable polymers are extensively utilized in drug delivery and are being investigated in clinical trials. These include ethyl cellulose, albumin, and other degradable polymers, such as polylactic acid and polyglycolic acid, as well as their copolymers. Another widely used structure involves self-assembling amphiphilic polymers with hydrophilic and hydrophobic units, resulting in polymeric micelles [14]. Engineered hydrophobic cores and hydrophilic shells of the polymeric micelles enable great design adaptability for the delivery of various therapeutics. The excellent biocompatibility, pharmacokinetics, adhesion to bio surfaces, targetability, and durability of the polymeric micelles and their engineered structures make them beneficial polymeric systems for biomedical applications. Polymeric micelles are extensively used in various clinical trials worldwide. Although most studies do not clarify specific polymeric micelles, the polymeric micelles are often Pluronic P123, an amphiphilic block copolymer, or Methoxy poly(ethylene glycol)-conjugated linoleic acid. Pluronic P123 is a symmetric triblock copolymer comprising Poly(Ethylene Oxide) (PEO) and Poly(Propylene Oxide) (PPO) in an alternating linear fashion, PEO-PPO-PEO.

Besides the delivery of drugs through controlled degradation of the polymeric delivery agent, other applications in cancer therapeutics involve embolization therapy for treating liver cancer with degradable microspheres [15]. Many commercially available microspheres that are made up of Poly(Methylacrylic Acid) coated with Polyzene-F, copolymer of PEG and Diacrylamide, Starch, Gelatin, Collagen-coated PLGA, Tris-Acryl Gelatin, PVA, PVA Hydrogel cross-linked with acrylic Polymer, Acrylamido sulfonate- PVA Hydrogel, Poly(Methylacrylic Acid) coated with Polyzene-F, copolymer of PEG and Diacrylamide, Starch, Gelatin, collagen-coated PLGA, Triiodobenzyl-Modified Acrylic Polymer, Triiodobenzyl- Modified Acrylamido-sulfonate PVA Hydrogels. As shown in Table 1, polymer beads made of hydrogel cores of polyvinyl alcohol are also used. One important application is in a clinical trial involving the use of drug eluting beads in combination with the Trans Arterial Chemoembolization (TACE) treatment for liver cancer. Proprietary microsphere beads are used. Typically, these are made of well calibrated, biocompatible, non-resorbable hydrogel materials. The beads are often produced from highly absorbent polymers such as polyvinyl alcohol. Bead microspheres consist of a polyvinyl alcohol or sodium Poly(Methacrylate hydrogel and an outer biocompatible shell of Poly(Bis[Trifluoroethoxy]Phosphazene) are used. The drug and microsphere are held together by the interaction of the cationic anticancer drugs (doxorubicin) with the anionic functional groups of the microspheres [16]. Superabsorbent polymer microspheres made of sodium acrylate and vinyl alcohol copolymer are a useful eluting agent attempted in many studies [17]. PLGA used as nanofiber membranes in proprietary structures are being tested for efficacy against Retroperitoneal Soft Tissue Sarcoma. Controlled drug delivery is attempted in tubular stents to prevent Pancreaticojejunal Anastomotic Stricture [18].

Although a large number of polymers are investigated for applications in cancer drug delivery systems, only a few are attempted for clinical trials worldwide. The extensive time and costs associated with animal models and other in vivo experiments needed by various federal agencies worldwide further diminishes the application of viable polymeric systems to clinical trials. There is a great need to screen therapeutics easily and at a low cost without using in vivo systems. Many new drug formulations are hence being evaluated as new anticancer drugs on in vitro models [19-23] that attempt to recapitulate the in vivo systems. The use of robust 3D in vitro models, often called testbeds, is showing increased prevalence in the literature [24], and more viable polymeric systems are likely to be used in cancer therapeutics in the future due to the reduced time and expense of testbeds compared to animal model experiments. The testbeds are likely to be used as screening tools to reduce the trials through animal models and speed up the benchto- bedside applications of polymers.

The author acknowledges support from her academic institution.

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