Local anticancer drug delivery using self-assembling
polymer driven by internal stimuli
Wenge Liu
Our editor from Department of Biomedical Engineering, Duke University,
136 Hudson Hall, P.O. Box 90281, Durham, NC, 27708, USA

Cancer describes a collection of diseases caused by multiple genetic mutations arising from accumulated environmental insults, somatic DNA replication error and inherited genetic defects. Cancer is the second leading cause of death in the United States with approximately half of all men and one third of all women developing cancer in their lifetime, resulting in an annual cost of about 170 billion dollars. The cancer phenotype is characterized by uncontrolled growth of abnormal cells with a limitless replicative potential and an invasion of surrounding tissues.  85% of cancer patients have solid tumors and 50% of those patients die as a result of malignant disease.

The modern treatment of cancer typically includes various combinations of external beam radiation, chemotherapy, surgery or experimental methods.  In general, both radiation and chemotherapy derive their therapeutic efficacy from selective toxicity to rapidly proliferating cells.  However, cancer cells are not the only rapidly proliferating cells in the body and toxic side effects are commonly found in hematopoietic progenitor cells of the bone marrow and epithelial cells of the gut.  Surgery involves the excision of the tumor mass but can be limited by the inability to adequately define the tumor margins and by the fact that micrometastases are too small to be surgically removed. Experimental methods, including immunotherapy, gene therapy and hyperthermia have shown some promise but require additional investigation to ascertain their widespread benefit.

All tumor therapy approaches involving drug delivery can be separated into systemic and local approaches. While each modality differs in the route of administration, the goal of both drug delivery approaches is to increase the concentration of a therapeutic agent within the tumor while limiting systemic exposure. Many systemic drug delivery technologies have been developed to accomplish this goal, including macromolecular drug carriers, liposomes, polymeric micelles, enzyme-prodrug therapy, photodynamic therapy and affinity targeting. Systemic delivery remains the standard method of administration for chemotherapy, biologics and targeted radionuclide therapy using antibodies for treatment of solid tumors.

These approaches are hampered by the heterogeneous vasculature, stagnant blood flow and high interstitial fluid pressure (IFP) within tumors, factors that combine to limit the access of systemically injected drugs to the tumors. Intravenously administered chemotherapy for these tumors also has limited effectiveness. Since only a small amount of the systemic blood flow is directed to the tumor, only a fraction of the total dose reaches the tumor site. The remainder is distributed throughout healthy organs and tissues, leading to a variety of undesirable side effects ranging from neutropenia to cardiomyopathy.  Many chemotherapeutic drugs also have very rapid plasma clearance, leading to short tumor exposure times.

Hence, there remains a critical, unmet need for alternatives to systemic delivery of cancer therapeutics.To improve the outcome of these cancer patients, a new paradigm of minimally invasive and loco regional cancer therapies has rapidly evolved and received considerable attention in the recent years. Image-guided, minimally invasive techniques for therapeutic interventions use regional tumor destruction as an alternative to surgical resection. Treatments that have been studied extens­ive­ly include intratumoral infusions, injections and implantable devices that deliver either chemotherapeutic drugs or other therapeuticagents.  In view of the transport barriers that limit systemic drug delivery, delivering the drug directly to the tumor is an intriguing alternative, especially for the treatment of solid tumors . There are many potential advantages of intratumoral administration (I.T.) therapy over systemic delivery. I.T. administration immediately achieves a high drug concentration at the desired site and can avoid the adverse effects of systemic administration, such as high off-site exposure to healthy organs.

I.T therapy is especially suitable for : (1) non-resectable tumors or tumors near critical organs where surgery and/or radiation therapy can lead to a permanent loss of function; (2) cancers where the tumor recurs at or near the primary site after resection such as glioblastomas; and (3) tumors where conventional chemotherapy, surgery and radiation therapy have all failed. Rapid drug clearance from the tumor interstitium leads to high acute dosing in normal tissues in most cases of local delivery. This results in toxicity from local drug diffusion and systemic re-absorption, limiting the clinical application of I.T. approaches. Macromolecular carriers can improve the I.T. delivery of small molecule antitumor agents to the tumor by slowing the rate at which the drug leaves the tumor.  Some of these strategies show increased antitumor efficacy and decreased systemic toxicity. However, significant improvements are still needed in the design of macromolecular carriers for local delivery to improve the temporal retention and spatial distribution of clinically-relevant therapeutics. Several inv­estigators have introduced injectable drug depots to prolong the extent of drug release. 

One method of I.T. therapy that is gaining popularity in the clinic is brachytherapy. This method involves locally positioning a permanent low-dose radiation seed within an accessible tumor site and is most commonly used for prostate tumors. Low dose brachy therapy which consists of permanently injecting low dose 125I and 103Pd seeds into the prostate, has become commonly used because it is a monotherapeutic outpatient procedure that allows for quick recovery of the patient. An alternative method, high dose brachytherapy, consists of strategically placing needles with a high concentration of 192Ir in the prostate for a short period of time. Both of these strategies have shown that I.T. delivery of radiotherapeutics is a clinical possibility.

          Although the success of permanent prostate brachy the­rapy is exemplified by excellent biochemical control rates between 5 –12 years, there are a few large constraints associated with its implementation. The seeds are known to migrate over time which can cause long-term complicat­ions. In one study, 29% of patients were found to have 1-5 seeds lodged in their lungs. Brachytherapy is also associated with an increased risk of urinary incontinence and impotence. The procedure to remove the seeds is also difficult and painful. An alternative approach is necessary to retain therapeutic efficacy while overcoming these limitations. The ideal depot would not only be injectable, biodegradable and biological compatible, but also would remain within the tumor until achieving a complete regression response.

Several related strategies have shown antitumor efficacy and decreased systemic toxicity. I.T. treatment has also become a common method for viral gene delivery in clinical trials. However, only a handful of these trials have demonstrated even a limited therapeutic effect, partially due to the lack of efficient, specific and safe delivery vectors. Moreover, there are several obstacles to the successful implementation of I.T. administration of antitumor agents using injectable polymer depots: (1) macromolecules and nanoparticles cannot effectively distribute across the tumor by diffusion which limits interstitial penetration;  (2) rapid clearance of soluble polymers and drugs from the tumor interstitium; (3) dose-limiting normal-tissue toxicity arising from proximal drug diffusion outside the region of interest and (4) distal normal-tissue toxicity caused by systemic re-absorption.

In an attempt to achieve the above goal, the local delivery systems capable of receiving, transmitting a stimulus and responding with a useful effect have been investigated in many research labs. Typical stimuli are pH, redox potential, glucose andtemperature (internal stimuli), light, magnetic field or ultrasound (external stimuli). The responses can be dissolution/precipitation, swelling/ collapsing, hydrophilic/ hydrophobic transition, bond cleav­age, degradation, drug release and so on. Considering their potential applications in therapeutics, product scale-up and cost considerations, internal stimuli responding systems are more interesting than those responding to external stimuli such as light, magnetic field and ultrasound. Thus, polymeric nanocarrier systems respon­sive to changes in temperature have been the focus of many studies. Generally, polymers used for carrier systems are designed in such a way that carrier structures can be assembled at temperatures higher than normal body temperature (37 °C).

Thermally responsive drug delivery system is generally prepared from thermal sensitive polymers which exhibit a volume phase transition at a certain temperature. Polymers, which become insoluble in an aqueous environment upon heating, have a lower critical solution temperature (LCST). Typical polymers are, for example, elastin-like polypeptides (ELP), poly(N-isopropylacrylam­ide) (PNIPAAM), poly(methyl vinyl ether) (PMVE), poly(N-alkylacrylamide), poly(N-vinylcaprolactam) (PVCa) and poly(N-ethyl oxazoline) (PEtOx). To apply temperature-sensitive systems, it is relevant to either combine thermal-sensitive carriers with hyperthermia therapyor to take advantage of the slightly higher temperature of tumor tissue (2-5 °C) as compared to healthy tissues. Alternatively, a local decrease in tissue­etemperature realized externally may also be applied and this requires the use of polymers with an LCST. In fact, most ofthermal-sensitive polymers so far studied have an LCST. When temperature is raised above LCST, the conformation of polymers changes from a coil (hydrophilic) to a globule (hydrophobic).

Therefore, in applications like thermal-sensitive nanocarriers and hydrogels the change from room temperature to body temperature is generally used to induce a change in the physical properties of the polymers, for instance, gelation, in the case of injectable in situ forming biodegradable scaffolds. Studies on thermal-sensitive polymers are so far mainly directed to their formation as well as the temperature-induced release of incorporated compounds.  

In the future, it will be highly desirable to develop new biocompatible,   biodegradable, injectable and drug release controllable stimuli-sensitive polymer carriers that respond quickly, in time scale of second to hours, to internal stimuli such as pH, temperature, redox potential and glucose level. In particular, temperature sensitive polypeptide is extremely attractive because the Tt is easily adjusted by controlling the in DNA sequence level to balance the hydrophilic and hydrophobic amino acid content for the target Tt.